NOD background genes influence T cell responses to GAD 65 in HLA-DQ8 transgenic mice.

The major histocompatibility complex (MHC) genes play a significant role in the predisposition to insulin-dependent diabetes mellitus or type 1 diabetes. HLA-DQ8 (DQB1*0302, DQA 1*0301) genes have been shown to have the highest relative risk for human type 1 diabetes. To develop a "humanized" mouse model of diabetes, HLA-DQ8 was transgenically expressed in mice lacking endogenous class II genes. Since non-MHC background genes of the NOD influence the disease process, AP"/DQ8 mice were mated with the NOD strain and backcrossed to generate Abeta degree/DQ8/NOD mice. These mice have DQ8 as the sole MHC class II restriction element with NOD background genes at the N 2 generation. The DQ8 transgenic mice were used to identify T cell epitopes on glutamic acid decarboxylase (GAD 65), an important putative autoantigen in type 1 diabetes. The NOD background genes strongly influenced antigen processing, that is, different T cell epitopes were generated from the processing of GAD 65 in vivo in the Abeta degree/DQ8 and in the Abeta degree/DQ8/NOD mice.     

Osteosarcoma of the sella

Primary osteosarcoma of the skull is rare. Osteosarcoma arising from the sellar region is extremely uncommon. The case of a 38-year-old man with osteosarcoma of the sella is described, and the literature is reviewed. The patient was treated with surgery followed by aggressive chemotherapy and radiotherapy. Currently he is in remission at 12 months.     

Progression of steroid-associated osteoporosis after heart transplantation

BACKGROUND: Osteoporosis has been recognized as an important side effect of long-term and of pulsed steroid application after heart transplantation. METHODS: In June 1989 a prospective clinical trial was started to study bone demineralization by quantitative computed tomographic scan. All patients received vitamin D and calcium. In group I (n = 30) synthetic calcitonin (40 Medical Research Council Standard Units subcutaneously per day was administered in 14-day cycles, whereas group II patients (n = 31) received a placebo preparation. Repeat trabecular and cortical quantitative computed tomographic scans of the thoracic (T12) and lumbar spine (L1, L2, L3) were obtained within 48 weeks after heart transplantation. RESULTS: Expressed as the means of T12, L1, L2, and L3, trabecular bone density decreased significantly from 100+/-24 to 79+/-29 mg/mL within 3 weeks after heart transplantation, followed by a further reduction to 67+/-29 mg/mL after 3 months in the calcitonin group. The values for cortical bone density decreased significantly from 229+/-37 to 202+/-40 mg/mL (calcitonin) 3 weeks after heart transplantation. Comparable results were obtained in the placebo group. In both groups bone density remained stable thereafter. Intergroup differences were not of statistical significance. CONCLUSIONS: In heart transplant recipients progressive trabecular bone demineralization is limited to the first 3 postoperative months. Thereafter, bone density remained stable. A positive effect of synthetic calcitonin in addition to prophylactic calcium and vitamin D application could not be proved by repeat quantitative computed tomography.     

Management of degenerative disc disease above an L5-S1 segment requiring arthrodesis.

Clear guidelines exist for treating spondylolisthetic deformity and instability. How the surgeon handles adjacent-level degenerative disease is not as well established. Because magnetic resonance imaging now provides us with far more information on the "health" of radiographically normal intervertebral discs, the treatment of dehydrated or degenerated discs adjacent to a fusion is becoming more problematic. In this discussion, two experts discuss their approach to symptomatic lumbosacral spondolisthesis accompanied by adjacent-level disc degeneration. Drs. Herkowitz and Abraham believe strongly that the adjacent segment should be left alone, whereas Dr. Albert recommends extending the fusion in many instances.     

Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (AMG-126737)

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.     

The steroid profile of a virilizing ovarian tumor.

A case report of a 25-year-old female with a sex cord stromal virilizing ovarian tumor is presented. The pathway of ovarian steroid secretion in this tumor is elucidated with the dominant elements being pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, androstenedione, and testosterone. The tumor primarily made testosterone (T) with lesser elevations of androstenedione (A), dehydroepiandrosterone (DHEA), and dihydrotestosterone (DHT). Expert pathologic opinions differed whether this neoplasm was a Sertoli-Leydig tumor or a virilizing granulosa tumor; therefore, it was probably a gynandroblastoma. A unilateral salpingo-oophorectomy was performed and the patient promptly resumed normal ovarian function with ovulation.     

Zusammenh?nge zwischen Arbeitst?tigkeit und Ruhestandspl?nen

Zusammenfassung Im Rahmen des Nationalfonds-Projekts «Arbeitstätigkeit und Ruhestandspläne» wurden in einer Erkundungsstudie Auswirkungen der langfristig ausgeübten Arbeitstätigkeit auf die Bildung von Plänen für die Zeit nach der Pensionierung untersucht. Dabei wurden 200 Personen im Alter von 64 Jahren aus der unmittelbaren Produktion in verschiedenen Betrieben der metallverarbeitenden Industrie mit Hilfe von halbstandardisierten Interviews befragt. Die Fragen betrafen im wesentlichen die Bereiche Arbeit, Freizeit und Pläne für die Zeit der bevorstehenden Pensionierung. Es bestand die Annahme, dass für die erfolgreiche Bewältigung der Pensionierungssituation Pläne notwendig und unabdingbare Voraussetzung für die Ausbildung von Plänen der Erwerb und die fortwährende Weiterentwicklung sozialer und kognitiver Handlungskompetenz sind. Es hat sich gezeigt, dass der prozentuale Anteil von Personen ohne oder mit nur unspezifischen Plänen mit abnehmender Grösse des Handlungsspielraums in der Arbeit zunimmt. Die Untersuchung ergab weiter, dass Personen, die ihre kognitive Handlungskompetenz in der Arbeit trainieren konnten, mehr Pläne mit kognitivem Inhalt bilden, als Personen mit kleinem kognitivem Handlungsspielraum in der Arbeit; analog verhält es sich mit der sozialen Handlungskompetenz in der Arbeit.

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Work Activities and retirement plans

In the course of the research project Work Activities and Retirement Plans financed by the National Foundation of Research, a study was made to explore the consequences of longterm working activities on planning of the time of retirement. 200 persons at the age of 64 years, working on shop floor of enterprises in the metal industry were asked about their work, leisure and plans about the approaching retirement. It was hypothesized that plans are necessary for the successful coping of the retirement situation. For the setting up of plans it is required that social and cognitive competence can be acquired and constantly trained. It has been shown that the proportion of persons with none or unspecific plans rises with the span of action getting smaller. Furthermore the study showed that persons who could train their cognitive competence at work set up more plans with cognitive content than persons who could not: the analogical result has been found with the social competence.

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Travail et plans de retraite

Résumé L'étude «Travail et Plans de Retraite» faite dans le cadre d'un projet financé par le Fond National, explorait les conséquences du travail longuement effectué sur la formation des plans pour le temps de la retraite. 200 personnes, à l'âge de 64 ans, travaillant dans la production directe des entreprises de l'industrie des métaux, étaient interrogées par la méthode des interviews demi-standardisés. Les questions concernaient les sujets du travail, du loisir et de la retraite proche. Il était supposé que la formation des plans était nécessaire pour survenir avec succès la situation de la retraite. Prémisse indispensable pour la formation des plans est l'acquisition et le développement permanent de la compétence sociale et cognitive. Il s'est montré que la proportion des personnes sans plans ou avec des plans sans contenu spécifique augmente avec la latitude d'action. De plus, le résultat de l'étude était que des personnes qui pouvaient entraÎner leur compétence cognitive en travail forment plus de plans avec un contenu cognitif que des personnes qui n'en avaient pas l'occasion; ainsi se présente le résultat avec la compétence sociale.

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Nationalfonds-Projekt Nr. 1.656-077, durchgeführt am Lehrstuhl für Arbeits- und Betriebspsychologie der Eidgenössischen Technischen Hochschule in Zürich (Prof. Dr. Eberhard Ulich)     

Effects of various exposure levels of 2-phenylethanol on fetal development and survival in Long-Evans rats

Phenylethanol was given at different levels (432, 43, or 4.3 mg/kg) by gavage to pregnant Long-Evans rats during the "critical period" of organogenesis. Examination of offspring revealed adverse reproductive and teratogenic effects in a dose-related manner. Intrauterine growth retardation occurred at levels of 432 and 4.3 mg/kg. Embryolethality was 18% at 43 mg/kg and 10% at 4.3 mg/kg. Malformations occurred in the following sequence: 100% at 432 mg/kg; 93% at 43 mg/kg, and 50% at 4.3 mg/kg. Noteworthy dose-related teratogenic effects of phenylethanol in offspring manifested themselves in increased incidences of malformed eyes, neural-tube defects, hydronephrosis, and limb defects.     

Comparative effect of heme analogues on hematopoiesis in lymphoproliferative disorders

Anemia is a common characteristic of lymphoproliferative disorders (LPD) and the impairment of blood formation in these disorders is not fully understood. Heme synthesis and the heme degradative enzyme heme oxygenase are critical to hematopoietic differentiation and disturbances may contribute to anemic states. Tin protoporphyrin (SnPP) is a potent inhibitor of heme oxygenase, and has proven to be a useful clinical agent. Bone marrow cells from seven patients with LPD were studied for their in vitro hemopoietic response to growth factors and SnPP. Heme oxygenase mRNA levels were determined by Northern blot analysis of bone marrow samples. Quantitation of hematopoiesis in cultures with erythropoietin or GM-CSF revealed adequate CFU-E, BFU-E and CFU-GM growth by LPD bone marrow. Inclusion of 10 μM SnPP in cultures was found to significantly enhance CFU-E/BFU-E growth by LPD marrows, whereas Zinc protoporphyrin had a marked inhibitory effect. Little or no effect by SnPP was seen on CFU-GM. In contrast, normal bone marrow cultures failed to show an enhanced response to 10 μM SnPP. Analysis of heme oxygenase mRNA levels revealed that LPD marrows had elevated expression of heme oxygenase mRNA as contrasted with normals. Furthermore, measurements revealed that heme oxygenase activity was markedly suppressed by SnPP in the LPD bone marrow cultures. Results lend further support to the importance of heme oxygenase in the differentiation process. Although LPD bone marrow cells may respond to erythropoietin in vitro, in stressed conditions where heme oxygenase is elevated, suppression of heme oxygenase may potentiate the erythropoietic response in this disease.     

The renal cytochrome P-450 arachidonic acid system

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and /-1 hydroxylases to epoxyeicosatrienoic acids and /-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na⁺–K⁺-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.