Polyubiquitin up-regulation in corpora lutea of prostaglandin-treated ewes

Genes that encode mRNAs for ubiquitin are activated by cells in metabolic distress. Cytosolic proteins that consequently become conjugated to ubiquitin are targeted for degradation. We hypothesized that ubiquitin mediates the endocrine demise of the corpus luteum induced by prostaglandin (PG) F2alpha. Indeed, polyubiquitin gene expression increased abruptly (within 2 h) in luteal tissues of ewes treated with PGF2alpha--before the precipitous decline in glandular progesterone accumulation indicative of functional luteolysis. A corresponding elevation in ubiquitin immunostaining was localized to large (PG-sensitive) luteal cells. It is suggested that luteal progesterone biosynthesis is disrupted by ubiquitination of steroidogenic regulatory proteins--perhaps those involved in the mechanics of mitochondrial delivery and side-chain cleavage of cholesterol.     

Analysis of the external fixator pin-bone interface

External fixator pins were inserted into tibiae of dogs under four in vivo loading conditions to examine the mechanism of pin loosening. Pins were quantitatively measured for pin torque resistance, and the pin tracts were studied radiographically and histologically. The pins holding an unstable fracture had more gross pin loosening. Pins also may become loose under static loads. Radiographic lucency of 1 mm or more in the cortical bone around a pin was evidence of gross pin loosening. Histologic examination showed that tight pin tracts were characterized by a lack of bone remodeling. Loose pin tracts were characterized by extensive bone resorption and inflammatory infiltrates. Pin loosening can be detected radiographically. Pin insertion technique is important to improve the initial pin torque resistance to minimize pin loosening. Sixty-nine percent of pins with an initial torque resistance of less than 68 Ncm became grossly loose compared with only 9% of pins with an initial torque resistance greater than 68 Ncm, regardless of the experimental group. Unstable external fracture fixation is another important factor in producing pin loosening. Pins loaded under unstable fracture fixation had the highest incidence of gross loosening. When applying an external fixator, the fracture rigidity should be critically evaluated and, if necessary, protected weight bearing must be introduced initially to minimize pin loosening.     

Non-ionophoretic elevation of intracellular Ca2+ by Lonidamine

Lonidamine is an antispermatogenic and anticancer drug that is believed to act by inhibition of energy metabolism. In this study, the effects of Lonidamine on the concentration of intracellular free Ca2+ of several tumor cell lines were assessed because of the important role that cytosolic Ca2+ plays in cell viability and proliferation. The presence of 300 microM Lonidamine resulted in large elevations of cytosolic Ca2+ (> 100 nM) in AS-30D rat ascites hepatoma cells and in cultured EMT6 murine mammary adenocarcinoma cells but had little effect on cultured NCI-H345 human small cell lung cancer cells. The apparent EC50 for Lonidamine was approximately 175 microM. The source of elevated cytosolic Ca2+ was primarily intracellular stores, and the effects of Lonidamine on Ca2+ efflux from these stores did not appear to be due to an ionophoretic action of this compound or to a decline in the level of cellular ATP. These results indicate that the Ca2+ homeostasis of certain lines of tumor cells is specifically altered by Lonidamine at concentrations known to affect cell proliferation.     

Hypertensive nephrosclerosis in the Dahl/Rapp rat. Initial sites of injury and effect of dietary L-arginine supplementation

BACKGROUND: The Dahl/Rapp strains of salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rat were developed to examine pathogenetic mechanisms that produce hypertension in response to an increase in dietary salt. We have shown that providing SS/Jr rats with L-arginine, the metabolic precursor of nitric oxide, acutely prevented salt-sensitive hypertension, suggesting that SS/Jr rats developed hypertension because of inadequate nitric oxide production while on a high-salt diet. EXPERIMENTAL DESIGN: Male 23-day SS/Jr and SR/Jr rats were placed on chow that contained 8% sodium chloride. One group of SS/Jr rats also received L-arginine, 1.25 g/liter, in their drinking water. These three groups were examined at weekly intervals for 4 weeks. RESULTS: SS/Jr rats rapidly developed hypertension when placed on the high-salt chow. After 2 weeks on this diet, inulin clearance dramatically decreased, and albumin excretion rate increased. By the fourth week of study, SS/Jr rats on the high-salt diet had died or were dying. Coincident with the progressive decline in inulin clearance, renal morphologic analysis confirmed development of myointimal thickening, fibrinoid necrosis, and glomerulosclerosis. In contrast, over the 4 weeks of study, SS/Jr rats supplemented with oral L-arginine did not develop hypertension and any of the associated renal complications seen in age-matched SS/Jr rats on the high-salt diet. L-Arginine also corrected hypertension in SS/Jr rats exposed to the high-salt chow for 2 weeks before the inception of L-arginine. L-Arginine administration after 3 weeks on this chow, however, failed to reverse hypertension and the depressed inulin clearance and morphologic renal damage. CONCLUSIONS: Along with previous work (Chen PY, Sanders PW, J Clin Invest 88:1559-67), these studies were consistent with the hypothesis that hypertension and hypertensive nephrosclerosis developed in SS/Jr rats because, while on a high-salt diet, substrate (L-arginine) became a rate-limiting factor in the synthesis of nitric oxide.     

An intracellular study of the contrast-dependence of neuronal activity in cat visual cortex

Extracellular recordings indicate that mechanisms that control contrast gain of neuronal discharge are found in the retina, thalamus and cortex. In addition, the cortex is able to adapt its contrast response function to match the average local contrast. Here we examine the neuronal mechanism of contrast adaptation by direct intracellular recordings in vivo. Both simple (n = 3) and complex cells (n = 4) show contrast adaptation during intracellular recording. For simple cells, that the amplitude of fluctuations in membrane potential induced by a drifting grating stimulus follows a contrast response relation similar to lateral geniculate relay cells, and does not reflect the high gain and adaptive properties seen in the action potential discharge of the neurons. We found no evidence of significant shunting inhibition that could explain these results. In complex cells there was no change in the mean membrane potential for different contrast stimuli or different states of adaptation, despite marked changes in discharge rate. We use a simplified electronic model to discuss the central features of our results and to explain the disparity between the contrast response functions of the membrane potential and action potential discharge in simple cells.     

Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.     

A longitudinal causal model of cardiac invalidism following myocardial infarction

OBJECTIVE: To measure the distribution of the seriousness of illnesses and patients in primary care with the Duke Severity of Illness Scale (DUSOI) and relate it to resource use. DESIGN: Observational prospective study. SETTING: Eight primary care centres from the centre sub-section of the Catalan Health Service. PATIENTS AND OTHER PARTICIPANTS: For the first two months of the study, patients who attended for consultation at 9 general/family doctors' clinics were systematically sampled. 1,868 patients were selected and observed for 6 months. MEASUREMENTS AND MAIN RESULTS: The DUSOI was used to work out the seriousness of the illness and of the patient. The variables used as indicators of the use of resources for an illness were: the number of attendances, the time and costs of care. The same for the patient were: the number of attendances, number of episodes and costs of care. The average score for the seriousness of the episode was 31.4 with a standard deviation (SD) of 16.4. The correlations between use of resources and seriousness were under 0.4. The seriousness of the patient had an average of 44.9 (SD 21.3) and statistically significant correlations above 0.6 with the use of resources. CONCLUSIONS: The seriousness of the illnesses attended in primary care is low and is related moderately to the use of resources. DUSOI could be better employed in research, inasmuch as there are systems for classifying patients which have greater explanatory power and can be constructed from pre-existing data.     

Comment, on `A 1/f noise technique to extract the oxidetrap density near the conduction band edge of silicon' [and reply]

For the original article see ibid., vol.36, no.9, p.1773-82 (1989). The commenters show that, contrary to the calculations in the above-titled paper by R. Jayaraman and C.G. Sodini, the correlated noise power spectra of number and surface mobility fluctuations in n-channel MOSFETs are functions of the relative densities of the positive and neutral traps at the Si-SiO₂ interface. The authors, along with B.J. Gross, disagree with the commenters' assessment and support their calculations. The contend that the distribution of active traps assumed by the commenters is not representative of the distribution active in real MOSFET devices     

Genetic and antigenic analysis of human rotavirus prevalent in Al-Taif, Saudi Arabia

The subgroup, serotype and electropherotype diversity of human rotavirus strains was investigated in Al-Taif, Saudi Arabia. Out of 349 faecal samples collected from diarrhoeic children, 150 (43 percent) tested rotavirus positive by a group-A specific enzyme-linked immunosorbent assay (ELISA). The majority (87 percent) of the infected children were below 2 years of age. Subgrouping and serotyping of rotaviruses with specific monoclonal antibodies showed that of the 150 rotavirus positive specimens, 17 percent belonged to subgroup I, 59 per cent belonged to subgroup II, and 24 percent were neither subgroup I nor subgroup II. The specimens were typed, as serotype 1 (43 percent), serotype 2 (5 percent), serotype 3 (11 percent), serotype 4 (10 percent) or mixed serotypes (3 percent). The remaining 41 (27 percent) specimens were untypeable. None of the serotypes showed association with a particular age group. An electrophoretic analysis of viral RNA revealed 11 distinct patterns (six long and five short). The majority, 78 percent were long patterns and 22 percent were short patterns. Analysis of the specimens for which subgroups, serotypes and electropherotypes were available indicated that a given RNA pattern does not correspond to a particular subgroup or serotype.     

Cardiopulmonary responses to experimental venous carbon dioxide embolism

BACKGROUND: Although the low-flow CO2 insufflation rate used to initiate pneumoperitoneum may reduce the severity of potential venous embolism, its safety is not established. METHODS: Anesthetized pigs were ventilated with room air at a fixed minute ventilation. After 1 h of baseline, they were intravenously infused with CO2 at the rate of 0.3, 0.75, or 1.2 ml/kg/min for 2 h (n = 5 for each group), followed by 1 h of recovery. RESULTS: All animals experienced pulmonary hypertension, depressed stroke volume, hypoxemia, hypercarbia, and acidemia during intravenous CO2 infusion. They had systemic hypertension at the low rate of hypotension at the highest rate of infusion. End-tidal CO2 levels briefly decreased, then increased in all cases. In the highest rate group, three of the five animals (60%) died at 50, 65, and 100 min of infusion. These three animals had severe hypotension and hypoxemia, with visible coronary gas embolism. There was no patent foramen ovale at necropsy in any animals. CONCLUSIONS: The low-flow insufflation rate exceeds the fatal rate of continuous intravenous CO2 infusion. End-tidal CO2 levels were increased in venous CO2 embolism, not decreased as seen in venous air embolism. Severe hypoxemia and hypotension are predictors of potentially fatal cases.