Rat insulinoma-derived pancreatic beta-cells express a functional leptin receptor that mediates a proliferative response

In addition to its interaction at hypothalamic sites to affect feeding and energy expenditure, leptin has been shown to exhibit a proliferative response in erythropoietic cells. The functional leptin receptor is also present in pancreatic islets and we now demonstrate that a commonly used clonal insulin secreting beta-cell line, RINm5F, expresses high levels of the Ob-Rb mRNA. Leptin causes an increase in tyrosine phosphorylation of a number of intracellular proteins and a dose related (10 nM-200 nM) increase in expression of the immediate-early gene, c-fos. This precedes a leptin induced proliferative response in serum-deprived RINm5F cells, which suggests that leptin might be involved in the complex regulation of proliferation of the pancreatic beta-cell.     

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.     

The role of positron emission tomography in pharmacokinetic analysis

The physiological and biochemical measurements that can be performed noninvasively in humans with modern imaging techniques offer great promise for defining the precise state of a patient's disease and its response to therapy. In general, there are two critical points in drug development when PET measurements are likely to be particularly useful: (1) In preclinical studies, a new drug can be precisely compared to standard therapies or a series of analogs can be screened for further development on the basis of performance in appropriate animal models. (2) In phase I-II human studies, classic pharmacokinetic measurements can be coupled with imaging measurements (a) to define optimal dosing schedule; (b) to define the potential utility of interventions in particular clinical situations; and (c) to formulate the design of phase III studies that are crucial for drug licensure. In general, the types of measurements that are possible can be grouped into the following categories: 1. In those situations in which the drug can be radiolabeled, the time course of tissue delivery can be determined noninvasively in vivo in health and disease. Such information should be useful for determining dosing schedules, establishing efficacy, and predicting possible toxicity. 2. Ligand-receptor binding can be assessed in vivo in two ways. The ability of the drug to displace standard radiolabeled ligands from their receptors can be determined; alternatively, labeled drug can be used to more directly assess the distribution and time course of binding. These measurements are particularly useful for studying drugs that are active in the central nervous and cardiovascular systems. 3. Measurements of tissue metabolism will be useful in determining the effects of therapies aimed at particular metabolic abnormalities. In addition, these measurements may be useful in defining viability and function of tissues in such widely disparate clinical situations as cancer chemotherapy and cardiology. For example, effects of CNS or cardiovascular drugs can be monitored by observing 18FDG metabolism in brain and heart. We suggest that the joining of classic clinical pharmacology to exquisite imaging measurements will help form the basis for 21st-century clinical drug development.     

Properties of soluble and membrane intestinal hydrolases in Macaca rhesus monkeys

Evidence from several central nervous system (CNS) inflammatory disease models suggests that intrathecal complement synthesis may contribute to early inflammatory events in the brain. In this study, we examined the expression of the receptor for C5a (C5aR), a potent inflammatory and chemotactic factor, in the brains of transgenic mice with constitutive astrocyte expression of interleukin-3 (IL-3), a hematopoietic and immunomodulatory cytokine. By in situ hybridization, we demonstrated that cells infiltrating the cerebellar meninges, the cerebellum, and demyelinating lesions in the cerebellum were strongly positive for C5aR mRNA. By immunohistochemistry, the infiltrating cells expressing the C5aR were identified as macrophages based on staining with antibodies to the complement receptor type 3 and F4/80, a mouse macrophage-specific marker. In addition, some of the cells in cerebellar lesions were positive for the astrocyte-specific marker, glial fibrillary acidic protein, suggesting that a subpopulation of astrocytes in these lesions express elevated levels of the C5aR. Increased C5aR expression was also observed in cortical neurons in the occipital cortex and in pyramidal neurons in the cornu ammonis and subiculum of the hippocampus, at both the protein and mRNA levels. These data suggest that IL-3 may play an immunomodulatory role in C5aR expression on several cell types in the brain and that increased C5aR expression correlates with the pathology seen in this model. The transgenic mice used in this study provide a useful tool for characterizing the mechanism of regulation of the C5aR expression and for examining the functions of this chemotactic receptor in CNS inflammation.     

Continuous spinal anaesthesia

CD59 is a cell membrane-bound complement regulatory protein on glomerular cells that inhibits C5b-9 assembly and insertion. This report describes a recently developed model of immune thrombotic microangiopathy (TMA) induced by the renal artery perfusion of anti-glomerular endothelial cell (anti-GEN) antibody. To examine the role of CD59 in protecting the GEN from immune-mediated injury, rats underwent selective renal artery perfusion with F(ab')2 fragments of anti-CD59 monoclonal antibody to block CD59 activity or control mouse IgG followed by anti-GEN antibody or control goat IgG. Neutralization of CD59 in normal rats did not result in any significant functional or histologic changes. Perfusion with anti-CD59 did not change deposition of the pathogenic anti-GEN IgG used to induce the TMA model. However, neutralization of CD59 in the TMA model resulted in more C5b-9 formation in glomeruli, accompanied by increased platelet and fibrin deposition, more severe endothelial injury, and reduced renal function compared with the animals perfused with control F(ab')2 fragments. These results demonstrate directly that CD59 serves a protective role for GEN in this TMA model of rats, and confirm that C5b-9 formation has a critical pathogenic role in the mediation of the disease. CD59 may play an important role in protecting glomerular endothelium from other complement-mediated types of injury.     

Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group

AIMS: To determine whether left ventricular volumes and ejection fractions calculated from single plane two-dimensional echocardiograms using the algorithm (0.85A2L) correlate with those calculated using the biplane Simpson's method, and whether small changes in volumes and ejection fraction occurring post-infarction could be detected from single-plane as well as from biplane two-dimensional echocardiograms. METHODS AND RESULTS: Serial two-dimensional echocardiograms were obtained in 371 patients from the DEFIANT II trial a mean of 2 days, 1 week and 6 months post-infarction. Single plane volumes from the apical four chamber and apical long axis correlated closely with biplane Simpson's left ventricular volumes. Both single-plane left ventricular volumes significantly over-estimated biplane Simpson's volumes. Biplane Simpson's ejection fractions were consistently slightly under-estimated from the single-plane images. Differences between biplane Simpson's and single-plane volumes increased independently with increasing left ventricular size and distortion. The small changes in left ventricular volumes and ejection fraction over time were as reliably detected from single plane as from biplane images. CONCLUSION: Single-plane left ventricular volumes over-estimate biplane Simpson's volumes and under-estimate ejection fraction, and these discrepancies are amplified in dilated hearts with abnormal shape.     

Relation of self-image to body size and weight loss attempts in black women: the CARDIA study. Coronary Artery Risk Development in Young Adults

It has been suggested that the prevalence of obesity in black women is high partly because self-image in black women is not strongly dependent on body size. To determine associations between self-image, body size, and dieting behavior among black women, the authors assessed an Appearance Evaluation Subscale (AES) score (range, 1-5), a Body Image Satisfaction (BIS) score (range, 2-11), and reported dieting behavior in a population-based sample of 1,143 black women aged 24-42 years from the fourth follow-up examination (1992-1993) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Lower AES and BIS scores indicate poorer self-image and lower body size satisfaction, respectively. After adjustment for age, education, smoking, and physical activity, women in the lowest, middle, and highest tertiles of body mass index (weight (kg)/height (m)2) had mean AES scores of 3.7, 3.3, and 2.9, respectively (p < 0.001), and mean BIS scores of 7.8, 6.7, and 5.9, respectively (p < 0.001). After additional control for body mass index as a continuous variable, both AES and BIS scores were inversely related to ever dieting, current dieting, and previous weight loss of 10 pounds (4.5 kg) or more in all tertiles of body mass index. These results suggest that among black women, a higher body mass index is associated with poorer self-image and lower body size satisfaction and that these perceptions may be an avenue to promoting weight control.     

Critical pharmacologic management in the emergency department

PURPOSE: Starting from a status hypercoagulability previous to substitutive hip and knee surgery, the aim of this work was to investigate the influence of different osteoarthropatic pictures for which arthroplasty is indicated in the activation of the clotting cascade, rheumatoid arthritis (RA) being one of such pictures. PATIENTS AND METHODS: Of 79 patients suitable for prosthetic surgery of hip (53) and knee (26), the preoperative values of several markers, namely, D dimers (D-D), thrombin-antithrombin (TAT) complex, and F1 + 2 prothrombin fragment (F1 + F2) were assessed by enzymoimmunoasay. The mean age of the patients was 65.5 years, and their sex distribution was 50 women and 29 men. The indications for arthroplasty were as follows: osteoarthrosis (62), aseptic necrosis (11), RA (9), articular gout (2), previous fracture (2), more than one diagnosis overlapped in some cases. The results attained were compared with a control group comprised of 33 subjects (16 women and 17 men) with mean age similar to the patient's group (68.06 years). RESULTS: The D-D values in the patients suitable for hip arthroplasty and the TAT values in patients suitable for both types of surgery were significantly higher than those found in the control group (p = 0.012 and 0.01, respectively). The preoperative TAT levels of the RA patients were significantly higher (p = 0.025) than those found in the patients with the other surgical indications. CONCLUSIONS: Previously to the performance of arthroplasty, the patients show hypercoagulative marker values higher than those of age-matched controls. The significant rising of TAT found in RA patients is concordant with the literature, and this fact makes it advisable to include RA among the pathologic situations associated with hypercoagulability, as this is a common indication for substitutive hip and knee surgery with high risk of venous thromboembolic disease.