Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity.

BACKGROUND: Bile acids (BAs) are nutrient-responsive hormones that modulate energy balance through cell surface and nuclear receptors. Postprandial plasma BAs have been found to be decreased in obesity. OBJECTIVE: We aimed to determine whether meal-stimulated circulating BA levels are altered by Roux-en-Y gastric bypass (RYGB), an operation that modifies the neurohumoral determinants of food intake and energy expenditure to cause significant and durable weight loss. DESIGN: Longitudinal study measuring fasting and postprandial plasma BAs before and after RYGB. SUBJECTS: Five obese surgical patients and eight lean controls underwent frequent blood sampling after a standard liquid meal. Obese subjects were also tested at 1, 4 and 40 weeks after RYGB. Primary and secondary circulating BAs, as well as their glycine and taurine conjugates, were measured via reverse-phase high-performance liquid chromatography/mass spectroscopy. RESULTS: We found that postprandial excursion of conjugated BAs was 52.4% lower in obese than in lean individuals by area-under-the-curve (AUC) analysis (378 vs 793 µmol min l(-1), respectively, P<0.05). By 40 weeks after RYGB, the meal-induced rise in conjugated BAs increased by 55.5% to the level of healthy lean controls (378 pre-op vs 850 µmol min l(-) post-op by AUC analyses, P<0.05). In contrast, postprandial concentrations of unconjugated BAs were similar in lean and obese individuals and were not affected by surgery. CONCLUSION: In light of the growing evidence that BAs have key roles in glucose, lipid and energy homeostasis, the observation that RYGB normalizes the blunted postprandial circulating BA response in obesity suggests that BAs may contribute to the improvement in meal-related physiology seen after RYGB. Further studies are warranted to examine this hypothesis and to determine the degree to which an augmented BA response to nutrient ingestion may mediate the increased incretin response, brown adipose tissue activation and thermic effect of feeding that has been observed after this operation.

Changes in serum ghrelin predict weight loss after Roux-en-Y gastric bypass in rats.

BACKGROUND: Although Roux-en-Y gastric bypass (RYGB) is an effective and widely used therapy for severe obesity, the mechanisms by which it induces weight loss are not well understood. Several studies have shown that RYGB in human patients causes a decrease in circulating levels of ghrelin, a gastric hormone that strongly stimulates food intake. Substantial variation in the effect of RYGB on serum ghrelin has been reported in different studies and among individual patients, suggesting that regulation of this hormone is complex and subject to genetic and other patient-specific factors. To control for these factors and to enable more detailed study of physiologic mechanisms, we have recently developed a clinically relevant rat model of RYGB. In this study, we used this model to examine the effect of RYGB on serum ghrelin levels. METHODS: Fifteen Sprague-Dawley rats that had received a high-fat diet to induce moderate obesity underwent RYGB. The operation closely resembled the procedure in humans. Serum samples were collected 1 month before and 3 months after RYGB, and serum ghrelin levels were measured. The primary outcomes of the study were the changes in body weight, food intake, and circulating ghrelin levels after RYGB. A multiple linear regression model was developed to examine the relationship between ghrelin levels and weight change after RYGB. RESULTS: Three months after the procedure, RYGB-treated rats weighed 20 +/- 5% less than they would have, had they not undergone the procedure. Despite the weight loss, serum ghrelin levels were 38 +/- 6% lower than before surgery. There was appreciable variation in the weight loss in individual animals, and preoperative weight and pre- and postoperative ghrelin levels were the best predictors of postoperative weight loss. Thus, the animals who had the greatest weight loss were those that were heaviest before surgery. These rats had the highest preoperative and lowest postoperative ghrelin levels. CONCLUSIONS: Using our recently developed rat model of RYGB, we found that postoperative weight loss is correlated with the magnitude of the decrease in circulating ghrelin levels. This correlation provides the strongest evidence to date that altered ghrelin signaling contributes to weight loss after this operation. The lower level of circulating ghrelin after RYGB likely blunts the appetitive drive, leading to decreased food intake in these animals.

Sexually dimorphic expression of the growth hormone-releasing hormone gene is not mediated by circulating gonadal hormones in the adult rat.

The sexual dimorphism characterizing GH secretion in the rat is thought to be related to differences in the hypothalamic synthesis and release of the GH-regulating peptides, GH-releasing hormone (GHRH), and somatostatin. Therefore, the influence of gender and sex steroid hormones on hypothalamic expression of the GHRH gene in adult rats were examined. GHRH messenger RNA (mRNA) levels were measured in individual rat hypothalami by Northern hybridization analysis using a 32P-labeled complementary DNA encoding rat GHRH. Destruction of hypothalamic GHRH neurons by neonatal treatment with monosodium glutamate caused similar 3-fold reductions in the levels of GHRH mRNA in adult male and female animals. In three separate experiments, hypothalamic GHRH mRNA concentrations in male rats were 2- to 3-fold greater than in randomly cycling females (four or five rats per group; P less than 0.01). In spite of the greater abundance of GHRH mRNA abundance in the male rat hypothalamus, circulating gonadal steroids lacked the ability to modulate GHRH gene expression in adult animals, since neither gonadectomy nor pharmacological sex steroid replacement changed GHRH mRNA levels in the hypothalamus of male and female adult rats. Furthermore, GHRH mRNA concentrations in female rats were similar during the proestrus, estrus, and diestrus phase of the estrous cycle. Also, GH inhibited hypothalamic GHRH gene expression in a sex-specific manner. Exposure to high levels of GH secreted by the MtTW15 tumor for 4 weeks reduced GHRH mRNA concentrations 7-fold in male rats (P less than 0.001) but only 2-fold in females (P less than 0.05). These studies demonstrate that GHRH gene expression in the rat hypothalamus is sexually dimorphic. Basal mRNA levels are greater in male rats, and expression in male hypothalami is more sensitive to feedback inhibition by GH than expression in females. There is no evidence for regulation of GHRH mRNA levels by either testosterone or estrogen in adult rats. These gender differences in GHRH gene expression likely contribute to the generation of a sex-specific pattern of GH secretion.

Estrogen increases galanin immunoreactivity in hyperplastic prolactin-secreting cells in Fisher 344 rats.

Galanin is a widely distributed regulatory peptide which modulates the pituitary secretion of PRL and GH. Estrogen administration strongly stimulates galanin gene expression in the rat anterior pituitary. In adult female Fischer 344 rats, estrogen also induces hyperplasia of lactotropes. We used immunocytochemical analysis to assess the effects of estrogen on galanin-like immunoreactivity (Gal-IR) in the rat pituitary and hypothalamus during sc diethylstilbestrol (DES) implantation and after its removal at 30 days. In the anterior pituitary, DES implantation increased the portion of Gal-IR-containing cells from less than 2% in the control rats to 18.3% after 3 days of DES and 36% after 30 days. These changes paralleled the lactotrope hyperplasia exhibited in response to DES exposure. Ten and 30 days after removal of the DES capsules, the percentage of Gal-IR-containing cells in the anterior pituitary decreased to 6.3% and 1.5%, respectively. Colocalization studies revealed that Gal-IR-containing cells were predominantly lactotropes. Immunoelectron microscopy demonstrated that Gal-IR was concentrated in the Golgi region of these hyperplastic lactotropes and suggests that little of the synthesized galanin is secreted. The distribution of Gal-IR in the hypothalamus, median eminence, and neurohypophysis was unaffected by DES treatment. These data demonstrate that galanin is synthesized by hyperplastic pituitary lactotropes of Fischer 344 rats and that peptide accumulation is dependent on the presence of circulating estrogens. In contrast, neuronal galanin synthesis in the hypothalamus does not appear to be regulated by estrogen.

The effect of verapamil in reducing the severity of acute tubular necrosis in canine renal autotransplants.

Calcium channel blockade has been shown to prevent warm renal ischemic damage. The ability of verapamil to decrease the severity of acute tubular necrosis (ATN) after 24-hr cold storage and autotransplantation was studied in a randomized paired study of 12 dogs. Experimental animals pretreated with intraarterial verapamil and flushing of the harvested kidney with cold intracellular solution containing verapamil demonstrated significantly (P less than .05) greater renal function preservation over their matched controls. A subsequent nonpaired study of 6 dogs treated only with flushing of the harvested kidney with perfusate containing verapamil demonstrated no significant preservation advantage over controls. We conclude that verapamil, administered prior to the ischemic event, can enhance the protective effect of hypothermia and decrease the severity of ATN in ischemically injured kidneys.

Q-T prolongation and torsades de pointes ventricular tachycardia produced by the tetracyclic antidepressant agent maprotiline.

Tricyclic antidepressant drugs such as imipramine and desipramine have long been known to produce cardiovascular side effects including sinus tachycardia, prolongation of the P-R, QRS, and Q-T intervals, and decreased T-wave amplitude. Life-threatening ventricular ectopic activity has occurred after tricyclic drug overdose. Recently, maprotiline (Ludiomil), a tetracyclic anthracene-derivative antidepressant, has become available for the treatment of affective disorders. It appears as effective as the tricyclic drugs in relieving unipolar depression. Although several studies have reported a low incidence of cardiovascular side effects, others show little difference between the tetracyclic and tricyclic drugs. This report describes a patient in whom maprotiline treatment caused Q-T prolongation and life-threatening torsades de pointes ventricular tachycardia (VT).

Regulation of anterior pituitary galanin gene expression by thyroid hormone.

Thyroid hormone is required for basal and estrogen-induced expression of anterior pituitary galanin. Steady-state anterior pituitary galanin mRNA levels decreased 6-fold in hypothyroid rats after 3 weeks of treatment. Similarly, hypothyroidism resulted in a 2.6-fold decrease in estrogen induction of galanin gene expression. The effect of thyroid hormone on anterior pituitary galanin gene expression appears to be exerted, at least in part, at the pituitary itself. Transient expression assays in GH3 cells suggest the involvement of transcriptional mechanisms in the regulation of galanin gene expression by thyroid hormone. A region between -41 and -132 bp upstream of the transcriptional start site confers thyroid hormone responsiveness to the galanin gene. Gel-mobility shift assays show specific binding of 'SPI-like' proteins in GH3 nuclear extracts to this region of the galanin gene. This binding was greatly enhanced by thyroid hormone.

Response to symptom-limited exercise in patients with the hepatopulmonary syndrome.

OBJECTIVE: To study the response to symptom-limited exercise in patients with the hepatopulmonary syndrome (HPS). DESIGN: The response to maximal cardiopulmonary exercise (CPX) was studied in 5 patients with HPS and compared with 10 case control (normoxemic, NC) cirrhotics (matched for age, gender, etiology and severity of liver disease, tobacco use, and beta-blocker therapy) and 9 hypoxemic control cirrhotics (HC) without clinical evidence of HPS. SETTING: Cardiopulmonary exercise physiology laboratory in a tertiary care referral center. PATIENTS: Cirrhotics referred for CPX as part of their preliver transplantation evaluation. MEASUREMENTS: Standard pulmonary function tests and echocardiography were performed to assess resting pulmonary and cardiac function. Peak oxygen consumption (VO2), minute ventilation, arterial blood gases, and dead space (VD/VT) were determined during symptom-limited maximal CPX. RESULTS: Resting spirometry and lung volumes were similar between HPS and NC subjects, while HC subjects had restrictive physiology. Differences existed in diffusing capacity corrected for hemoglobin and alveolar volume percent predicted (HPS, 45+/-2 vs NC, 68+/-3, p<0.05; vs HC, 70+/-4, p<0.05), PaO2 (HPS, 70+/-5 mm Hg; HC, 79+/-3 mm Hg, vs NC, 102+/-3 mm Hg, p<0.05) and alveolar-arterial (A-a) O2 gradient (HPS, 42+/-8 mm Hg vs HC, 27+/-2 mm Hg, p<0.05; vs NC, 6+/-2 mm Hg, p<0.05). During CPX, HPS patients achieved a lower peak VO2 percent predicted (HPS, 55+/-6 vs NC, 73+/-3, p<0.05; vs HC, 71+/-5, p<0.05) and VO2 at the ventilatory threshold as percent predicted peak VO2 (HPS, 36+/-2 vs NC, 55+/-4, p<0.05; vs HC 55+/-5, p<0.05). While no differences existed in heart rate and breathing reserve, HPS patients had significantly lower PaO2 (HPS, 50+/-5 mm Hg vs NC, 97+/-4 mm Hg, p<0.05; vs HC, 87+/-6 mm Hg, p<0.05), wider A-a O2 gradient (HPS, 73+/-5 mm Hg vs NC, 13+/-3 mm Hg, p<0.05; vs HC, 31+/-5 mm Hg, p<0.05) and higher VD/VT (HPS, 0.36+/-.03 vs NC, 0.18+/-.02, p<0.05; vs HC, 0.28+/-.02, p<0.05) at peak exercise. For HPS patients, VO2 was negatively correlated with VD/VT (r2=0.9) and positively correlated with PaO2 (r2=0.41) at peak exercise. CONCLUSIONS: Patients with HPS demonstrate a severe reduction in aerobic capacity, beyond that found in cirrhotics without syndrome. The significant hypoxemia and elevated VD/VT at peak exercise suggest that an abnormal pulmonary circulation contributes to further exercise limitation in patients with HPS.

Increase in plasma leptin and Lep mRNA concentrations by food intake is dependent on insulin.

Obese (Lep) gene expression and leptin secretion are regulated by changes in food intake. However, the mechanism by which leptin concentrations are altered by fasting and feeding is unclear. Since these changes occur in parallel with changes in plasma insulin, it is possible that the changes observed are mediated by insulin. To test this hypothesis, we studied the role of insulin in the regulation of Lep gene expression in epididymal fat and leptin secretion during feeding. As shown previously, fasted animals showed significant reductions in Lep mRNA, plasma leptin, and plasma insulin concentrations. Conversely, feeding increased plasma insulin, Lep mRNA, and plasma leptin. In streptozotocin (STZ)-treated animals, plasma insulin concentrations were low. This was associated with low Lep mRNA and plasma leptin concentrations. Changes in food intake, whether fasting or feeding, did not significantly alter plasma insulin levels in STZ-treated animals. Under these circumstances, Lep mRNA and plasma leptin concentrations also remained low. Our results demonstrate that the decrease in Lep mRNA and plasma leptin during fasting and the increase with feeding are dependent on changes in the plasma insulin concentration.

Tissue-specific sex differences in galanin-like immunoreactivity and galanin mRNA during development in the rat.

Galanin-like immunoreactivity (Gal-LI), as determined by radioimmunoassay, was detectable in the brain and gastrointestinal tract by day 15 of gestation. Concentrations of Gal-LI increased after birth in the hypothalamus but decreased in the stomach and duodenum. A sex difference in Gal-LI concentrations appeared during puberty in the median eminence, neurointermediate lobe, and the anterior pituitary (AP), where females had higher Gal-LI concentrations compared to males. This difference was most pronounced in the AP; adult females had up to 4-fold greater Gal-LI concentrations and 5-fold more abundant rGal-specific mRNA compared to males.

Spontaneous rupture of ureter.

A patient with spontaneous ureteral rupture in the absence of obstruction or calculus disease is presented. In addition to ureteral rupture this patient also had a penile squamous cell carcinoma and infected inguinal lymph nodes. A review of the literature discloses that all reported cases with spontaneous rupture of the ureter had an underlying process leading to that rupture. It is considered, therefore, that rupture of the ureter should be designated as "traumatic" or "nontraumatic." The term "spontaneous," implying a primary event, is a misnomer. No such case has been reported occurring in an otherwise healthy individual.

Respiratory dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the voluntary motor system. Involvement of the respiratory system is inevitable and leads to the development of respiratory failure, the usual cause of death in this disorder. ALS at present is incurable, and only symptomatic treatment is available. This article presents guidelines for the recognition and management of respiratory failure.

Methods for the study of sequence-specific binding of proteins to the HCV RNA genome.

The appropriate formation of specific RNA-protein complexes regulates the normal synthesis, trafficking, and metabolism of intracellular RNA. For RNA viruses, these interactions are essential for replication and translation of the viral genome, as well as packaging of progeny strands into mature virions. Sequence-specific RNA-protein interactions allow the replication and translation machinery to distinguish between viral and host-cell RNA species, thus insuring that the viral replicative apparatus acts on the appropriate RNA targets. Identifying these proteins and determining their biological activities provide important clues about the mechanisms of viral replication. Their physiological importance suggests that blocking these interactions may be effective means of inhibiting viral replication. Thus, the identification and characterization of sequence-specific RNA-binding proteins are valuable steps in the development of potent and selective antiviral agents.

Extended fractal analysis for texture classification and segmentation.

The Hurst parameter for two-dimensional (2-D) fractional Brownian motion (fBm) provides a single number that completely characterizes isotropic textured surfaces whose roughness is scale-invariant. Extended self-similar (ESS) processes were previously introduced in order to provide a generalization of fBm. These new processes are described by a number of multiscale Hurst parameters. In contrast to the single Hurst parameter, the extended parameters are able to characterize a greater variety of natural textures where the roughness of these textures is not necessarily scale-invariant. In this work, we evaluate the effectiveness of multiscale Hurst parameters as features for texture classification and segmentation. For texture classification, the performance of the generalized Hurst features is compared to traditional Hurst and Gabor features. Our experiments show that classification accuracy for the generalized Hurst and Gabor features are comparable even though the generalized Hurst features lower the dimensionality by a factor of five. Next, the segmentation accuracy using generalized and standard Hurst features is evaluated on images of texture mosaics. For these experiments, the performance is evaluated with and without supplemental contrast and average grayscale features. Finally, we investigate the effectiveness of the Hurst features to segment real synthetic aperture radar (SAR) imagery.

An improved method for 2-D self-similar image synthesis.

We propose a new method called incremental Fourier synthesis to generate 2-D self-similar images based on a 2D fractional Brownian motion (fBm) model. With this method, the stationary increments of fBm are created by a Fourier synthesis method and the increments are added up to generate the nonstationary 2D fBm process. Since the new method takes advantage of the FFT, its computational complexity is only O(N(2)log(2)(N)), and its memory requirement is only O(N(2)) for a self-similar image of size NxN.

Parenterally transmitted hepatitis: viruses, vaccines, and antiviral therapy.

The introduction of safe and effective vaccines as well as the identification of antiviral therapy that eradicates virus in many infected patients augurs well for the control of HBV and, by extension, HDV infection. The key to ultimate success will be the universal availability of immunization. The recent elucidation of the hepatitis C genomic structure will eventually lead to fundamental understanding of the mechanisms underlying the life cycle of HCV, which appears to elude both natural and synthetic defensive measures. The best hope for control of this virus in the near future rests in careful screening of the blood supply and alteration of high-risk lifestyles. The next phase of antiviral and vaccine development for all of these agents will depend on recently acquired knowledge of virus-specific enzymatic processes, molecular interactions between viruses and host cells, and our ability to interfere selectively with these processes.

[Prevention and treatment of pneumonia in infectious complications of trauma]. / Profilaktika i lechenie pnevmonii pri infektsionnykh oslozhneniiakh travmy.

Based on the examination and treatment of 79 patients with traumas the authors consider ventilation exercises to be necessary for prevention of pneumonia.

Increasing handwashing compliance with more accessible sinks.

The frequency of handwashing in two intensive care units (ICUs) was observed. Handwashing after direct contact with patients or their support equipment was recorded. The ratio of beds to sinks was 1:1 in the medical ICU and 4:1 in the surgical ICU. Surveillance of physicians, nurses, and other personnel demonstrated a greater frequency of handwashing by nurses (63%) compared with physicians (19%) and other personnel (25%). The nurses in the unit with one sink per bed had a significantly greater number of handwashes (76%) than those in the unit with fewer sinks (51%).

Heterogeneous nuclear ribonucleoprotein I (hnRNP-I/PTB) selectively binds the conserved 3' terminus of hepatitis C viral RNA.

Hepatitis C virus (HCV) is a positive-strand RNA virus whose genome is replicated by a direct RNA-to-RNA mechanism. Initiation of negative-strand RNA synthesis is believed to proceed from the 3' end of the genomic RNA. The high conservation of the 3' terminus suggests that this region directs the assembly of proteins required for the initiation of RNA replication. We sought to determine whether host proteins bind specifically to this RNA structure. We observed specific binding of cellular proteins to labeled 3'-terminal RNA by mobility shift analysis. UV crosslinking revealed that the predominant 3'-terminal RNA-binding protein migrates as a single, 60-kDa species that can be precipitated by monoclonal antibodies directed against heterogeneous nuclear ribonucleoprotein I, also called polypyrimidine tract-binding protein (hnRNP-I/PTB), a protein previously shown to bind to the 5' internal ribosome entry site (IRES) of the HCV genome. Purified hnRNP-I/PTB also bound selectively to the 3' end of the HCV genome. hnRNP-I/PTB binding requires the upstream two stem-loop structures (SL2 and SL3) but not the most 3'-terminal stem-loop (SL1). Minor alteration of either the stem or loop sequences in SL2 or SL3 severely compromised hnRNP-I/PTB binding, suggesting extremely tight RNA structural requirements for interaction with this protein. hnRNP-I/PTB does not bind to either end of the antigenomic RNA strand and binds to the 5' IRES element of the genome at least 10-fold less avidly than to the 3' terminus. The strong, selective, and preferential binding of hnRNP-I/PTB to the 3' end of the HCV genome suggests that it may be recruited to participate in viral replication, helping to direct initiation of negative-strand RNA synthesis, stabilize the viral genome, and/or regulate encapsidation of genomic RNA.