Gemfibrozil treatment increases low-density lipoprotein particle size in Type 2 diabetes mellitus but does not alter in vitro oxidizability

The aim of this study was to determine the effect of the lipid modifying agent gemfibrozil on lipid and coagulation risk factors in patients with Type 2 diabetes mellitus (Type 2 DM). Twenty-six subjects with Type 2 DM and dyslipidaemia were treated for 24 weeks with either gemfibrozil 600 mg orally twice daily or placebo in a double-blind randomized trial. Lipid profiles, fibrinogen, Factor VII, and plasminogen activator inhibitor-1 (PAI-1) were measured by routine laboratory methods. Low density lipoprotein (LDL) size was determined by gradient gel electrophoresis and the resistance of LDL to copper-induced oxidation was assessed by measuring absorbance at 234 nm. Gemfibrozil significantly reduced total cholesterol (-0.9 (-0.48, -1.32) mmol l(-1); p < 0.05) and triglycerides (-2.7 (-1.55, -1.35) mmol l(-1); p < 0.001) vs placebo. The fall in triglyceride was reflected by a fall in VLDL cholesterol levels in the gemfibrozil treated group vs placebo (-1.31 mmol l(-1); p < 0.001). LDL-cholesterol level did not change but LDL particle size increased by 0.5 nm (0.01, 0.93); P < 0.02. The increase in particle size was inversely correlated with the change of triglyceride level (r = -0.79, p < 0.0001) but did not result in any reduction of susceptibility to copper-induced oxidation. There were no significant changes in the coagulation parameters studied. Because of its ability to correct the lipid abnormalities associated with Type 2 DM particularly hypertriglyceridaemia, gemfibrozil provides a useful therapeutic option in the management of diabetic dyslipidaemia but it does not alter in vitro oxidizability of LDL.     

Obfuscation of allosteric structure-function relationships by enthalpy-entropy compensation

The pH and temperature dependence of the allosteric properties of phosphofructokinase (PFK) from Bacillus stearothermophilus have been studied from 5 to 9 and 6 to 40 degrees C, respectively. Throughout this pH and temperature range the allosteric ligands MgADP and phospho(enol)pyruvate (PEP) have no effect on kcat. The dissociation constants of the substrate, fructose 6-phosphate, and the allosteric ligands, as well as the absolute value of the coupling free energies between these ligands, all increase when the pH is raised, indicating that the inhibition by PEP and the activation by MgADP increase despite each ligand's somewhat lower affinity. However, the constituent coupling enthalpies and entropies substantially diminish in absolute value as pH is increased, suggesting that the magnitudes of molecular perturbations engendered by the binding of allosteric ligands do not correlate with the magnitudes of the functional consequences of those perturbations. Temperature and pH exert their influence on the observed allosteric behavior by changing the relative contributions made by the largely compensating DeltaH and TDeltaS terms to the coupling free energy.     

Bacterial walls, peptidoglycan hydrolases, autolysins, and autolysis

The use of a spacer has been recommended in interstitial brachytherapy for tongue cancer to reduce the radiation dose to the mandible. This article describes the development of two types of acrylic resin spacers, a mouth guard-type spacer for dentate patients, and a replica denture-type spacer for edentulous patients. These spacers can be used without suture retention and are comfortable for patients.     

Amplitude-dependent modulation of brush border enzymes and proliferation by cyclic strain in human intestinal Caco-2 monolayers

Little is known about the effects of repetitive deformation during peristaltic distension and contraction or repetitive villus shortening on the proliferation and differentiation of the intestinal epithelium. We sought to characterize the effects of repetitive deformation of a physiologically relevant magnitude and frequency on the proliferation and differentiation of human intestinal epithelial Caco-2 cells, a common cell culture model for intestinal epithelial biology. Human intestinal epithelial Caco-2 cells were cultured on collagen-coated membranes deformed by -20 kPa vacuum at 10 cycles/minute, producing an average 10% strain on the adherent cells. Proliferation was assessed by cell counting and 3H-thymidine incorporation. Alkaline phosphatase and dipeptidyl dipeptidase specific activity were measured in cell lysates. Since cells at the membrane periphery experience higher strain than cells in the center, the topography of brush border enzyme histochemical and immunohistochemical staining was analyzed for strain-dependence. Cyclic strain stimulated proliferation compared to static cells. Proliferation was highest in the membrane periphery where strain was maximal. Strain also modulated differentiation independently of its mitogenic effects, selectively stimulating dipeptidyl dipeptidase while inhibiting alkaline phosphatase. Strain-associated enzyme changes were also maximal in areas of greatest strain. The PKC inhibitors staurosporine and calphostin C ablated strain mitogenic effects while intracellular PKC activity was increased by strain. The strain-associated brush border enzyme changes were attenuated but not blocked by PKC inhibition. Thus, strain of a physiologically relevant frequency and magnitude promotes proliferation and modulates the differentiation of a well-differentiated human intestinal epithelial cell line in an amplitude-dependent fashion. PKC may be involved in coupling strain to increased proliferation.     

The human gallbladder increases cholesterol solubility in bile by differential lipid absorption: a study using a new in vitro model of isolated intra-arterially perfused gallbladder

In this study, we first developed and validated a new in vitro isolated, intra-arterially perfused, gallbladder model and then applied the method to investigate the absorption of biliary lipids by the gallbladder wall and the effect of this process on the composition of human bile. Oxygenated and glucose-added buffer was perfused through the cystic artery to maintain organ viability. A standard pooled natural bile, radiolabeled with H3-cholesterol and C14-palmitoyl-linoleoyl-phosphatidylcholine, was instilled in the lumen via a cystic duct catheter. Changes in bile volume and lipid concentrations were monitored at time intervals to evaluate the disappearance of lipids from bile caused by gallbladder absorptive function. Organ viability was demonstrated by stable lactate dehydrogenase (LDH) organ release and oxygen consumption throughout the experiments. In the pig, disappearance rates of lipids from bile were similar in vitro and in vivo, demonstrating the validity of the isolated in vitro model for functional studies. By applying our in vitro isolated preparation to the human gallbladder, we found that 23% of cholesterol and 32% of phosphatidylcholine, but only 9% of bile salts, disappeared from bile in 5 hours. As a consequence, at the end of the experiments, cholesterol (P < .05) and phospholipid (P < .05) molar percentages were significantly reduced, while the bile salt (P < .05) molar percentage was significantly increased with respect to values at the beginning of the studies. Our findings are of pathophysiological relevance and support the concept that the human gallbladder modifies the relative composition of biliary lipids in such a way as to increase cholesterol solubility in bile.     

Modification of a hydrogen bond to a bacteriochlorophyll a molecule in the light-harvesting 1 antenna of Rhodobacter sphaeroides

Site-directed mutagenesis has been used to examine the function of a highly conserved aromatic residue, alpha Trp43, in the light-harvesting 1 antenna of the photosynthetic bacterium Rhodobacter sphaeroides. In this antenna alpha Trp43 is thought to be located near the putative binding site for bacteriochlorophyll; in this work it was changed to both Tyr and Phe, and in each case the main near-infrared absorbance peak was shifted to the blue, from 876 nm to 865 nm and then to 853 nm, respectively. Resonance Raman spectroscopy of the resulting complexes shows a shift of one component of the 1640-cm-1 peak to 1632 cm-1 for the Tyr mutant and to 1660 cm-1 for the Phe mutant. This demonstrates a strengthening of an existing H bond for the Tyr change and a breakage of this bond for the change to Phe. The 1640-cm-1 peak has been previously assigned to H-bonded C2 acetyl carbonyl groups of both bacteriochlorophylls in the light-harvesting 1 antenna dimer [Robert, B. & Lutz, M. (1985) Biochim. Biophys. Acta 807, 10-21]. These results indicate that one of these H bonds is to alpha Trp43, placing this residue in close proximity to the bacteriochlorophyll a macrocycle with which it interacts. The existence of this bond places constraints on the conformation of the alpha polypeptide, and a model of an alpha beta heterodimer is presented incorporating these data.     

Dorothy and The Wizard. Intergenerational issues in mental health and aging

Among patients undergoing maintenance hemodialysis, a high prevalence of hepatitis C virus (HCV) infection can be observed. In a prospective study, sera of 273 patients were examined for the presence of HCV infection by serological tests and by PCR. Thirty-five patients (12.8%) were HCV antibody positive, and in 31 of them HCV RNA could be detected by PCR. Among the 238 seronegative patients HCV infection was detected in 12 cases (5.0%) exclusively by PCR. Only in 1 of these patients seroconversion could be observed within the 18-month follow-up period. These findings demonstrate that in hemodialysis patients PCR is necessary for the diagnosis of HCV infection.     

Superior temporal gyrus and planum temporale in schizophrenia: a selective review

1. The normal structure of the superior temporal gyrus (STG) has been elucidated from human and non-human primate research. This brain region is structurally complex, contains several distinct cellular regions and the area known as the planum temporale. 2. The STG connects with heteromodal neocortical regions and temporolimbic areas. 3. Functional studies of the normal STG in animals and in humans, using electrophysiology and PET/fMRI, emphasize the STG's role as part of a cortical network important in the interpretation, production and self-monitoring of language. 4. There is evidence for structural abnormalities of the STG in schizophrenia including both volume reductions and disturbances of normal asymmetries. 5. Functional studies of this region in schizophrenic patients, including measurements of evoked potentials and of bloodflow, are abnormal, especially when patients perform language tasks or experience hallucinations. 6. This structural and functional pathology in the STG probably represents one example of a more general disruption in schizophrenia of the neocortical network of which this region is an essential part. This disturbance may be closely associated with the symptoms of formal thought disorder and of auditory hallucinations commonly seen in the disorder.     

Isolation rearing enhances the locomotor stimulant properties of intra-perifornical sulpiride, but impairs the acquisition of a conditioned place preference

This article synthesizes theoretical material from psychology research into a practical model for conceptualizing violence in psychiatric settings. Relevant research and theory are reviewed, focusing on two important behavioral models of aggressive behavior, hostile aggression and instrumental aggression. The concepts of reinforcement, anticipated rewards, specific and nonspecific stimulus-driven aggression, intermediary emotional states in aroused persons, and the aggression stimulus threshold are developed into a bimodal model applicable to the clinical management of violence. The model provides a broad framework for categorizing, understanding, and addressing aggressive behavior in clinical settings.