Period and phase adjustments of human circadian rhythms in the real world

Entrainment of the circadian rhythm has 2 aspects, period and phase adjustments, which are established simultaneously in most nonhuman circadian systems. The human circadian system is unique in its functional structure in which 2 different subsystems are involved; one is the circadian pacemaker analogous to that located in the suprachiasmatic nucleus, and the other is the oscillatory system of unknown nature that drives the rest-activity cycle. The human circadian system shows the endogenous period very close to 24 h under entrainment and less sensitive to photic stimuli than under free running, which may explain stable entrainment in the real word where natural sun lights are unpredictable in terms of the intensity and time of appearance. On the other hand, nonphotic entrainment seems to play a significant role in phase adjustment of the human circadian system. Nonphotic zeitgebers initially directed to the rest-activity cycle may affect the circadian pacemaker through feedback and/or associated LD cycles.     

The formation of g=2.49-species of cytochrome P450 in the rat liver by PCB126 oral administration: identification of heme axial ligands by EPR spectroscopy

Rat livers and microsomes were subjected to electron paramagnetic resonance (EPR) measurements at 77 K. The EPR spectra of the livers from the control group, carbon tetrachloride-, 3-methylcholanthrene-, and 3,3',4,4',5-pentachlorobiphenyl (PCB126)-treated rats exhibited an EPR spectrum at g=2.40, 2.24, and 1.93, which is characteristic of P450 in a resting state. The liver of the PCB126-treated rats showed an additional distinct EPR spectrum at g=2.49, 2.26, and 1.87 (g=2.49-species). The heme environmental structure of g=2.49-species was identified by crystal field analysis using three EPR g-values of the microsome treated with various chemicals. These results indicated that g=2.49-species is a hemeprotein with cysteine thiolate at the 5th coordination site, and a nitrogenous ligand at the 6th site.     

Capability of intensity discrimination in multiple receptor model of insect taste

A simple model in which one CNS taste neuron integrates inputsfrom multiple peripheral receptors is introduced in order toinvestigate the mechanism of acute intensity taste discriminationin flies. Information theory is applied to evaluate the acuteability of discrimination provided by the model. The presentanalysis is carried out under two statistical conditions concerningthe uncertainty of receptor response. Based on experimentaldata obtained by Smith et al. (1983), we estimate the mutualinformation entropy of the model. The numerical results obtainedhere indicate that the uncertainty observed in a single receptorresponse is dramatically reduced by the central integration.Furthermore, each of the eleven stimulus intensity levels experimentallyapplied by Smith et al., can be discriminated completely byintegrating the responses of the realistic number of receptors(33–212). Such a great improvement of the differentialsensitivity in the model resolves the discrepancy between thelow differential sensitivity of single sugar receptors (Smithet al., 1983) and the high sensitivity obtained in the feedingbehavior (Dethier and Rhoades, 1954; Dethier and Bowdan, 1984)of the blowfly.     

Identification and estimation algorithm for stochastic neural system. II

The algorithm for identifying the stochastic neural system and estimating the system process which reflects the dynamics of the neural network are presented in this papar. The analogous algorithm has been proposed in our preceding paper (Nakao et al., 1984), which was based on the randomly missed observations of a system process only. Since the previous algorithm mentioned above was subject to an unfavorable effect of consecutively missed observations, to reduce such an effect the algorithm proposed here is designed additionally to observe an intensity process in a neural spike train as the information for the estimation.The algorithm is constructed with the extended Kalman filters because it is naturally expected that a nonlinear and time variant structure is necessary for the filters to realize the observation of an intensity process by means of mapping from a system process to an intensity process. The performance of the algorithm is examined by applying it to some artificial neural systems and also to cat's visual nervous systems. The results in these applications are thought to prove the effectiveness of the algorithm proposed here and its superiority to the algorithm proposed previously.     

New categories designated as healthcare‐associated and community‐associated methicillin‐resistant Staphylococcus pseudintermedius in dogs

The incidence of MRSP has been increasing, and treatment options in veterinary medicine are limited. Few previous studies of MRSP have described the relationships between the genotypes, phenotypes, and clinical backgrounds of the isolates. To gain insight into the associations between the microbiological and clinical characteristics of MRSP, we analyzed 282 Staphylococcus pseudintermedius isolates from dogs. A total of 195 (69.1%) strains were identified as mecA‐positive MRSP and were classified into mainly two genotypes: SCCmec types III (II‐III) (52.8%) and V (37.4%). SCCmec type III MRSP strains were significantly correlated with hospital admission and antimicrobial therapy of the dogs, and exhibited a homogeneous genotype similar to sequence type 71‐MRSP, which is a globally endemic clone in dogs. In contrast, SCCmec type V MRSP strains were not highly correlated with hospital admission and antimicrobial therapy and exhibited genotypic and phenotypic heterogeneity. Properties of MRSP strains SCCmec types III and V were similar to those of HA‐ and CA‐MRSA, respectively. Therefore, we designated these isolates carrying SCCmec types III and V as HA‐MRSP and CA‐MRSP, respectively. Discrimination between HA‐ and CA‐MRSP by oxacillin MIC will provide useful information for treatment and infection control measures for canine MRSP infections.     

Nitric oxide donors inhibit the acetylcholine-induced Cl− current in identified Onchidium neurons

The present study was undertaken to assess the effects of sodium nitroprusside (SNP) and diethylamine NO(C₂H₅)₂N[N(O)NO]⁻Na⁺ (DEA/NO), NO donors, on an acetylcholine (ACh)-induced Cl⁻ current in identified Onchidium neurons using voltage-clamp and pressure ejection techniques. Bath-applied SNP (10 μM) and DEA/NO (5–10 μM) reduced the ACh-induced Cl⁻ current in the neurons without affecting the resting membrane conductance and holding current. The suppressing effects of NO donors were concentration-dependent and completely reversible. Pretreatment with 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (1 μM), a specific inhibitor of NO-stimulated guanylate cyclase, and hemoglobin (50 μM), a nitric oxide scavenger, decreased the SNP-induced inhibition of the ACh-induced current. Intracellular injection of guanosine 3′,5′-cyclic monophosphate (cGMP) or bath-application of 3-isobutyl-1-methylxanthine (50 μM), a non-specific phosphodiesterase inhibitor, inhibited the ACh-induced current, mimicking the effect of NO donors. These results suggest that SNP and DEA/NO inhibit the ACh-induced Cl⁻ current and that this effect is mediated by an increase in intracellular cGMP. © 1998 John Wiley & Sons, Inc. J Neurobiol 35: 388–394, 1998     

Prophylactic Effects of the Glucagon-Like Peptide-1 Analog Liraglutide on Hyperglycemia in a Rat Model of Type 2 Diabetes Mellitus Associated with Chronic Pancreatitis and Obesity

The objective of this study was to investigate the effects of liraglutide, an analog of human glucagon-like peptide 1 (GLP1), on WBN/Kob-Lepr^fa (fa/fa) rats, which spontaneously develop type 2 diabetes mellitus with pancreatic disorder and obesity. Male fa/fa rats (age, 7 wk) were allocated into 4 groups and received liraglutide (37.5, 75, 150 μg/kg SC) or saline (control group) once daily for 4 wk. All rats in the control group became overweight and developed hyperglycemia as they aged. Although the rats given liraglutide showed a dose-dependent reduction in food intake, no significant effects on body weight or fat content occurred. In the liraglutide groups, the development of hyperglycemia was suppressed, even as plasma insulin concentrations increased in a dose-dependent manner. Intravenous glucose tolerance testing of the liraglutide-treated rats confirmed improvement of glucose tolerance and enhanced insulin secretion. Histologic examination revealed increased numbers of pancreatic β-cell type islet cells and increased proliferation of epithelial cells of the small ducts in the liraglutide-treated groups. Although our study did not reveal a significant decrease in obesity after liraglutide administration, the results suggest a marked antidiabetic effect characterized by increased insulin secretion in fa/fa rats with pancreatic disorders.Abbreviations: GLP1, glucagon-like peptide-1; IVGTT, intravenous glucose tolerance testing; T2DM, type 2 diabetes mellitusThe number of patients diagnosed with diabetes has more than doubled over the last 30 y, and diabetes has become an important public health concern worldwide.⁶ Approximately 90% of patients with diabetes are diagnosed with type 2 diabetes mellitus (T2DM).³¹ The onset of T2DM is determined by multiple factors that lead to reduced insulin secretion or insulin resistance, including genetic predisposition and lifestyle-associated habits such as lack of exercise, overeating, and obesity. Many drugs are already used clinically to treat T2DM;^9,11 nevertheless, the search and development of more efficient and safe drugs is currently underway. In this regard, incretin has recently gained attention as a member of a class of drugs used to treat T2DM.^9,11Enteroendocrine cells secret incretin hormones, which augment glucose-induced insulin secretion in response to food ingestion, in a glucose-dependent manner. Currently, the 2 confirmed incretins are glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP1). Research has shown that GLP1 derivatives have functions in addition to the promotion of insulin secretion, including facilitation of β-cell proliferation,²⁸ suppression of β-cell apoptosis,¹² and promotion of β-cell differentiation or de novo formation of β cells.^29,30 GLP1 derivatives have been reported to have multiple nonpancreatic functions, including suppression of appetite and body weight,^7,13 suppression of gastric secretions,¹⁹ reduction of lipid accumulation in the liver,¹⁷ and promotion of sensitivity to insulin in adipose cells and skeletal muscle.^8,22WBN/Kob-type male rats are a relevant animal model for diabetes without obesity. These rats typically show disease conditions including chronic pancreatitis and pancreatic endocrine disorders.^18,26 A new model rat for diabetes was established recently by crossing rats carrying the Lepr^fa obesity gene with wild-type WBN/Kob rats, yielding a fa/fa congenic strain.¹ The obesity gene (Lepr^fa) is a spontaneous mutation derived from Zucker-fatty rats that leads to dysfunction of the leptin receptor. Rats homozygous for this gene are obese, resistant to insulin, and hyperinsulinemic.^4,16,32 Male WBN/Kob-Lepr^fa rats (hereafter referred to as fa/fa rats) represent a new animal model in which the animals spontaneously develop diabetes in addition to endogenous insulin resistance. Compared with the parental strains, fa/fa rats are characterized by an earlier onset of diabetes and more severe pancreatic complications.^1,2 Our previous investigations have revealed that fa/fa rats present with hyperinsulinemia at a prediabetic stage as a compensatory response to insulin resistance, but these rats show high blood glucose levels because of a difficulty in maintaining blood insulin concentrations as a consequence of declining pancreatic β-cell function associated with advancing age.¹⁴In the current study, to further validate fa/fa rats as a T2DM model, we investigated the effects of a GLP1 analog in fa/fa rats with hyperglycemia (age, 7 to 11 wk). We used liraglutide, a human GLP1 analog, which has been shown to be clinically effective in T2DM patients.^9,11     

Combinational effects of farnesoid X receptor antagonist and statin on plasma lipid levels and low-density lipoprotein clearance in guinea pigs

Aims

We previously reported anti-dyslipidemic effects of a farnesoid X receptor antagonist in monkeys. In this study, we compared the cholesterol-lowering effects of single and combined administration of a farnesoid X receptor antagonist, compound-T8, and the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor atorvastatin in a guinea pig model.

Main methods

Plasma levels of 7α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroxylase activity, were measured after a single administration of compound-T8. The effects of compound-T8 or atorvastatin on plasma cholesterol levels and low-density lipoprotein (LDL) clearance were investigated after 14 or 16 days of repeated dosing, respectively. Fractional catabolic rate of plasma LDL was estimated by intravenous injection of DiI-labeled human LDL. The cholesterol-lowering effects of combination therapy were investigated after 7 days of repeated treatment.

Key findings

Compound-T8 (10 and 30 mg/kg) increased plasma 7α-hydroxy-4-cholesten-3-one levels in a dose-dependent manner. Single administration of compound-T8 (30 mg/kg) and atorvastatin (30 mg/kg) reduced plasma non-high-density lipoprotein (non-HDL) cholesterol levels by 48% and 46%, respectively, and increased clearance of plasma DiI-labeled LDL by 29% and 35%, respectively. Compound-T8 (10 mg/kg) or atorvastatin (10 mg/kg) reduced non-HDL cholesterol levels by 19% and 25%, respectively, and combination therapy showed an additive effect and lowered cholesterol levels by 48%.

Significance

Similar to atorvastatin, compound-T8 reduced plasma non-HDL cholesterol levels accompanied with accelerated LDL clearance in guinea pigs. Combination therapy additively decreased plasma non-HDL cholesterol levels. Therefore, monotherapy with a farnesoid X receptor antagonist and combination therapy of a farnesoid X receptor antagonist with atorvastatin would be attractive dyslipidemia treatment options.