The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress

The risk of suicide, which causes about 1 million deaths each year, is considered to augment as the levels of stress increases. Dysregulation in the stress response of the hypothalamic-pituitary-adrenocortical (HPA) axis, involving the corticotrophin-releasing hormone (CRH) and its main receptor (CRHR1), is associated with depression, frequent among suicidal males. Here we have analyzed single nucleotide polymorphisms (SNPs) in these genes, in family trios with suicide attempter offspring ( n = 542), by using the transmission disequilibrium test both in a two-staged screening/replication sample design and in detailed reanalysis in the entire sample. Stratification based on the levels of lifetime stress showed reproducible association and linkage of an SNP in the CRHR1 gene (rs4792887) to suicide attempters exposed to low levels of stress ( P = 0.002), among whom most males were depressed ( P = 0.001). The identified allele may represent a part of the genetic susceptibility for suicidality by increasing HPA axis activity upon exposure to low levels of stress.     

吡格列酮联合瑞舒伐他汀钙对2型糖尿病患者高密度脂蛋白的干预效应

动脉粥样硬化性心血管疾病是糖尿病最常见的并发症,而患者高密度脂蛋白(high density lipoprotein,HDL)水平和功能是影响AS发生发展的重要指标之一。本文旨在探讨吡格列酮与瑞舒伐他汀钙联合治疗对2型糖尿病(type 2 diabetes mellitus, T2DM)患者HDL的改善作用,以期在临床上预测该治疗措施对糖尿病并发症的防治效果。将70例T2DM患者,按年龄、性别、病情、药物基本匹配的原则,分为对照组和吡格列酮组,每组35人,两组患者除常规使用胰岛素降糖治疗外,对照组给予瑞舒伐他汀钙片,吡格列酮组给予瑞舒伐他汀钙片及盐酸吡格列酮片,治疗3个月后临床观察患者空腹血糖(fasting blood sugar, FPG)、餐后血糖（post-prandial glycaemia, PPG）、糖化血红蛋白(glycated hemoglobin, HbA1c)、甘油三酯(triglycerides, TG)、总胆固醇(total cholesterol, TC)、高密度脂蛋白胆固醇（high density lipoprotein cholesterol, HDL-C）、低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)水平,同时提取患者HDL,检测不同药物治疗对HDL功能的改善效果。与治疗前相比,吡格列酮组患者FPG、PPG、HbA1c、TC、TG及LDL-C 均明显下降,HDL-C水平明显升高;治疗后组间比较显示：与对照组相比,吡格列酮干预后患者HDL-C水平升高10.67%。HDL功能检测显示：药物治疗3月后,与对照组相比,吡格列酮组患者HDL介导细胞胆固醇外排效率增加25%,并使细胞内相关转运蛋白ATP结合盒转运体A1 (ATP-binding cassette transporter A1,ABCA1)表达增加;同时,吡格列酮组患者HDL抗巨噬细胞凋亡功能亦明显提高。在2型糖尿病治疗中,吡格列酮联合瑞舒伐他汀钙不仅可以稳定血糖、血脂水平,而且可以升高HDL水平,改善HDL的功能,对于延缓T2DM患者出现心血管并发症具有重要意义。     

The olfactory responses of the antenna and maxillary palp of the fleshfly,Neobellieria bullata (Diptera: Sarcophagidae), and their sensitivity to blockage of nitric oxide synthase

The relative sensitivities of the olfactory receptors in the antenna and maxillary palp of the fleshfly, Neobellieria bullata, were assessed using simultaneous electroantennograms (EAGs) and electropalpograms (EPGs). In general, the antennae and maxillary palps were more sensitive to odors related to animals (blood extract and saturated carboxylic acid) than to odors that were plant-derived (citral, hexenol, hexenal). In addition, the maxillary palps were relatively less sensitive to plant-derived odorants than the antennae, perhaps related to their anatomical position. Scanning electron microscopy was also used to assess the types of sensilla found on the two organs. In addition, NADPH-diaphorase histochemistry was used in an attempt to localize the enzyme nitric oxide synthase (NOS) in the antenna and the maxillary palps. We found evidence of NADPH-diaphorase staining in both organs, with localized staining in the antennal cells and more general staining in the maxillary palps. When NOS was selectively blocked using the antagonist L-NAME, the amplitude of the EAGs and EPGs to odorants fell by 30-50%. In contrast, application of the inactive enantiomer, D-NAME, did not change the amplitude of the EAGs or the EPGs. Our results indicate that NOS is involved in the function of olfactory receptor cells in the fleshfly.     

Prior exercise and the response to insulin-induced hypoglycemia in the dog

To test whether hepatic insulin action and the response to an insulin-induced decrement in blood glucose are enhanced in the immediate postexercise state as they are during exercise, dogs had sampling (artery, portal vein, and hepatic vein) catheters and flow probes (portal vein and hepatic artery) implanted 16 days before a study. After 150 min of moderate treadmill exercise or rest, dogs were studied during a 150-min hyperinsulinemic (1 mU.kg(-1).min(-1)) euglycemic (n = 5 exercised and n = 9 sedentary) or hypoglycemic (65 mg/dl; n = 8 exercised and n = 9 sedentary) clamp. Net hepatic glucose output (NHGO) and endogenous glucose appearance (R(a)) and utilization (R(d)) were assessed with arteriovenous and isotopic ([3-(3)H]glucose) methods. Results show that, immediately after prolonged, moderate exercise, in relation to sedentary controls: 1) the glucose infusion rate required to maintain euglycemia, but not hypoglycemia, was higher; 2) R(d) was greater under euglycemic, but not hypoglycemic conditions; 3) NHGO, but not R(a), was suppressed more by a hyperinsulinemic euglycemic clamp, suggesting that hepatic glucose uptake was increased; 4) a decrement in glucose completely reversed the enhanced suppression of NHGO by insulin that followed exercise; and 5) arterial glucagon and cortisol were transiently higher in the presence of a decrement in glucose. In summary, an increase in insulin action that was readily evident under euglycemic conditions after exercise was abolished by moderate hypoglycemia. The means by which the glucoregulatory system is able to overcome the increase in insulin action during moderate hypoglycemia is related not to an increase in R(a) but to a reduction in insulin-stimulated R(d). The primary site of this reduction is the liver.     

Fiber type-specific determinants of Vmax for insulin-stimulated muscle glucose uptake in vivo

The aim of this study was to determine barriers limiting muscle glucose uptake (MGU) during increased glucose flux created by raising blood glucose in the presence of fixed insulin. The determinants of the maximal velocity (V(max)) of MGU in muscles of different fiber types were defined. Conscious rats were studied during a 4 mU x kg(-1) x min(-1) insulin clamp with plasma glucose at 2.5, 5.5, and 8.5 mM. [U-(14)C]mannitol and 3-O-methyl-[(3)H]glucose ([(3)H]MG) were infused to steady-state levels (t = -180 to 0 min). These isotope infusions were continued from 0 to 40 min with the addition of a 2-deoxy-[(3)H]glucose ([(3)H]DG) infusion. Muscles were excised at t = 40 min. Glucose metabolic index (R(g)) was calculated from muscle-phosphorylated [(3)H]DG. [U-(14)C]mannitol was used to determine extracellular (EC) H(2)O. Glucose at the outer ([G](om)) and inner ([G](im)) sarcolemmal surfaces was determined by the ratio of [(3)H]MG in intracellular to EC H(2)O and muscle glucose. R(g) was comparable at the two higher glucose concentrations, suggesting that rates of uptake near V(max) were reached. In summary, by defining the relationship of arterial glucose to [G](om) and [G](im) in the presence of fixed hyperinsulinemia, it is concluded that 1) V(max) for MGU is limited by extracellular and intracellular barriers in type I fibers, as the sarcolemma is freely permeable to glucose; 2) V(max) is limited in muscles with predominantly type IIb fibers by extracellular resistance and transport resistance; and 3) limits to R(g) are determined by resistance at multiple steps and are better defined by distributed control rather than by a single rate-limiting step.     

Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice

Muscle glucose uptake (MGU) is distributively controlled by three serial steps: delivery of glucose to the muscle membrane, transport across the muscle membrane, and intracellular phosphorylation to glucose 6-phosphate by hexokinase (HK). During states of high glucose fluxes such as moderate exercise, the HK activity is of increased importance, since augmented muscle perfusion increases glucose delivery, and increased GLUT4 at the cell membrane increases glucose transport. Because HK II overexpression augments exercise-stimulated MGU, it was hypothesized that a reduction in HK II activity would impair exercise-stimulated MGU and that the magnitude of this impairment would be greatest in tissues with the largest glucose requirement. To this end, mice with a HK II partial knockout (HK+/-) were compared with their wild-type control (WT) littermates during either sedentary or moderate exercise periods. Rg, an index of glucose metabolism, was measured using 2-deoxy-[3H]glucose. No differences in glucose metabolism were detected between sedentary groups. The increase in Rg due to exercise was impaired in the highly oxidative heart and soleus muscles of HK+/- compared with WT mice (7 +/- 10 vs. 29 +/- 9 and 8 +/- 3 vs. 25 +/- 7 micromol. 100 g-1. min-1, respectively). However, the increase in Rg due to exercise was not altered in gastrocnemius and superficial vastus lateralis muscles in HK+/- and WT mice (8 +/- 2 vs. 12 +/- 3 and 5 +/- 2 vs. 8 +/- 2 micromol. 100 g-1. min-1, respectively). In conclusion, MGU is impaired by reductions in HK activity during exercise, a physiological condition characterized by high glucose flux. This impairment is critically dependent on the tissue's glucose metabolic rate and correlates with tissue oxidative capacity.     

Time versus size: which characteristic of a neural response carries more information?

 Considering a variety of quite different candidate neural codes, Cheng and Wasserman [(1996) Biol Cybern 75, 93–103, 105–115] reported data which suggested that amplitude codes transmitted information more faithfully than temporal codes. Reanalyzing their data, the present study measured how well size and time represented information resident within the same neural response feature, namely the response peak. Responses from photoreceptor cells and optic nerve fibers in the peripheral visual system of Limulus polyphemus were therefore re-examined using signal detectability values provided by receiver-operating-characteristic analyses to compare how well the timing and the amplitude of the response peak represent information within a single cell and how well they transmit information between cells. Data were available for several cells in several different light-adaptation states onto which several different test-flash intensities had been superimposed. The present reanalysis of these data replicated the results yielded earlier by the peak candidate code, and compared them with the data produced by two different measurements of the timing of the same response peak. A relative-timing code was derived from measurements of the time that elapsed between the moment when the response exceeded a criterion potential and when it reached its peak. An absolute-timing code was derived from the time that elapsed between test flash onset and the peak. The results clearly indicated that the peak code represented information within cells better than either of the two timing codes. However, both peak and absolute-timing codes clearly transmitted the available information between cells more faithfully than the relative-timing code. These data lead to two conclusions. First, that the same response feature, when measured in different ways, can produce remarkably different information processing outcomes. In this particular case, time represented information resident within a cell less well than did size. Second, that the fidelity of information transmission between nerve cells may be relatively independent of the quantity of information resident within any particular cell. Received: 5 November 2001 / Accepted in revised form: 8 July 2002 Acknowledgements. We are deeply indebted to Huiqi Yin for her technical assistance with all the calculations and the graphics. We also sincerely thank Tony Hosking, who wrote the computer programs that extracted the code data for this project, and Brendan Marr, who assisted with data analysis. Correspondence to: G.S. Wasserman (e-mail: codelab@purdue.edu, Fax: +1-765-4961264)     

Evaluation of cystic salivary gland lesions by fine needle aspiration: an analysis of 21 cases

OBJECTIVE: To analyze the potential sources of diagnostic errors and overall accuracy rate of the fine needle aspiration biopsy (FNAB) diagnosis of cystic salivary gland neoplasms. STUDY DESIGN: A 10-year (1993-2002) retrospective review of the cytopathology slides from the Division of Cytopathology, Department of Pathology, Long Island Jewish Medical Center, New Hyde Park, New York, identified a total of 97 consecutive salivary gland FNAB cases that microscopically were interpreted as representing cystic lesions. Of these, 21 cases had histologic follow-up at our institution. RESULTS: A correct diagnosis was rendered by FNAB in 15 of 21 (72%) cases. This included 9 Warthin's tumors, 2 mucoepidermoid carcinomas, 2 simple cysts, 1 cystadenoma and 1 abscess. Clinically insignificant discrepancies were identified in 3 of 21 (14%) FNABs. Clinically significant misdiagnoses were identified in a further 3 of 21 (14%) cases. CONCLUSION: A systematic approach to the diagnosis of cystic salivary gland lesions by FNAB can result in a correct diagnosis in > 70% of cases. Careful attention should be directed at identifying the extracellular fluid components present (mucoid vs. watery proteinaceous) as well as the predominant cellular component (e.g., lymphocytes, histiocytes, epithelial cells and oncocytes). It is important to recognize, however, that occasionally epithelial cells may not be detected on FNAB of cystic salivary gland lesions, as a result of either cellular dilution by cystfluid or inadequate sampling. Regardless, with all FNABs tentatively diagnosed as a mucinous cystic lesion, the referring clinician should be informed that a low grade mucoepidermoid carcinoma cannot be ruled out.