Chronic cough and pain: Janus faces in sensory neurobiology?

Both chronic cough and chronic pain are critical clinical issues in which a large number of patients remain unsatisfied with available treatments. These conditions have considerable effects on sufferers' quality of life, who often show co-morbidities such as anxiety and depression. There is therefore a pressing need to find new effective therapies. The basic neurobiological mechanisms and pathologies of these two conditions show substantial homologies. However, whilst chronic pain has received a great deal of attention over the last few decades, the same cannot be said for the neurological underpinnings of chronic cough. There is a substantial literature around mechanisms of chronic pain which is likely to be useful in advancing knowledge about the pathologies of chronic cough. Here we compare the basic pain and cough pathways, in addition to the clinical features and possible pathophysiologies of each; including mechanisms of peripheral and central sensitisation which may underlie symptoms such as hyperalgesia and allodynia, and hypertussitvity and allotussivity. Due to the substantial overlap that emerges, it is likely that therapies may be effective over both areas.     

CD4 + Th1-cells Predominate in Low-grade B-Cell Lymphoma of Gastric Mucosa-associated Lymphoid Tissue (MALT type)

Background: Little is known about the function of T cells in the inflammatory infiltrate in Helicobacter pylori -associated gastritis and B-cell lymphoma of mucosa-associated lymphoid tissue (MALT type). Previous studies have proposed a dominant Th1-type response in low-grade MALT lymphoma consistent with the Th1 response observed in H. pylori -associated gastritis. Methods: We performed a novel flow cytometric approach in which CD3 panning for enrichment and activation of small numbers of T cells and intracellular cytokine analysis were combined to selectively characterize the cytokine profile of T cells (IFN- &#110 for Th1) derived from the gastric mucosa of 23 patients with low-grade MALT lymphoma stage IEI 1 (lymphoma infiltration of mucosa/submucosa sparing the muscularis). Endosonography was performed in each case to control the depth of lymphoma infiltration. For comparison, 19 patients with H. pylori -positive gastritis were also analysed. Results: There was a CD4/CD8 ratio of 4 in patients with MALT lymphoma and of 2 in chronic gastritis. The proportion of IFN- &#110 producing cells within the CD4- positive T-cell population in MALT lymphoma was 22%; in chronic gastritis it was 13% while no such difference could be encountered in CD8-positive T cells. Conclusions: The data point towards a dominant intratumoral IFN- &#110 dominated T-cell response associated with early low-grade MALT lymphoma. A polarized IFN- &#110 dominated Th1-type response may either contribute to the inability of the immune system to eradicate H. pylori infection, thereby promoting the activation status of the lymphocytic infiltrate in low-grade MALT lymphoma, or may mirror a concomitant tumor-specific T-cell response accompanying early stages of tumor progression.     

Perception of Risk for Subsequent Drinking and Driving Related Offenses and Locus of Control among First-Time DUI Offenders

It is estimated that approximately one third of first-time driving-under-the-influence (DUI) offenders are at risk for committing a subsequent offense. To reduce the risk of recidivism, most states require mandatory screening and counseling of convicted DUI offenders. Unfortunately, the majority of offenders are not receptive to either screening or recommendations for further interventions designed to reduce their level of risk. The current study examines the relationship between locus of control and receptivity to risk status. To test this hypothesis, both the Rotter Internal-External Locus of Control Scale (I-E) and the Drinking Related Internal-External Locus of Control Scale (DRIE) were administered to a group of convicted first DUI offenders. The results indicate that the offenders manifesting a more internal locus of control were more receptive to risk information compared to their external locus of control counterparts. Important clinical implications of these findings are discussed.     

Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes

Aims/hypothesis Insulin hypersecretion may be an independent predictor of progression to type 2 diabetes. Identifying genes affecting insulin hypersecretion are important in understanding disease progression. We have previously shown that diabetes-susceptible DBA/2 mice congenitally display high insulin secretion. We studied this model to map and identify the gene(s) responsible for this trait. Methods Intravenous glucose tolerance tests followed by a genome-wide scan were performed on 171 (C57BL/6 × DBA/2) × C57BL/6 backcross mice. Results A quantitative trait locus, designated hyperinsulin production-1 (Hip1), was mapped with a logarithm of odds score of 7.7 to a region on chromosome 13. Production of congenic mice confirmed that Hip1 influenced the insulin hypersecretion trait. By studying appropriate recombinant inbred mouse strains, the Hip1 locus was further localised to a 2 Mb interval, which contained only nine genes. Expression analysis showed that the only gene differentially expressed in islets isolated from the parental strains was Nnt, which encodes the mitochondrial proton pump, nicotinamide nucleotide transhydrogenase (NNT). We also found in five mouse strains a positive correlation (r ²  = 0.90, p < 0.01) between NNT activity and first-phase insulin secretion, emphasising the importance of this enzyme in beta cell function. Furthermore, of these five strains, only those with high NNT activity are known to exhibit severe diabetes after becoming obese. Conclusions/interpretation Insulin hypersecretion is associated with increased Nnt expression. We suggest that NNT must play an important role in beta cell function and that its effect on the high insulin secretory capacity of the DBA/2 mouse may predispose beta cells of these mice to failure. G. Morahan and S. Andrikopoulos contributed equally to this study.     

Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFE-hemochromatosis modifier gene

BACKGROUND & AIMS: Genetic hemochromatosis is one of the most common genetic disorders, with progressive tissue iron overload leading to severe clinical complications. In Northern European populations, genetic hemochromatosis is usually caused by homozygosity for the C282Y mutation in the HFE protein. However, penetrance of this mutation is incomplete, suggesting that other genetic and environmental factors contribute to its differential biologic or clinical expression. METHODS: To identify genes modifying iron homeostasis, we screened the 27 recombinant congenic strains of the C3H/DiSnA-C57BL/10ScSnA/Dem series for tissue and serum iron indices and genotyped 18 microsatellite markers in (C3H/DiSnA x HcB-2) F2 hybrid mice. RESULTS: We identified 1 locus encompassing the Ceruloplasmin (Cp) gene with a strong linkage with liver iron, serum iron, and transferrin levels but not with spleen iron. Sequencing of Cp showed an R435X nonsense mutation in exon 7 in C3H/DiSnA mice. To evaluate whether Cp might act as a modifier gene of genetic hemochromatosis, we intercrossed C3H Hfe(-/-) and C3HDiSnA Cp(R435X/R435X) mice. As expected, we found that double-mutant mice deposited more iron in the liver than mice defective for either one or both genes. In contrast, Hfe(-/-) x Cp(R435/R435X) or Cp(R435X/R435X) x Hfe(+/-) showed 30% decrease in liver iron when compared with single mutant mice. CONCLUSIONS: This study highlights the existence of complex interactions between Cp and HFE and represents the first example of a modifier gene with a protective effect, in which heterozygosity reduces the iron load in the context of HFE deficiency.     

中国南方四省区流行的HIV-1 CRF01_AE病毒株基因特征研究

目的 分析中周南方四省区HIV-1感染者中流行CRF01 AE病毒株的遗传特征.方法 从广东、广西、江西和湖南省(自治区)2006年新报告HIV-1感染者的血浆样本中提取病毒RNA,用反转录/巢式PCR方法扩增gag和env基因片段,对获得的CRF01 AE病毒株核酸序列进行系统进化分析,并通过计算基因距离和Entropy核苷酸多态性差异方法分析毒株的遗传特征.结果 从210例CRF01_AE病毒株感染者中,发现四省区流行的CRF01 AE病毒株存在2个主要的流行簇.流行簇Ⅰ共有123例样本,未发现与之直接相关的国际参考毒株.流行簇Ⅱ共有57例样本,与越南CRF01 AE病毒株关系密切,且存在不同时间样本的混杂.gag和env基因遗传距离分析结果表明,流行簇Ⅰ内基因遗传多样性均明显小于流行簇Ⅱ;核苷酸多态性分析结果显示,在gag基因片段42个位点核苷酸组成具有显著差异,env基因片段40个位点核苷酸组成存在显著差异;流行簇Ⅰ相对于流行簇Ⅱ多态性减少的位点上有61个,多态性增加的位点有21个.结论 在中国南方四省区流行的CRF01 AE病毒株中首次观察到2个独立的流行簇.流行簇Ⅰ病毒株为该地区最主要的CRF01 AE病毒株,其流行时间相对较短,在人群中所占比例较多,可能是病毒在流行过程中形成的具有传播优势的病毒株.流行簇Ⅱ病毒与来自于越南的CRF01 AE病毒株有较高同源性,且存在与越南病毒株间的多次传播.     

静脉注射肾上腺素引起的瞬时血压升高对大鼠颈动脉体IL-1β和TH表达的影响

目的：探讨反复瞬时血压升高对大鼠颈动脉体中IL-1β和酪氨酸羟化酶（TH）表达的影响.方法：雄性大鼠8只,随机分为肾上腺素组和对照组.肾上腺素组通过每日1次、连续1wk的尾静脉注射20μg/kg肾上腺素造成动物反复瞬时血压升高,采用免疫组织化学和图像分析方法观察瞬时血压升高对大鼠颈动脉体中IL-1β和TH表达的影响.结果：与对照组相比,实验组颈动脉体中IL-1β与TH表达均上调（P〈0.05）.结论：反复瞬时血压升高可引起颈动脉体中IL-1β与TH表达增加,有可能会影响颈动脉体化学感受的敏感性.     

Alteration of xenobiotic metabolizing enzymes by resveratrol in liver and lung of CD1 mice

Conflicting data on the anticancer properties of the polyphenolic natural product resveratrol (RSV) have been reported. Since the inhibition of “bioactivating” Phase-I xenobiotic metabolizing enzymes (XMEs) and/or induction of “detoxifying” Phase-II XMEs have long been considered important cancer chemopreventive strategies, in the current study we investigated the effect of RSV treatment on several Cytochrome P450 (CYP)-dependent oxidations and Phase-II markers in liver and lung subcellular preparations from CD1 male mice. These mice were i.p treated with RSV (25 or 50 mg/Kg b.w.) daily for one or for seven consecutive days. Using either specific probes for different CYPs, or the regio- and stereo-selective metabolism of testosterone, we found that most of the Phase-I XMEs were significantly suppressed (up to ∼61% loss for the CYP3A1/2-linked 6 β-hydroxylation of testosterone in liver and up to ∼97% loss for 2 α-hydroxylase in lung) following RSV treatment for 7 days at 50 mg/kg b.w. Glutathione S-transferase was significantly inhibited, particularly in lung (∼76% loss of activity) after single administration of 25 mg/kg b.w. A different response for the UDP-glucuronosyl transferase was observed, where a significant induction was seen (∼83%) in the liver and a significant reduction was observed in the lung (up to ∼83% loss) following treatment with 25 mg/kg b.w. for seven days. These data indicate that murine XMEs are altered by RSV, and that this alteration is dependent on the RSV dose, duration and way of administration. These results could provide mechanistic explanations for the conflicting chemopreventive results reported for RSV.     

Phylodynamic analysis of the dissemination of HIV-1 CRF01_AE in Vietnam

To estimate the epidemic history of HIV-1 CRF01_AE in Vietnam and adjacent Guangxi, China, we determined near full-length nucleotide sequences of CRF01_AE from a total of 33 specimens collected in 1997-1998 from different geographic regions and risk populations in Vietnam. Phylogenetic and Bayesian molecular clock analyses were performed to estimate the date of origin of CRF01_AE lineages. Our study reconstructs the timescale of CRF01_AE expansion in Vietnam and neighboring regions and suggests that the series of CRF01_AE epidemics in Vietnam arose by the sequential introduction of founder strains into new locations and risk groups. CRF01_AE appears to have been present among heterosexuals in South-Vietnam for more than a decade prior to its epidemic spread in the early 1990s. In the late 1980s, the virus spread to IDUs in Southern Vietnam and subsequently in the mid-1990s to IDUs further north. Our results indicate the northward dissemination of CRF01_AE during this time.