DRB1*15 and DRB1*03 extended haplotype interaction in primary Sj?gren's syndrome genetic susceptibility

OBJECTIVE: Sj?gren's syndrome (SS) is a chronic autoimmune disease with a genetic component. Among the genetic factors, the role of HLA class II genes has been suggested and a positive association with DRB1*03 allele has been described. However, there is no consensus on a unique HLA locus for this disease nor on the role of the HLA gene product in the disease. The aim of this study was to analyse prospectively MHC region involvement in the genetic susceptibility to SS by studying DRB1, DQB1, DPB1, TAP1, TAP2 genes and TNF microsatellites in a population of 45 primary SS patients. METHODS: All the polymorphisms studied were analysed at the genomic level using PCR-based methodologies. RESULTS: Concerning HLA class II alleles, the highest relative risk to develop the disease was associated with the DRB1*15-DRB1*0301 heterozygous genotype (17.8% vs 3.5% in controls - pc < 0.005, OR = 5.96). Analysing other genes located on the same region allowed us to further determine the DRB1 haplotypes at risk. For instance, the DRB1*0301 haplotype involved in the genetic susceptibility to SS was more often associated with the DPB1* 0201 and TNF-a2 alleles in SS patients than in controls. Moreover, all the DRB1*15-DRB1*0301 SS patients were TAP1-0101, TAP2-0101 homozygous, allowing us to deduce the extended genotype at risk as DRB1*15, TAP1-0101, TAP2-0101/DRB1*0301, TAP1-0101, TAP2-0101 which was carried by only 3 controls out of the 130 tested (p < 0.01, OR = 6.68). CONCLUSION: This study confirmed the role of the MHC region in the susceptibility to Sj?gren's disease, and for the first time suggests a synergistic interaction between two HLA-DRB1 extended haplotypes in the genetic mechanisms controlling the disease.     

Contribution of DRB1*04 variants to predisposition to or protection from insulin dependent diabetes mellitus is independent of dq

Certain DQ alpha/beta dimeric molecules have been shown to play a major role in determining susceptibility or resistance to IDDM. Whether or not predisposition associated with DR4 haplotypes is exclusively due to linkage to DQB1*0302 and DQA1*0301 alleles is still a controversial issue. A modifying effect of certain DRB1*04 subtypes on the susceptibility encoded by DQ alleles is possible, since not all DRB1*04-DQB1*0302 haplotypes are associated with the disease. The distribution of DRB1*04 subtypes was analysed in 240 DR4-positive Caucasian IDDM patients and 110 DR4-positive healthy controls using allele-specific hybridization after genomic amplification. Although an important contribution to IDDM predisposition was encoded by the DQB1*0302 allele which was found in the majority of patients (94.2% vs 64.7% in controls, Odd's ratio OR = 8.8, P < 0.0001), differences between DRB1*04 variants persisted after the effect of the DQB1 locus was removed by matching patients and controls for DQB1*0302. Thus, the DRB1*0402 allele conferred a strong IDDM-predisposing effect (OR = 3.1, P < 0.02) which was highly significant in the absence of DR3 on the second haplotype (OR = 5.6, P < 0.0001) but was not visible among DR3/4 heterozygote individuals. Conversely, the DRB1*0404 allele conferred a strong protective effect (OR = 0.26, P < 0.0001) which was dominant even in the presence of the associated high risk DR3 haplotype (OR = 0.21, P < 0.03). These data indicate that DQ molecules are not the sole contributors to the DR4-associated IDDM predisposition, and that peculiar DR4 subtypes play a significant role in susceptibility to or protection from the disease. DRB1*0402 differs from DRB1*0404 by only two acidic residues at positions 70 and 71 within the peptide binding groove, instead of amide and basic amino acids. This might induce changes of peptide binding specificity that correlate with the genetic linkage of IDDM predisposition.     

Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation

Hereditary non-polyposis colorectal cancer (HNPCC) is characterised by a genetic predisposition to develop colorectal cancer at an early age and, to a lesser degree, cancer of the endometrium, ovaries, urinary tract, and organs of the gastrointestinal tract other than the colon. In the majority of families the disease is linked to mutations in one of the two mismatch repair genes, hMSH2 or hMLH1. We have found a novel hMLH1 nonsense mutation in a Swiss family with Lynch syndrome, which has been transmitted through at least nine generations. A different tumour spectrum of neoplasms of the skin, soft palate, breast, duodenum, and pancreas was observed in three branches of this family, where there was a virtual absence of colonic tumours. The hMLH1 mutation could not be detected in members of these branches suggesting that at least a second genetic defect predisposing to cancer is segregating in part of the kindred.     

An heuristic model for the inherited predisposition to alcoholism.

Presents a research program for studying individuals genetically at high risk for alcoholism. Data from multigenerational nonproblem-drinking sons of male alcoholics indicate that the sons display a pattern of autonomic hyperreactivity to a variety of stimuli. This pattern of reactivity is significantly dampened by high doses of alcohol. These individuals also display difficulty on cognitive tests suggestive of prefrontal lobe dysfunction. This response pattern is not characteristic of controls nor of daughters of multigenerational male alcoholics. A model is presented that hypothesizes a cognitive disturbance underlying the hyperreactivity and posits a problem in the attribution of meaning to novel stimuli and threatening events. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Human leukocyte antigen A1-B8-DR3-DQ2-DPB1*0401 extended haplotype in autoimmune hepatitis

Genetic susceptibility to autoimmune hepatitis is associated with the human leukocyte antigen haplotype A1-B8-DR3 and DR4. To date, only one study in Japan has considered the human leukocyte antigen DP locus in this disease, and no studies have been reported in whites. In this study we used a series of sequence-specific oligonucleotide probes to determine human leukocyte antigen DPB1 genotypes in 101 unrelated white northern European patients and 105 racially and geographically matched controls. The aims of the study were twofold: first, to determine the degree of DPB-encoded susceptibility to autoimmune hepatitis, and, second, to establish whether susceptibility can be extended to include human leukocyte antigen DPB. None of 17 DPB1 alleles was significantly associated with the susceptibility to autoimmune hepatitis. Although one particular seven-locus haplotype A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201-++ +DPB1*0401 was significantly associated with the disease (27% vs. 7%, relative risk = 5.14, p < 0.0005), the association with this haplotype was weaker than that for the six-locus haplotype excluding DPB (40% vs. 11%, RR = 5.52, p < 0.0005). When the patients first seen at ages younger than 16 yr (pediatric patients) were considered separately, the greatest relative risk was for the seven-locus haplotype (41% vs. 7%; relative risk = 9.60, p < 0.0005). The results of this study further confirm that major histocompatibility complex-encoded susceptibility to autoimmune hepatitis is located at or close to the human leukocyte antigen DR locus; however, the A1-B8-DR3-DQ2-DPB1*0401 extended haplotype may be important in determining the age of onset and severity of disease.     

Paraventricular hypothalamic clonidine increases rather than decreases susceptibility to activity-based anorexia in the rat.

Anorexia has been related to reduced activity of the paraventricular hypothalamic (PVN) noradrenergic-feeding system. This study attempted to determine whether clonidine (an α2-adrenergic agonist) infused into the PVN reduced susceptibility to activity-based anorexia (ABA) in the rat. In Exp 1, clonidine (6 doses) was chronically infused into the PVN of male Sprague-Dawley rats. All animals were exposed to ABA (1.5 hrs/day food access; 22.5 hrs/day running wheel access) until a 25% body weight loss was reached. Dose-related increases in susceptibility to ABA and decreases in food intake were observed. In Exp 2, for which heavier animals and 3 doses of clonidine were used, no difference was found in food intake and wheel activity, but there was increased susceptibility to ABA. Chronic clonidine infused into the PVN does not produce hyperphagia and exacerbates rather than attenuates susceptibility to ABA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hydroxide rather than histidine is coordinated to the heme in five-coordinate ferric Scapharca inaequivalvis hemoglobin

The ferric form of the homodimeric Scapharca hemoglobin undergoes a pH-dependent spin transition of the heme iron. The transition can also be modulated by the presence of salt. From our earlier studies it was shown that three distinct species are populated in the pH range 6-9. At acidic pH, a low-spin six-coordinate structure predominates. At neutral and at alkaline pHs, in addition to a small population of a hexacoordinate high-spin species, a pentacoordinate species is significantly populated. Isotope difference spectra clearly show that the heme group in the latter species has a hydroxide ligand and thereby is not coordinated by the proximal histidine. The stretching frequency of the Fe-OH moiety is 578 cm-1 and shifts to 553 cm-1 in H218O, as would be expected for a Fe-OH unit. On the other hand, the ferrous form of the protein shows substantial stability over a wide pH range. These observations suggest that Scapharca hemoglobin has a unique heme structure that undergoes substantial redox-dependent rearrangements that stabilize the Fe-proximal histidine bond in the functional deoxy form of the protein but not in the ferric form.     

HLA class II associations in juvenile Graves' disease: indication of a strong protective role of the DRB1*0701,DQA1*0201 haplotype

Previous studies have shown that HLA-DRB1*0301 and DQA1*0501 are associated with susceptibility to Graves' disease. Ninety Danish patients with early onset of Graves' disease and 102-192 controls were analyzed for HLA-DR and -DQ to investigate if the same associations exist in the juvenile form of Graves' disease. Both DRB1*0301 and DQA1*0501 were highly significantly increased in the patients with relative risks of 8.0 and 4.6, which are higher than those seen in adults. Stratification showed that DRB1*0301 is more strongly associated than DQA1*0501. Surprisingly, the DRB1*0701,DQA1*0201 haplotype was completely absent from this group of patients, indicating a strong protective role of this haplotype in juvenile Graves' disease.     

I'd rather have a baby than root canal, or how to treat the fearful patient

I have tried to enumerate the ways that can be used to communicate with the apprehensive patient in order to dispel the myths and allay the fears of root canal therapy. The categories discussed were communication, local anesthesia, nitrous oxide analgesia, pre-visit sedation and i.v. sedation. Some or all of these disciplines can be used depending on the situation.     

Looking to science rather than convention in adjusting IQ scores when death is at issue.

The progressive obsolescence of IQ test norms and associated score inflation (i.e., the Flynn effect) may have literal life and death significance in capital mental retardation determinations (i.e., Atkins hearings). Hagan, Drogin, and Guilmette (2008) asserted that IQ score corrections for the Flynn effect were inconsistent with a “standard of practice” they deduced from custom, convention, and authority. More accurately, this reflected a proposed practice guideline or recommendation for practice, rather than a standard of practice. Whether a proposed guideline or recommendation for practice, these are better informed by an analysis of the available science than accepted convention. The authors reviewed research findings regarding the occurrence of the Flynn effect in the “zone of ambiguity” (IQ = 71–80), and proposed a best practice recommendation for discussing and reporting Flynn effect correction of IQ scores in capital mental retardation determinations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Beta3-integrins rather than beta1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration

BACKGROUND: Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin-extracellular matrix interactions are essential for cell migration. SMCs express both beta1- and beta3-integrins. In this study, we examined the relative functional roles of beta1- and beta3-integrin-matrix interactions in postinjury SMC migration. METHODS AND RESULTS: Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-beta1 and anti-alpha(v)beta3/5 antibodies (Abs) revealed expression of both beta1- and beta3-integrins, with beta1 observed as linear streaks and beta3 found in focal contacts. In a scrape-wound migration assay, anti-beta1 Abs (92.0+/-10.7% of control, P=.1) and 0.5 mmol/L linear RGD (105+/-5% of control, P=.2) did not alter SMC migration at 48 hours after injury. Beta3-blockade, however, via Abs (anti-beta3/5 35.7+/-4.5% of control, anti-beta3 61+/-12% of control, both P<.001) and cyclic RGD (0.5 mmol/L) (12+/-10% of control, P<.001) decreased migration. Neither beta1- nor beta3-inhibition altered postinjury [3H]thymidine incorporation. In the rat carotid injury model, local adventitial polymer-based delivery of radiolabeled linear or cyclic RGD led to uptake and retention of label, for both peptides, over a 72-hour period after injury. Local arterial wall beta1-blockade via polymer-based delivery of linear RGD had no effect on SMC migration at 4.5 days (11.5+/-3.2 versus 12.8 SMCs per x600 field [control], P=.6) or on neointimal thickening at 14 days (I/M area ratio, 0.664+/-0.328 versus 1.179+/-0.324 [control], P=.6) after injury. In contrast, local beta3-blockade via cRGD limited migration (0.8+/-0.8 versus 12.8+/-4.4 SMCs per x600 field [control], P<.01) and thickening (I/M area ratio, 0.004+/-0.008 versus 1.179+/-0.324 [control], P<.01). CONCLUSIONS: In postinjury migrating SMCs, beta3- rather than beta1-integrin-matrix interactions are of greater functional significance in adhesive processes essential for SMC migration in vitro and in vivo. Blockade of dominant SMC integrin (beta3)-matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.     

浅谈西门子6 RA70系列直流调速装置及应用

韶钢炼轧厂主轧线设备,通过技术改造,把原有的主传动模拟电控直流调速装置改用西门子6RA7系列全数字直流调速装置,取得了成功．文章简单介绍了6RA70系列全数字直流调速装置的特点,外部回路的接线端子功能,简易的基本操作和调试方法．     

Managing drug reactions to sulfonamides and other drugs in HIV infection: desensitization rather than rechallenge?

Drug reactions in patients with HIV infection, e.g. fever or rash, are a frequently occurring clinical problem. These side effects particularly are observed with sulfonamides; however, many other drugs have also shown to induce allergic reactions when given to patients with HIV infection. The production of hydroxylamines has been put forward as one of the explanations for these high incidence of reactions on drugs. Since sulfonamides are the first choice of therapy for the treatment and prophylaxis of Pneumocystis carinii pneumonia, several strategies have been developed to circumvent drug reactions. In general rechallenge or desensitization are recommended in literature. This article discusses the results and risks of rechallenge and desensitization with sulfonamides or other drugs, as mentioned in the literature. Furthermore preliminary results of rechallenge with a sulfonamide, which is not metabolized into hydroxylamines, are presented. From the data in the literature it is concluded that desensitization should be preferred to rechallenge.     

An argument against dual valuation system competition: Cognitive capacities supporting future orientation mediate rather than compete with visceral motivations.

The dynamic inconsistency of preference is well documented in behavioral research, but its basis remains controversial. In this article, the authors summarize recent functional MRI (fMRI) work in the domain of intertemporal choice, specifically considering evidence bearing on the hypothesis that delay discounting in humans is determined by competition between an evolutionarily older system that discounts precipitously with delay (System 1) and a newer system that exhibits very little discounting (System 2). The authors argue that neuroimaging evidence does not support the hypothesized separate and competing value systems. While it is clear that the sophisticated cognitive capacities that lead to greater valuation of larger later alternatives (e.g., selective attention and self-signaling) depend critically on neocortical structures, these capacities affect intertemporal choice through mediation of (rather than competition with) older cortical and subcortical structures central to reward and motivation. Taken together, neuroimaging evidence supports the alternative hypothesis that intertemporal choice is guided by a single valuation system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains

The covalent rejoining of DNA ends at single-stranded or double-stranded DNA breaks is catalyzed by DNA ligases. Four DNA ligase activities (I-IV) have been identified in mammalian cells [1]. It has recently been demonstrated that DNA ligase IV interacts with and is catalytically stimulated by the XRCC4 protein [2,3], which is essential for DNA double-strand break repair and the genomic rearrangement process of V(D)J recombination [4]. Together with the finding that the yeast DNA ligase IV homologue is essential for nonhomologous DNA end joining [5-7], this has led to the hypothesis that mammalian DNA ligase IV catalyzes ligation steps in both of these processes [8]. DNA ligase IV is characterized by a unique carboxy-terminal tail comprising two BRCT (BRCA1 carboxyl terminus) domains. BRCT domains were initially identified in the breast cancer susceptibility protein BRCA1 [9], but are also found in other DNA repair proteins [10]. It has been suggested that DNA ligase IV associates with XRCC4 via its tandem BRCT domains and that this may be a general model for protein-protein interactions between DNA repair proteins [3]. We have performed a detailed deletional analysis of DNA ligase IV to define its XRCC4-binding domain and to characterize regions essential for its catalytic activity. We find that a region in the carboxy-terminal tail of DNA ligase IV located between rather than within BRCT domains is necessary and sufficient to confer binding to XRCC4. The catalytic activity of DNA ligase IV is affected by mutations within the first two-thirds of the protein including a 67 amino-acid amino-terminal region that was previously thought not to be present in human DNA ligase IV [11].