Anti-GQ1b antibody syndrome: anti-ganglioside complex reactivity determines clinical spectrum.

BACKGROUND AND PURPOSE: Anti-GQ1b antibodies have been found in patients with Miller Fisher syndrome as well as its related conditions. Our aim was to identify the mechanism by which autoantibodies produce various clinical presentations in 'anti-GQ1b antibody syndrome'. METHODS: Immunoglobulin G antibodies to ganglioside complex (GSC) of GQ1b or GT1a with GM1, GD1a, GD1b or GT1b were tested in sera from patients with anti-GQ1b (n = 708) or anti-GT1a (n = 696) IgG antibodies. Optical densities of the single anti-GQ1b or anti-GT1a antibodies were used as reference (100%), and those of anti-GSC antibodies were expressed in percentages to reference. The relationships between anti-GSC antibody reactivity and the corresponding clinical features were assessed by multivariate logistic regression analysis. RESULTS: Ophthalmoplegia and hypersomnolence were significantly associated with complex-attenuated anti-GQ1b and anti-GT1a antibodies. Ataxia was associated with GD1b- and GT1b-enhanced anti-GQ1b antibodies or GM1-enhanced anti-GT1a antibodies. Bulbar palsy was associated with GT1b-enhanced anti-GQ1b antibodies. Neck weakness was associated with GD1a-enhanced anti-GQ1b antibodies. Arm weakness was associated with GD1b-enhanced anti-GQ1b and GD1a-enhanced anti-GT1a antibodies. Leg weakness was associated with GD1a-enhanced anti-GQ1b and anti-GT1a antibodies. CONCLUSIONS: Differences in fine specificity of anti-GQ1b antibodies are associated with clinical features, possibly due to the different expression of gangliosides in different parts of the nervous system.

Complete Genome Sequence of Staphylococcus arlettae AHKW2e, Isolated from a Dog's Paws in Hong Kong.

Staphylococcus arlettae is commonly found on the skin of animals. Here, we describe the complete genome sequence of S. arlettae AHKW2e (2,649,260 bp; GC content, 33.6%), isolated from a dog's paws in Hong Kong, established through hybrid assembly and representing the second complete genome sequence of this species.

Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex.

OBJECTIVE: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. METHODS: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. RESULTS: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. CONCLUSIONS: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SIGNIFICANCE: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.

Influence of country of study on student responsiveness to the H1N1 pandemic.

OBJECTIVES: University students, both travelling abroad on holiday or exchange students entering a country, can serve as mobile carriers of infectious diseases during a pandemic, and thus require special attention when considering preventive measures. The objectives of this study were to evaluate student compliance and opinions on preventive measures of a university before and during an H1N1 influenza pandemic, and to explore environmental and behavioural factors that might contribute towards compliance. STUDY DESIGN: Cross-sectional, self-administered questionnaire. METHODS: Local and foreign students attending an international summer school programme were invited to participate in a self-administered survey. RESULTS: Respondents complied with most of the preventive measures, excluding website viewing and mask wearing. Significant differences in compliance and perceived necessity were found amongst students from Singapore, Hong Kong and the USA. Singaporean students were significantly more likely to comply with all measures and consume antiviral medication in response to the pandemic than students studying in the US. CONCLUSIONS: Students' responses towards university pandemic measures were largely positive, but sensitivity towards these measures varied between groups by country of study. This should be considered in further comparative studies.

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers.

Promoter CpG methylation of tumour suppressor genes (TSGs) is an epigenetic biomarker for TSG identification and molecular diagnosis. We screened genome wide for novel methylated genes through methylation subtraction of a genetic demethylation model of colon cancer (double knockout of DNMT1 and DNMT3B in HCT116) and identified DLEC1 (Deleted in lung and oesophageal cancer 1), a major 3p22.3 TSG, as one of the methylated targets. We further found that DLEC1 was downregulated or silenced in most colorectal and gastric cell lines due to promoter methylation, whereas broadly expressed in normal tissues including colon and stomach, and unmethylated in expressing cell lines and immortalised normal colon epithelial cells. DLEC1 expression was reactivated through pharmacologic or genetic demethylation, indicating a DNMT1/DNMT3B-mediated methylation silencing. Aberrant methylation was further detected in primary colorectal (10 out of 34, 29%) and gastric tumours (30 out of 89, 34%), but seldom in paired normal colon (0 out of 17) and gastric (1 out of 20, 5%) samples. No correlation between DLEC1 methylation and clinical parameters of gastric cancers was found. Ectopic expression of DLEC1 in silenced HCT116 and MKN45 cells strongly inhibited their clonogenicity. Thus, DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.

LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis.

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.

Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53.

The tumor suppressor p53 plays a key role in inducing G1 arrest and apoptosis following DNA damage. The double-stranded-RNA-activated protein PKR is a serine/threonine interferon (IFN)-inducible kinase which plays an important role in regulation of gene expression at both transcriptional and translational levels. Since a cross talk between IFN-inducible proteins and p53 had already been established, we investigated whether and how p53 function was modulated by PKR. We analyzed p53 function in several cell lines derived from PKR+/+ and PKR-/- mouse embryonic fibroblasts (MEFs) after transfection with the temperature-sensitive (ts) mutant of mouse p53 [p53(Val135)]. Here we report that transactivation of transcription by p53 and G0/G1 arrest were impaired in PKR-/- cells upon conditions that ts p53 acquired a wild-type conformation. Phosphorylation of mouse p53 on Ser18 was defective in PKR-/- cells, consistent with an impaired transcriptional induction of the p53-inducible genes encoding p21(WAF/Cip1) and Mdm2. In addition, Ser18 phosphorylation and transcriptional activation by mouse p53 were diminished in PKR-/- cells after DNA damage induced by the anticancer drug adriamycin or gamma radiation but not by UV radiation. Furthermore, the specific phosphatidylinositol-3 (PI-3) kinase inhibitor LY294002 inhibited the induction of phosphorylation of Ser18 of p53 by adriamycin to a higher degree in PKR+/+ cells than in PKR-/- cells. These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation, possibly through a PI-3 kinase pathway.

Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse.

Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia.

The interaction between TPH2 promoter haplotypes and clinical-demographic risk factors in suicide victims with major psychoses.

Tryptophan hydroxylase isoform 2 (TPH2) is a rate-limiting enzyme in the biosynthesis of serotonin (5-HT) and is predominantly localized in the brain. Previous studies have suggested that there is an association between serotonergic dysfunction in the brain and suicidality. This study was designed to examine whether the -473T > A and -8396G > C polymorphisms of the TPH2 gene may be associated with completed suicide in subjects with major psychoses from the Stanley Foundation Brain Bank sample. TPH2 genotypes were determined in 69 subjects with a diagnosis of schizophrenia or bipolar disorder, among which 22 died by suicide. Genomic DNA was amplified by polymerase chain reaction and typed by automated methods. Both markers were found to be in Hardy-Weinberg equilibrium and in strong linkage disequilibrium. No association with history of suicide was found for either polymorphism. Haplotype analysis with EHAP showed no association between completed suicide and haplotype distribution (chi2 = 1.877; 3 df; P = 0.598). Nor was there any association between suicide and these genetic markers even when clinical-demographic factors were considered as covariates in the haplotype analysis. These findings suggest that these 5' marker haplotypes in the TPH2 gene do not influence suicidal behaviour.

Comparison of cellular immunotherapies and anti-CD3 in the treatment of MCA-38-LD experimental hepatic metastases in C57BL/6 mice.

An experimental model of hepatic metastases in C57BL/6 mice was used to compare the antitumor effects of lymphokine-activated killer (LAK) cells, anti-CD3-activated T-cells (ATC), and anti-CD3 alone. Liver metastases were produced by in vivo passage of MCA-38-LD adenocarcinoma via the ileocolic vein. LAK cells and ATC were generated by 3-day in vitro incubation of spleen cells in interleukin 2 and anti-CD3, respectively. Percentage of tumor volume in livers was determined with a morphometric technique. With less than therapeutic LAK cell doses (0.5-1.0 x 10(7) cells), no effect was seen in mean (+SE, -SE) percentage of tumor volume of control [23.3 (29.3, 18.5)] compared to LAK cell-treated [21.6 (29.3, 15.9)] animals. The same number of ATC significantly reduced the mean percentage of tumor volume [2.7 (4.7, 1.4)] (P less than 0.005). High dose interleukin 2 also significantly decreased tumor volume. More strikingly, a single dose of anti-CD3 alone had a beneficial effect on mean percentage of tumor volume when given i.p. [1.0 (1.9, 0.4)] or i.v. [1.2 (1.7, 0.7)] (P less than 0.0003). A total of 33% of anti-CD3-treated mice had no detectable liver metastases. In 51Cr release assays, the cytotoxicity of ATC was shown to be partially mediated by nylon wool-adherent accessory cells. The effectiveness of anti-CD3 in this immunotherapy model suggests that a similar approach may be taken to immunotherapy of human malignancies, without the requirements for in vitro-generated killer cells or exogenously administered interleukin 2.

The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.

The tumor suppressor p53 is a multifunctional protein that plays a critical role in modulating cellular responses upon DNA damage or other stresses. These functions of p53 are regulated both by protein-protein interactions and phosphorylation. The double-stranded RNA activated protein kinase PKR is a serine/threonine kinase that modulates protein synthesis through the phosphorylation of translation initiation factor eIF-2alpha. PKR is an interferon (IFN)-inducible protein that is thought to mediate the anti-viral and anti-proliferative effects of IFN via its capacity to inhibit protein synthesis. Here we report that PKR physically associates with p53. The interaction of PKR with p53 is enhanced by IFNs and upon conditions that p53 acquires a wild type conformation. PKR/p53 complex formation in vitro requires the N-terminal regulatory domain of PKR and the last 30 amino acids of the C-terminus of human p53. In addition, p53 may function as a substrate of PKR since phosphorylation of human p53 on serine392 is induced by activated PKR in vitro. These novel findings raise the possibility of a functional interaction between PKR and p53 in vivo, which may account, at least in part, for the ability of each protein to regulate gene expression at both the transcriptional and the translational levels.

The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha.

We have examined the effects of human papilloma virus (HPV) E6 proteins on interferon (IFN) signaling. Here we show that expression of the 'malignant' HPV-18 E6 in human HT1080 cells results in inhibition of Jak-STAT activation in response to IFN-alpha but not IFN-gamma. This inhibitory effect is not shared by the 'benign' HPV-11 E6. The DNA-binding and transactivation capacities of the transcription factor ISGF3 are diminished in cells expressing HPV-18 E6 after IFN-alpha treatment as a result of decreased tyrosine phosphorylation of Tyk2, STAT2 and STAT1. However, HPV-18 E6 does not affect the induction of tyrosine phosphorylation and DNA-binding of STAT1 by IFN-gamma. In addition, HPV E6 proteins physically interact with Tyk2. This interaction takes place preferably with HPV-18 E6 and to a lesser extent with HPV-11 E6. The E6/Tyk2 interaction requires the JH6-JH7 domains of Tyk2, which are important for Tyk2 binding to the cytoplasmic portion of IFN-alpha receptor 1 (IFNAR1). These findings demonstrate an inhibitory role of HPV-18 E6 in the IFN-alpha-induced Jak-STAT pathway, which may be explained, at least in part, by the ability of E6 to interact with and impair Tyk2 activation.

Herbal remedies in psychiatric practice.

Patients' use of alternative and complementary health services has created a need for physicians to become informed about the current literature regarding these treatments. Herbal remedies may be encountered in psychiatric practice when they are used to treat psychiatric symptoms; produce changes in mood, thinking, or behavior as a side effect; or interact with psychiatric medications. English-language articles and translated abstracts or articles (where available) found on MEDLINE and sources from the alternative/complementary health field were reviewed. Each herb was assessed for its safety, side effects, drug interactions, and efficacy in treating target symptoms or diagnoses. A synopsis of the information available for each herb is presented. In many cases the quantity and quality of data were insufficient to make definitive conclusions about efficacy or safety. However, there was good evidence for the efficacy of St John's wort for the treatment of depression and for ginkgo in the treatment of memory impairment caused by dementia. More research is required for most of the herbs reviewed, but the information published to date is still of clinical interest in diagnosing, counseling, and treating patients who may be taking botanical remedies.

The sensitivity and responsiveness of an oral health related quality of life measure to tooth whitening.

OBJECTIVES: To assess the sensitivity and responsiveness of an oral health related quality of life measure to tooth whitening. METHODS: Following screening at a clinic, 87 subjects were given an array of tooth whitening products to use at home and reviewed 8 weeks later. Subjects self-completed the 49-item Oral Health Impact Profile (OHIP) at baseline and follow-up, and rated their satisfaction with the whiteness of their teeth compared to baseline on a global transition scale. RESULTS: In terms of sensitivity, observed changes were apparent in overall OHIP scores (P<0.05) and across several domains, notably functional limitation (P<0.01). However, the magnitude of change (effect size) was generally small except for the functional domain. There was an observed gradient in observed change in OHIP scores and in the magnitude of such changes (effect sizes) in relation to global rating of satisfaction with the outcome, supporting the responsiveness of the measure. CONCLUSION: The OHIP scale is sensitive and responsive to the effects of tooth whitening. Greatest sensitivity and responsiveness was in relation to functional limitations. These findings have implications for the use of oral health related quality of life measures as an outcome measure of interventions aimed at improving dental aesthetics through tooth whitening.

Natural attenuation, biostimulation and bioaugmentation on biodegradation of polycyclic aromatic hydrocarbons (PAHs) in mangrove sediments.

The biodegradability of a mixture of PAHs, namely fluorene (Fl), phenanthrene (Phe) and pyrene (Pyr), in mangrove sediment slurry was investigated. At the end of week 4, natural attenuation based on the presence of autochthonous microorganisms degraded more than 99% Fl and Phe but only around 30% of Pyr were degraded. Biostimulation with addition of mineral salt medium degraded over 97% of all three PAHs, showing that nutrient amendment could enhance Pyr degradation. Bioaugmentation with inoculation of a PAH-degrading bacterial consortium enriched from mangrove sediments did not show any promotion effect and the degradation percentages of three PAHs were similar to that by natural attenuation. Some inhibitory effect was observed in bioaugmentation treatment in week 1 with only 50% Fl and 70% Phe degraded. These results indicate that autochthonous microbes may interact and even compete with the enriched consortium during PAH biodegradation. Natural attenuation appeared to be the most appropriate way to remedy Fl- and Phe-contaminated mangrove sediments while biostimulation was more capable to degrade Pyr-contaminated sediments. The study also shows that although a large portion of the added PAHs (more than 95%) was adsorbed onto the sediments at the beginning of the experiment, most PAHs were degraded in 4 weeks, suggesting that the degraders could utilize the adsorbed PAHs efficiently.

Promoter-independent regulation of cell-specific dopamine receptor expression.

Here we describe the construction of recombinant adenoviruses expressing dopamine D2 and D4 receptors, and their ability to mediate high levels of heterologous expression in a variety of cell types in vitro and in vivo for at least 7 days post infection. These experiments demonstrated that maximum receptor expression is achieved generally within 24 h and remains constant thereafter. Maximum expression levels were highly variable between cell lines and dependent on infection efficiency and promoter strength. Correction for these two variables revealed differences in relative expression levels between cell lines varying by two orders of magnitude. Our results indicate that in addition to gene transcription, post-transcriptional mechanisms play a dominant role in determining dopamine receptor levels in this system.

The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke.

Fasting serum glucose, glycosylated hemoglobin, and fructosamine concentrations were determined in 304 consecutive subjects admitted with acute stroke, within 48 hours of ictus. Based on the medical history and these results, subjects were divided into known diabetics, newly diagnosed diabetics, subjects with stress hyperglycemia, and nondiabetics. The type of stroke was classified as lacunar infarct, cerebral infarct, or intracerebral hemorrhage, based on clinical examination by a neurologist and computed tomographic brain scan and/or autopsy. Immediate and 3-month outcomes were examined in relation to (1) fasting glucose, glycosylated hemoglobin, and fructosamine levels by stroke subtypes, and (2) glucose tolerance categories by stroke subtypes. A high fasting glucose level was associated with an increased mortality, but this was observed only among patients with intracerebral hemorrhage. Patients with stress hyperglycemia, but not diabetics, had increased mortality. In spite of having similar glucose concentrations to those patients with stress hyperglycemia, diabetics did not have a worse outcome compared with nondiabetics. It is concluded that the association between glucose concentration and outcome is a reflection of stress relating to stroke severity, rather than a direct harmful effect of glucose on damaged neurons.

Neurocognitive deficits and neurological signs in schizophrenia.

OBJECTIVE: This is a comprehensive study designed to examine the association between specific clusters of neurological abnormalities and several clinically relevant aspects of schizophrenia such as positive and negative symptoms, neurocognitive deficits and psychosocial performance. METHODS: Thirty-seven clinically stable schizophrenic (DSM-III-R) patients maintained on antipsychotic medication were comprehensively examined and Convit's Quantified Neurologic Scale (QNS) was completed. In addition, patients' psychopathology was rated on the Positive and Negative Syndromes Scale (PANSS); psychosocial performance was rated on the Global Scale of Adaptive Functioning (GAF) and the Social Performance Schedule (SPS); and neurocognitive deficits were measured with a computer-assisted neurocognitive test battery, COGLAB. The association between these factors was determined using Pearson's correlation coefficients. RESULTS: Frontal and soft neurological scores on the QNS correlated significantly with negative syndrome scores (r = 0.45-0.51, p < 0.05) and general psychopathology scores (r = 0.46-0.49, p < 0.02) on PANSS; poor psychosocial performance on GAF (r = 0.43-0.56, p < 0.02) and SPS (r = 0.37-0.54, p < 0.007); and performance on the span of apprehension (r = 0.48-0.67, p < 0.0001), backward masking (r = 0.34-0.54, p < 0.01) and Wisconsin card sorting (r = 0.48-0.67, p < 0.001) tasks. CONCLUSION: Frontal and soft neurological signs in schizophrenic patients are associated with prominent negative symptoms, relatively poor psychosocial performance and significantly more cognitive impairment. Past research has associated soft neurological signs, cognitive impairment and structural brain abnormalities with poor outcome and prognosis in patients with schizophrenia.

Epidemiology of bacteriuria caused by vancomycin-resistant enterococci--a retrospective study.

BACKGROUND: The epidemiology of vancomycin-resistant enterococcal (VRE) bacteriuria has not been previously described. Our objectives are to describe the frequency of VRE bacteriuria, to use strict definitions to distinguish symptomatic urinary tract infection (UTI) versus urine colonization without pyuria versus asymptomatic bacteriuria with pyuria, and to describe the outcomes of each group. METHODS: We used a retrospective analysis of patients with VRE bacteriuria in an academic medical center. RESULTS: During the 18-month study period, 98 of the 107 patients (92%) with urine cultures positive for VRE (23/10,000 admissions), had charts that were available for review. In 94 of 98 patients, the organism was Enterococcus faecium, and in only 4 was Enterococcus faecalis recovered. Thirty-seven patients were colonized with VRE; 21 patients had asymptomatic bacteriuria, and the status of 27 patients was not ascertainable. Thirteen patients had VRE UTIs with two associated bacteremias and one death. Patients with UTI versus patients without UTI were more likely to have an underlying malignancy (39% vs 9%, P =.014). CONCLUSION: The majority of urine cultures yielding VRE do not represent true infection, rather colonization or asymptomatic bacteriuria.

Dopamine receptor gene transfer into rat striatum using a recombinant adenoviral vector: rotational behaviour.

To study the role of dopamine (DA) receptor expression on dopamine-mediated rotational behaviour, adenovirus expressing the lacZ reporter gene (AdCMVLacZ) or D2R expressing adenoviral vector (AdRSVD2) viruses, mediating expression of beta-galactosidase and DAD2 receptors, respectively, were microinjected stereotactically into Sprague-Dawley rat striatum. Apomorphine stimulated rotational behaviour was measured in rats unilaterally injected with either AdCMVLacZ or AdRSVD2. No significant difference in rotational direction was observed until day 14 post-injection, when animals showed a tendency to rotate away from the injected side. Our data indicate that unilateral changes in receptor density mediated by a non-cell type selective adenoviral vector results in minor changes in rotational behavior. This suggests that supersensitivity in dopamine receptor signaling, rather than receptor levels per se, are the major factor in determining rotational response with dopamine agonist stimulation in unilateral striatal dopamine depleted animals.