Evidence of a diverse T cell receptor repertoire for acetylcholine receptor,the autoantigen of myasthenia gravis

We utilized two methods to look for T cell clonal expansions in myasthenia gravis (MG). We analyzed TCRBV CDR3 length polymorphism (spectratyping) to look for evidence of clonal expansion of CD4 or CD8 T cells directly from peripheral blood of MG patients. No statistically significant differences were found between the diversity of TCR repertoires in MG patients compared to normal control individuals when analyzed as groups. Rare oligoclonal expansions were detected in some individual MG patients but the significance of these findings is unclear. Next, we analyzed a panel of T cell hybridomas from acetylcholine receptor (AChR) immunized, MG-susceptible HLA-DR3 transgenic mice. The epitope specificity, TCRBV gene usage and CDR3 sequences of these hybridomas were highly diverse. We conclude there is only limited evidence for restricted TCR repertoire usage in human MG and suggest this may be due to the inability of HLA-DR molecules to select for restricted TCR recognition of AChR epitopes.     

Assessment of 54 biomarkers for biopsy-detectable prostate cancer.

OBJECTIVE: We analyzed the association of 54 biomarkers from seven classes including adipokines, immune response metalloproteinases, adhesion molecules, and growth factors with prostate cancer risk adjusting for the Prostate Cancer Prevention Trial (PCPT) risk score. METHODS: A total of 123 incident prostate cancer cases and 127 age-matched controls were selected from subjects in the San Antonio Center for Biomarkers of Risk of Prostate Cancer cohort study. Prediagnostic serum concentrations were measured in the sample collected at baseline using LabMAP technology. The odds ratios (OR) of prostate cancer risk associated with serum concentrations of 54 markers were estimated using univariate conditional logistic regression before and after adjustment for the PCPT risk score. Two-way hierarchical unsupervised clustering techniques were used to evaluate whether the 54-marker panel distinguished cases from controls. RESULTS: Vascular endothelial growth factor, resistin, interleukin 1Ra (IL-1Ra), granulocyte colony-stimulating factor, matrix metalloproteinase-3, plasminogen activator inhibitor, and kallikrein-8 were statistically significantly (P < 0.05) underexpressed in prostate cancer cases, and alpha-fetoprotein was statistically significantly overexpressed in prostate cancer cases, but all had area underneath the receiver-operating characteristic curve <60%; none were statistically significant adjusting for multiple comparisons (P < 0.0008) or after adjustment for the PCPT risk score. Statistical clustering of patients by the marker panel did not distinguish a separate group of cases from controls. CONCLUSIONS: This age-matched case-control study did not support findings of increased diagnostic potential from a 54-marker panel when compared with the conventional risk factors incorporated in the PCPT risk calculator. Future discovery of new biomarkers should always be tested and compared against conventional risk factors before applying them in clinical practice.     

Integrated obesity care management system -implementation and research protocol

Background  

Nearly 50% of Canadians are overweight and their number is increasing rapidly. The majority of obese subjects are treated by primary care physicians (PCPs) who often feel uncomfortable with the management of obesity. The current research proposal is aimed at the development and implementation of an innovative, integrated, interdisciplinary obesity care management system involving both primary and secondary care professionals.     

Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity

OBJECTIVE: To determine whether insulin-sensitizing drugs would improve ovulation and T levels in women with polycystic ovary syndrome (PCOS), without clinical or biochemical criteria indicating insulin resistance and whether the combination of two distinct insulin-sensitizing drugs would be of any benefit over either drug alone. DESIGN: Randomized controlled double-blind trial. SETTING: A referral center in Caracas, Venezuela. PATIENT(S): One hundred twenty-eight nonobese PCOS women with normal indices of insulin sensitivity-that is, normal glucose tolerance, fasting insulin, peak insulin during an oral glucose tolerance test (OGTT), and fasting glucose-to-insulin ratio. Twenty-eight women were lost to follow-up initially and did not receive any intervention. INTERVENTION(S): One hundred women received twice daily one of the following for 6 months: metformin (850 mg), rosiglitazone (4 mg), combination of both drugs, or at least one placebo. MAIN OUTCOME MEASURE(S): Frequencies of ovulation and serum free T after 6 months. RESULT(S): Frequencies of ovulation were higher after treatment with an insulin-sensitizing drug (ovulations per subject in 6 months: metformin, 3.3; rosiglitazone, 2.4; and combination, 3.4) than with placebo (0.4). Ovulatory frequencies increased significantly more with metformin than rosiglitazone, and the combination was not more potent. After treatment, serum free-T levels were comparable among all active treatment groups (metformin: 2.34 pg/mL, rosiglitazone: 3.06 pg/mL, and combination: 2.39 pg/mL) and were significantly lower than in the placebo group (7.26 pg/mL). Compared with placebo, fasting insulin levels, area under the insulin curve during OGTT, the homeostatic model assessment of insulin sensitivity, and OGTT-derived insulin sensitivity index improved significantly after metformin or combination therapies but not after rosiglitazone. CONCLUSION(S): These findings suggest that insulin-sensitizing drugs increase ovulatory frequency and ameliorate hyperandrogenemia, even in nonobese women with PCOS who appear to have normal insulin sensitivity.     

Prevalence of methylphenidate use and change over a two-year period: a nationwide study of 2- to 11-year-old Canadian children

OBJECTIVE: To provide age- and sex-specific estimates of methylphenidate use and to determine use changes over a 2-year period. STUDY DESIGN: We examined the first and second data collection cycles of the National Longitudinal Survey of Children and Youth, a Canadian household survey of children. Participants were children aged 2 years to 11 years at both the first and second cycles whose mothers responded; thus, 16,798 (13,059) children were assessed for the first (second) cycle. Logit modeling was used to estimate prevalence of methylphenidate use, to determine sex and age effects on prevalence, and to examine use changes from cycle 1 to 2. RESULTS: Methylphenidate prevalence ranged from 0.09% to 3.89% across 2- to 11-year old children from the first cycle. Boys were 4.6 times more likely than girls to consume methylphenidate. Use was >4 times greater among 6- to 7-year-old children compared with 4- to 5-year-old children and almost 2 times greater among 8- to 9-year-old children compared with 6- to 7-year-old children. Methylphenidate prevalence increased by 36% from cycle 1 to 2. CONCLUSIONS: Methylphenidate prevalence was relatively low. Boys and school-age children had higher rates of methylphenidate use, and use among 2- to 11-year-old children appeared to be increasing over time.     

Modeling interinformant agreement in the absence of a "gold standard"

Epidemiological surveys of child and adolescent mental disorders often rely on multiple informants to get a complete diagnostic picture. A consistent finding in the literature is that different informants often do not identify the same children as being disordered. However, because current strategies for estimating interinformant agreement often involve categorizing children using less than perfectly sensitive and/or specific symptoms, biased estimates of interinformant agreement are likely. The aim of this report was to illustrate how latent class analysis (LCA) can be used to model interinformant agreement in the absence of a "gold standard". The proposed model consists of informant-specific latent variables each made up of two or more latent classes corresponding to different levels of symptomatology. Unlike most previous applications of LCA this model allows us to model the extent to which the prevalence of the disorder is the same across informants; and, in addition, the association between informants. The data set comes from a prospective longitudinal study of 2,264 children from Quebec (1,155 boys and 1,109 girls). In grade 2, teachers and mothers independently rated each child on three physical aggression behavior symptoms. We satisfactorily accounted for the cross-classification of the behavior symptoms by postulating the existence of two latent variables--one for each informant each made up of three latent classes of children: low-, medium-, and high-aggressive. The results showed that the prevalence of low- and medium-aggressive children in the population differed from teacher to mother, but that the prevalence of high-aggressive children did not. We found that the association between teacher and mother was large and positive and did not vary according to the child's physical aggression state or gender; in contrast, the association between physical aggression and gender was not the same for mother and teacher. Limitations and other potential applications of the proposed model are discussed.