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.     

Risk of type 2 diabetes and cumulative excess weight exposure in the Framingham Offspring Study

AimMid-life obesity is associated with T2D risk. However, less is known about the cumulative effect of obesity during adulthood.MethodsFramingham Offspring Study participants who had an examination at 35 ± 2 years and were initially free of T2D were included in this study (N = 1026). A cumulative excess weight (CEW) score (year*kg/m²) was calculated until T2D diagnostic or the end of follow-up.ResultsEighty-four individuals (8.2%) developed T2D over 20 ± 6 years. Mean CEW scores were 118.0 ± 114.6 year*kg/m² in individuals who developed T2D and 30.2 ± 91.4 year*kg/m² in those who did not develop T2D (P < 0.01). T2D risk was doubled for each standard deviation increase in the CEW score (OR = 1.99 [1.64-2.40]; P < 0.001). However, CEW score was only significantly associated with T2D incidence for participants with a baseline BMI < 25 kg/m² (OR = 2.13 [1.36–3.36]; P < 0.001).ConclusionsAccumulating weight between the mid-thirties to the mid-fifties increases the risk of developing T2D. However, BMI in mid-thirties remains a stronger predictor of T2D risk.     

Is the effect of inguinal field block with 0.5% bupivacaine on postoperative pain after hernia repair enhanced by addition of ketorolac or S(+) ketamine?

OBJECTIVE: The aim of the study was to assess whether coadministration of S(+) ketamine or ketorolac would enhance or prolong local analgesic effect of bupivacaine after inguinal hernia repair. DESIGN: Prospective double-blind randomized study evaluating pain intensity after surgery under general anesthesia. SETTING: Outpatient facilities of the University Hospital of Lausanne. PATIENT: Thirty-six ASA I-II outpatients scheduled for elective day-case inguinal herniorraphy. INTERVENTION: Analgesia strategy consisted of a wound infiltration and an inguinal field block either with 30 mL bupivacaine (0.5%) or with the same volume of a mixture of 27 mL bupivacaine (0.5%) + 3 mL S(+) ketamine (75 mg) or a 28 mL bupivacaine (0.5%) + 2 mL ketorolac (60 mg). Postoperative analgesic regimen was standardized. OUTCOME MEASURES: Pain intensity was assessed with a Visual Analog Scale, a verbal rating score, and by pressure algometry 2, 4, 6, 24, and 48 hours after surgery. RESULTS: The 3 groups of patients experienced the highest Visual Analog Scale pain score at 24 hours, which was different from those at 6 and 48 hours (P < 0.05). Apart from a significantly lower pain sensation (verbal rating score) in the ketorolac group at 24 and 48 hours and only at 48 hours with ketamine, there were no other differences in pain scores, pain pressure thresholds, or rescue analgesic consumption between groups throughout the 48-hour study period. CONCLUSION: The addition of S(+)-ketamine or ketorolac only minimally improves the analgesic effect of bupivacaine. This may be related to the tension-free hernia repair technique associated with low postoperative pain.     

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.