Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m² ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCR_I was calculated during the insulin-clamp performed with [3-³H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCR_I during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m², P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCR_I during the insulin clamp was strongly and inversely correlated with IR (r = −0.52, P < 0.0001). During the OGTT, the MCR_I was suppressed within 15–30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.     

Long-term azithromycin use is not associated with QT prolongation in children with cystic fibrosis

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.     

Pregnancy outcome of patients with pruritic urticarial papules and plaques of pregnancy.

OBJECTIVE: The study was designed to investigate obstetric risk factors and pregnancy outcome of patients with pruritic urticarial papules and plaques of pregnancy (PUPPP). METHODS: A population-based study comparing all pregnancies of women with and without PUPPP was conducted. Deliveries occurred during the years 1988-2002 at the Soroka University Medical Center. A multivariable logistic regression model was constructed in order to find independent risk factors associated with PUPPP. RESULTS: During a 15-year period, 159 197 deliveries took place. PUPPP complicated 42 (0.03%) of all pregnancies. Using a multivariable analysis, the following conditions were significantly associated with PUPPP: multiple pregnancies (odds ratio (OR) = 4.9, 95% confidence interval (CI) 1.7-14.1), hypertensive disorders (OR = 2.2, 95% CI 1.1-4.7), and induction of labor (OR = 7.6, 95% CI 4.0-14.5). Higher rates of 5-minute Apgar scores lower than 7 (OR = 8.0, 95% CI 4.4-14.9) and of cesarean deliveries (OR = 2.9, 95% CI 1.5-5.6) were noted in the PUPPP as compared to the comparison group. While investigating other perinatal outcome parameters such as oligohydramnios, intrauterine growth restriction, meconium-stained amniotic fluid and perinatal mortality, no significant differences were observed between the groups. CONCLUSION: Pruritic urticarial papules and plaques of pregnancy is a condition significantly associated with multiple pregnancies, hypertensive disorders, and induction of labor. Perinatal outcome is comparable to pregnancies without PUPPP.     

Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies

Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6–48 h) and dose related (0.1–10 μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the “initiation and adaptation” model to explain the mechanism of action of psychotropic drugs.     

Oligometastatic disease,the curative challenge in radiation oncology

The concept of oligometastatic disease was first described by Hellman and Weichselbaum in 1995. The mere insight of this concept led to the hypothesis that this disease may be cured using local ablative weapons. Surgery has already demonstrated this hypothesis. Surgery limitations, either technical or due to refusal or associated comorbidity, have led to implement alternative ablative options such as stereotactic body radiation therapy (SBRT). SBRT evolved from (stereotactic radiosurgery) because of the need to irradiate extracranial lesions and has been shown to be safe and effective. SBRT achieves local control rates ranging from 70%-90%, but highly variable survival rates depending on the group analyzed. Series with heterogeneous metastatic sites and tumor origin have reported 20% survival rates at 2-3 years, similar to those achieved with surgery. Despite its excellent results, SBRT still faces significant clinical challenges. Its optimal integration with systemic treatment is unknown, and response assessment is very difficult. However, the greatest challenge lies in selection of patients most likely to remain oligometastatic, those who will most benefit from the technique. Biomarkers, molecular signatures, that accurately predict the biological behavior of malignancy are needed. The expression profile of specific miRNAs has been shown to have a potential in this regard.