Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach

OBJECTIVEIn a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT).RESEARCH DESIGN AND METHODSLatent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling.RESULTSFour latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity.CONCLUSIONSWe identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.     

Transvaginal ultrasonography combined with water-contrast in the rectum in the diagnosis of rectovaginal endometriosis infiltrating the bowel

This prospective study evaluated the efficacy of transvaginal ultrasonography combined with water-contrast in the rectum (RWC-TVS) in the diagnosis of rectal infiltration in 35 women with rectovaginal endometriosis; ultrasonographic findings were compared with surgery and histology. The sensitivity of RWC-TVS in identifying rectal infiltration reaching at least the muscular layer was 100%, the specificity was 85.7%, the positive predictive value was 91.3%, and the negative predictive value was 100%. In 4 of 5 (80.0%) nodules reaching the submucosa, the depth of infiltration was underestimated by RWC-TVS. The RWC-TVS reliably determined the largest diameter of the endometriotic nodules and was well tolerated by the patients.     

Sodium pancratistatin 3,4-o-cyclic phosphate, a water-soluble synthetic derivative of pancratistatin, is highly effective in a human colon tumor model

Sodium pancratistatin 3,4- O-cyclic phosphate ( 2) is a novel water-soluble synthetic derivative of pancratistatin ( 1), a natural alkaloid constituent of Amaryllidaceae plants, that exhibits good cytostatic and antineoplastic activity but is highly insoluble. Unlike most other natural alkaloids it does not act by binding to tubulin, and its mechanism of action has yet to be fully elucidated. Here the efficacy of 2 in a human colon adenocarcinoma model, DLD-1, and some understanding of its mode of action are investigated. Agreeing with previous studies, low cytotoxicity in vitro was seen for 2 with IC 50's of 253 and 19.7 microM for 1 and 96 h exposures, respectively. However in vivo the compound caused statistically significant tumor growth delays ( p < 0.01) at its maximum tolerated dose, and significant vascular shutdown and tumor necrosis were observed. Like 1, the compound appeared to have an unconventional mechanism of action with no effect on microtubule structure, yet causing a G 2/M block, while it was seen to disrupt mitochondrial function. The mechanism of action of 1 and 2 appears to be similar. Thus compound 2, being considerably more soluble than 1, has good potential as an anticancer agent, and further investigation is warranted.     

Down syndrome biochemical markers and screening for preeclampsia at first and second trimester: correlation with the week of onset and the severity

OBJECTIVES: To estimate the combined screening performance of first and early second trimester prenatal serum markers for Down syndrome, in screening for the development of preeclampsia, and analyze the correlation among marker levels, week of onset, and severity of the disease. METHODS: A retrospective cohort study was carried out on 32 women with preeclampsia and 3044 controls. Serum samples from these pregnancies were assayed for pregnancy-associated plasma protein-A (PAPP-A), alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotrophin (hCG), and inhibin-A. A likelihood ratio and the odds of being affected given a positive result (OAPR) of various combinations of markers were calculated and receiver operating characteristic (ROC) curves analysis was performed. RESULTS: In the pregnancies that subsequently developed preeclampsia, first trimester PAPP-A concentration was significantly lower and concentrations of early second trimester inhibin-A and hCG significantly elevated. Levels of early second trimester uE3 and AFP were not significantly altered. We also found that inhibin-A correlates with both onset of the disease and the severity. CONCLUSION: Down syndrome biochemical markers levels are altered in those patients who subsequently developed preeclampsia and may be a useful screening test for preeclampsia. Inhibin-A is the most predictive marker and correlates with the severity of subsequent preeclampsia and inversely with the week of occurrence of preeclampsia.     

Foetal and neonatal ovarian cysts: a 5-year experience

Background Abdominal cystic formations in newborns are relatively common and often diagnostic suspicion arises in this regard even before birth as a result of ultrasound scans carried out during pregnancy. The aim of this study is to highlight the problems posed by the prenatal diagnosis of abdominal cysts in order to outline the most appropriate therapeutic approach in case of suspected ovarian cysts. Materials and methods Between January 2003 and January 2007, 57 women were enrolled in this study for a prenatal ultrasound (US) that revealed the presence of an echo-rare or echo-free area in the foetal abdomen. After birth all babies underwent blood tests and abdominal US scans in order to confirm or identify the nature of the cyst. If abdominal US could not show the nature of the cystic formation, magnetic resonance imaging with sedation was performed. When the radiological tests were not useful to identify the nature of the cysts and surgery was then necessary, surgical procedures were performed with laparoscopy. Results Ultrasounds were useful to identify the diameter of the cysts but not all their origins; also MRI confirmed the morphology and volume of the cysts, but could not give further details about their origin. Discussion Abdominal ultrasound and finally laparoscopy used to treat and remove the cysts were useful to monitor all simple abdominal cysts. MRI seemed not to be useful for the treatment of this condition, especially in the pediatric age when mild sedation is required.