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.     

Combination anti-CD137 and anti-CD40 antibody therapy in murine myc-driven hematological cancers

In order to stimulate antigen presentation and T cell activity against cancer, we treated three different tumor models in mice with the monoclonal antibodies anti-CD40 plus anti-CD137 (BiMab). In a subcutaneous transplantable MC38 colon cancer model, there was significant enhancement in the survival of mice following BiMab treatment. Anti-CD40 has shown considerable success against lymphoma in previous studies by other investigators, and we also showed in this study that, in a model of Eμ-Myc lymphoma, there was a statistically significant enhancement of survival of mice following BiMab treatment. Following the success of the BiMab treatment in the previous two models, we wished to determine if it would be successful in a mouse model of multiple myeloma. Firstly, we tested a transplantable model of disease in which multiple myeloma cells derived from Vk*MYC mice were injected intravenously. A minor proportion of anti-CD137 and BiMab treated mice experienced prolongation of life beyond 250 days. Then we tested the therapy in a spontaneously occurring multiple myeloma model, in Vk*MYC transgenic mice. The majority of mice treated survived longer than control mice, although statistical significance was not demonstrated.     

Aortico-right ventricular tunnel: prenatal diagnosis leading to neonatal survival

In the 36th week of gestation a large aortico-right ventricular tunnel with an otherwise structurally normal heart was diagnosed by fetal echocardiography. This report describes for the first time the impact of the timely prenatal diagnosis of an aortico-right ventricular tunnel followed by successful management in early infancy.     

Lactate dehydrogenase isoenzymes of the human periodontal ligament

The isoenzymes of lactate dehydrogenase (E. C. 1. 1. 1. 27.) from the periodontal ligament on the root surface of extracted erupted permanent human teeth have been separated and quantitated by means of cellulose acetate membrane electrophoresis.
LDH-3 and LDH-4 were the predominating isoenzymes. and smaller amounts of LDH-2 and LDH-5 were also present. Only traces of LDH-1 could be seen. The results indicate the presence of both aerobic and anaerobic metabolic pathways in the human periodontal ligament.
These pathways bring about an efficient, economical energy production under normal circumstances, and make the survival of this tissue possible under hypoxic conditions, when the blood supply is briefly interrupted. The results further show that determinations of the survival time of the periodontal ligament on a tooth outside its alveolus have to be made by activity measurements of both aerobic and anaerobic enzymes.     

Neue Ergebnisse zur Frage des Muskel Tonus

Ohne Zusammenfassung     

ACCUMULATION OF ANTIBODIES IN THE CENTRAL NERVOUS SYSTEM

1. Antibodies can be extracted from the brain and spinal cord of rabbits actively or passively immunized with typhoid bacilli. 2. The titers of the antibodies in the extracts of brain and cord depend upon the titer of the blood serum. In actively immunized rabbits the following numerical relationships exist between the titers of the serum and of these organ extracts: The ratio of the titer of the serum is to the titers of extract of brain and of the spinal cord about as 100 is to 0.8; the titer of the serum is to the titer of the cerebrospinal fluid as 100 is to 0.3. In passively immunized rabbits the titer of the serum is to the titer of brain and spinal-cord extract as 100 is to 0.7. 3. The antibodies recovered from the brain are not due to the presence of blood in it for perfusion of the brain does not reduce its antibody content appreciably. 4. Antibodies penetrate into the spinal fluid from the blood even in the absence of inflammation of the meninges. When the penetration is completed the following numerical relationship exists between the titer of the serum and that of the cerebrospinal fluid: 100 to 0.25. 5. The penetration into the cerebrospinal fluid of antibodies injected intravenously proceeds at a slow rate, being completed only several hours after the immune serum has been injected. The penetration of antibodies into the tissue of the brain occurs at a very rapid rate. It is completed within 15 minutes. 6. It is very unlikely that when the immune serum is injected intravenously the antibodies reach the brain tissue by way of the cerebrospinal fluid, for (1) the antibody titer of the cerebrospinal fluid is lower than that of the brain extract, and (2) antibodies penetrate faster into the tissue of the brain than into the cerebrospinal fluid.