Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents

Introduction

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by core differences and impairments in social behavioral functioning. There are no approved medications for improving social cognition and behavior in ASD, and the underlying mechanisms needed to discover safer, more effective medications are unclear.

Discussion

In this review, we diagram the basic neurocircuitry governing social behaviors in order to provide a neurobiological framework for the origins of the core social behavioral symptoms of ASD. In addition, we discuss recent technological innovations in research tools that provide unprecedented observation of cellular morphology and activity deep within the intact brain and permit the precise control of discrete brain regions and specific cell types at distinct developmental stages.

Conclusions

The use of new technologies to reveal the neural circuits underlying social behavioral impairments associated with ASD is advancing our understanding of the brain changes underlying ASD and enabling the discovery of novel and effective therapeutic interventions.     

Genetics of type 2 diabetes mellitus and other specific types of diabetes; its role in treatment modalities

Type 2 diabetes mellitus (T2DM) is among the most challenging health issues of the 21st century and is associated with an alarming rise in the incidence. The pathophysiological processes that lead to development of T2DM are still unclear, however impairment in insulin secretion and/or action is clearly indicated. Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility. Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder. Only a minority of cases of type 2 diabetes are caused by single gene defects and one example is maturity onset diabetes of the young (MODY). Previous studies indicated that variants in genes encoding the pancreatic β-cell K+ATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are associated with neonatal diabetes. Six different types of maturity onset diabetes of young (MODY) have been identified based on characteristic gene defect. The common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPAR-γ) gene was confirmed in several studies to be associated with type 2 diabetes as well. More recently, studies reported variants within a novel gene, TCF7L2, as a putative susceptibility gene for type 2 diabetes across many ethnic backgrounds around the world. MODY patients respond better to sulphonylureas and metformin, while neonatal diabetes patients with genetic mutations can be changed from insulin to oral drugs. We hereby provide a comprehensive review on the role of genetics in type 2 diabetes mellitus.     

Neuropsychiatric screening in type 2 diabetes mellitus

Diabetes mellitus is considered to be one of the most psychologically demanding of the chronic medical illnesses and is often associated with several psychiatric disorders. Psychiatric disorders can be a risk factor for, as well as a complication of, diabetes leading to bidirectional association between the two morbidities. Physicians caring for people with diabetes must be trained to recognize and manage comorbid psychiatric conditions that commonly occur. Our current article reviews the various screening procedures for effective evaluation of the neuropsychiatric illnesses coexisting with diabetes and other pertinent issues.     

A qualitative and quantitative assessment of the impact of three processing algorithms with halving of study count statistics in myocardial perfusion imaging: filtered backprojection, maximal likelihood expectation maximisation and ordered subset expectation maximisation with resolution recovery

Introduction

Ordered subset expectation maximisation with depth-dependent resolution recovery (OSEM-RR) is a processing algorithm reported to improve images with halved tracer activity in myocardial perfusion scintigraphy (MPS) compared to filtered backprojection (FBP) using conventional activities. OSEM-RR has not yet been compared with maximal likelihood expectation maximisation (MLEM).

Methods

39 patients undergoing MPS and two anthropomorphic phantoms (one with, one without an inferior wall insert) had full-time (FT) and half-time (HT) SPECT datasets acquired simultaneously and processed by FBP, MLEM and OSEM-RR. Two experienced reporters scored images of all clinical studies (n=234) for conspicuity of a perfusion defect, with results being compared using Wilcoxon paired and Kappa tests. A quantitative assessment based on mean segmental pixel counts taken from numbers automatically displayed over the 20 segments of Cedars Sinai Autoquant QPS image were compared using Pearson??s correlation and Bland Altman analysis.

Results

A small but consistent superior concurrence between FT and HT datasets for OSEM-RR compared to FBP and MLEM was observed for both qualitative and quantitative analyses. OSEM-RR resulted in better definition of the inferior wall defect on the phantom study.

Conclusion

OSEM-RR appears superior to both FBP and MLEM in terms of handling reduced count statistics.     

Differential concentration and time dependent effects of progesterone on kinase activity, hyperactivation and acrosome reaction in human spermatozoa

Progesterone has been identified to be one of the physiological regulators of sperm hyperactivation and acrosome reaction. However, the high sensitivity of human spermatozoa to progesterone implies that many may undergo premature hyperactivation and acrosome reaction thereby compromising their ability to fertilize. We hypothesized that if a spermatozoon has to preclude the occurrence of these events prematurely, there should be differential dose- and time-dependent effects on motility and acrosome reaction. We observed that low concentrations of progesterone (10 and 100?nm) induce sperm motility and activate tyrosine kinase; higher concentrations (1-10?μm) are required to induce extracellular signal regulated kinases 1/2 (Erk1/2), p90 ribosomal S6 kinase (p90RSK), p38 mitogen-activated protein kinase (p38MAPK), c-Jun N-terminal kinase (JNK1) and AKT phosphorylation, hyperactivation and acrosome reaction. The induction of acrosome reaction and tyrosine phosphorylation in response to higher concentration of progesterone is not absolutely dependent on activation of T-type voltage-gated Ca(2+) channel or CatSper as Mibefradil did not completely abrogate progesterone-mediated effects. These results imply that although the spermatozoa are sensitive to low concentrations of progesterone, they only activate motility and tyrosine kinase activation; higher concentrations are required to induce hyperactivation and acrosome reaction probably by activating multiple kinase pathways including the MAPK and AKT.     

Leukocyte Chemotaxis and Pyoderma Gangrenosum

Leukocyte chemotaxis (in five patients with pyoderma gangrenosum) was studied using a modification of the Boyden chamber method. In all patients the chemotactic response was significantly lower than in the controls. This abnormal chemotaxis was a result of an intrinsic neutrophil dysfunction. No significant difference was detected between the chemotactic response of leukocytes from patients with minimal or no skin involvement and those from patients with extensive lesions.