50 Grams Oral Glucose Challenge Test: Is It an Effective Screening Test for Gestational Diabetes Mellitus?

Aim

To find out whether 50 g oral glucose challenge test (OGCT) is an effective screening test for all pregnant women between 24 and 28 weeks gestation.

Method

A 50 g OGCT test was administered to 307 unselected women at 24–28 weeks of gestation. When venous plasma glucose (VPG) concentration after 1 h was >7.8 mmol/l, OGCT was positive. Women with a positive OGCT underwent 2 h 75 grams oral glucose tolerance test (OGTT) as a confirmatory diagnosis of GDM. When fasting and 2 h post 75 g OGTT values were >5.5 mmol/I and >8 mmol/l, respectively, women were considered diabetic.

Results

We screened 307 women for GDM by OGCT. Total number of women with positive OGCT was 83 (27.03 %). In the low-risk group, total number of women with GDM was 9/168 (5.35 %) while the total number of women with GDM in the high-risk group was 14/139 (10.07 %). There was no significant difference with respect to the total number of women with GDM in the groups.

Conclusions

A 50 g OGCT seems to be an effective screening test for both groups. More cases of GDM can be discovered when universal rather than risk-related screening is applied.

     

Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2'-O-2-methoxyethyl-modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system-directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic.     

Neural Stem Cell Transplantation as a Therapeutic Approach for Treating Lysosomal Storage Diseases

Treating the central nervous system manifestations of subjects with neuropathic lysosomal storage diseases remains a major technical challenge. This is because of the low efficiency by which lysosomal enzymes in systemic circulation are able to traverse the blood brain barrier into the central nervous system. Intracranial transplantation of neural stems cells genetically modified to overexpress the respective deficient enzymes represents a potential approach to addressing this group of diseases. The unique properties of neural stem cells and progenitor cells, such as their ability to migrate to distal sites, differentiate into various cell types and integrate within the host brain without disrupting normal function, making them particularly attractive therapeutic agents. In addition, neural stem cells are amenable to ex vivo propagation and modification by gene transfer vectors. In this regard, transplanted cells can serve not only as a source of lysosomal enzymes but also as a means to potentially repair the injured brain by replenishing the organ with healthy cells and effecting the release of neuroprotective factors. This review discusses some of the well-characterized neural stem cell types and their possible use in treating neuropathic lysosomal storage diseases such as the Niemann Pick A disease.     

Mouse neural progenitor cells differentiate into oligodendrocytes in the brain of a knockout mouse model of Canavan disease

Canavan disease (CD) is an autosomal recessive disorder that leads to spongy degeneration in the white matter of the brain. Aspartoacylase (ASPA) synthesizing cells, oligodendrocytes, are lost in CD. Transplantation of neural progenitor cells (NPCs) offers an interesting therapeutic approach for treating neurodegenerative diseases by replacing the lost cells. Therefore, the NPCs transplantation to the brain of the CD mouse was studied. Injection of mouse NPCs to the striatum and cerebellum of juvenile CD mouse showed numerous BrdU positive cells at 1 month after injection. The same result was also observed in the adult CD mouse brain after 5 weeks of post-transplantation period. The implanted cells differentiated into oligodendrocytes and fibrous astrocytes, as observed using glial cell marker. This is the first report to describe the survival, distribution and differentiation of NPCs within the brain of CD mouse and a first step toward the potential clinical use of cell therapy to treat CD.     

Cytotoxic assays for screening anticancer agents

In the process of identifying potential anticancer agents, the ability of a new agent is tested for cytotoxic activity against a panel of standard cancer cell lines. The National Cancer Institute (NCI) present the cytotoxic profile for each agent as a set of estimates of the dose required to inhibit the growth of each cell line. The NCI estimates are obtained from a linear interpolation method applied to the dose-response curves. In this paper non-linear fits are proposed as an alternative to interpolation. This is illustrated with data from two agents recently submitted to NCI for potential anticancer activity. Fitting of individual non-linear curves proved difficult, but a non-linear mixed model applied to the full set of cell lines overcame most of the problems.Two non-linear functional forms were fitted using random effect models by both maximum likelihood and a full Bayesian approach. Model-based toxicity estimates have some advantages over those obtained from interpolation. They provide standard errors for toxicity estimates and other derived quantities, allow model comparisons. Examples of each are illustrated.     

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease.     

Stem cell transplantation for neurometabolic and neurodegenerative diseases

Over the last decade, the potential for therapeutic use of stem cell transplantation for cell replacement or as cellular vectors for gene delivery for neurometabolic and neurodegenerative diseases has received a great deal of interest. There has been substantial progress in our understanding of stem cell biology. Potential applications of cell-mediated therapy include direct cell replacement or protection and repair of the host nervous system. Given the complexities of the cellular organization of the nervous system, especially in diseased states, it seems that using stem cells as cellular vectors to prevent or ameliorate neurological disorders rather than cell replacement and the regrowth of damaged circuitry is more likely to succeed in the near term. Recent success in the treatment of lysosomal storage diseases with genetically modified stem cells support this notion. In Alzheimer's and Parkinson's diseases, stem cell therapy is at its early stages and data generated in animal models and clinical trials using other cell types suggest that a combination of gene and stem cell therapy may be an optimal therapeutic paradigm.