SB‐334867, an orexin receptor 1 antagonist,decreased seizure and anxiety in pentylenetetrazol‐kindled rats

Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin‐A and orexin‐B are brain neuropeptides originating from postero‐lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist (SB‐334867) on seizure‐ and anxiety‐related behaviors of pentylenetetrazol (PTZ)‐kindled rats. Kindling was induced by repeated intraperitoneal (IP) injections of PTZ (32 mg/kg) with two‐day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular (ICV) injections of SB‐334867 (2.5, 5, and 10 μg/rat) before PTZ injections. Two control groups received vehicle (2 μL/rat, ICV) and valproate (26 μg/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure‐related behaviors were monitored for 30 min following PTZ administration. The anxiety‐like behaviors were also assessed using elevated plus‐maze in the first and last days of the study. The results revealed that ICV injection of SB‐334867, mainly at the dose of 10 μg/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ‐induced anxiety‐like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders.     

Impact of polymorphism in <Emphasis Type="Italic">IL-1RA</Emphasis> gene on the risk of cervical cancer

Introduction Cervical cancer, the second most common malignancy in women worldwide, is almost invariably associated with infection by human papillomavirus (HPV). However, although many women are infected with high-risk types of HPV, only a subset of infected women will ever develop cervical cancer. Therefore, host genetic factor may play a role in cervical carcinogenesis. Several studies suggested that immunological components play a key role in the development of cervical cancer. Polymorphism in the IL-1RA gene was associated with various malignant diseases. Data are lacking for cervical cancer. Materials and methods In a case−control study we analyzed the polymorphism of IL-1RA in 150 women with cervical cancer and 209 healthy controls. Genomic DNA fragments were amplified by PCR. Results There was a strong significantly protective association between heterozygous AB genotype and HPV 18 (OR = 0.11, 95% CI = 0.04–0.30, p = 0.0000000). Similarly this result was demonstrated, in combined AB + BB genotypes of IL-1RA with HPV 18 (OR = 0.12, 95% CI = 0.05–0.30, p = 0.0000000) and HPV type 16 + 18 (OR = 0.18,95% CI = 0.08–0.38, p = 0.000005). We found high protective significant association between heterozygous genotype AB with adenocarcinoma (OR = 0.19, 95% CI = 0.09–0.40, p = 0.0000002) as well. Conclusion These findings therefore suggest that the IL1-RA polymorphism is associated with cervical cancer.     

Impact of methylenetetrahydrofolate reductase (<Emphasis Type="Italic">MTHFR</Emphasis>) codon (677) and methionine synthase (<Emphasis Type="Italic">MS</Emphasis>) codon (2756) on risk of cervical carcinogenesis in North Indian population

Cervical cancer continues to be the most common cause of death among women in developing countries. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are critical enzymes of folate metabolic pathways. In this work, we have conducted a case–control study to assess the role of these two polymorphisms in cervical cancer development. We obtained blood samples from 200 women with cervical cancer and from equal matched controls and analysed using PCR-RFLP method. We found that the methylenetetrahydrofolate reductase variant CT and CT + TT genotypes decreased cervix cancer risk, statistically significant (OR:0.30, 95% CI: 0.18–0.51, P < 0.001 for CT and OR:0.29, 95% CI: 0.18–0.49, P = 0.0000006 for CT + TT). Similarly in those patients who used oral contraceptive with variant CT genotype, there was statistically highly significant reduced risk of cervix cancer (OR:0.25, 95% CI: –0.12–0.49, P < 0.001) of methylenetetrahydrofolate reductase gene. For the methionine synthase, 2756 variant AG and AG + GG genotypes were similarly associated with highly significant reduced risk of cervix cancer (OR: 0.13, 95% CI: 0.07–0.26, P < 0.001 for AG, and OR: 0.15, 95% CI: 0.08–0.27, P < 0.001 for AG + GG) genotypes. In conclusion, our study suggested that methylenetetrahydrofolate reductase and methionine synthase polymorphisms might have protective effect on the risk of cervical cancer in the North Indian women.     

Interleukin 1 beta gene polymorphism and risk of cervical cancer.

OBJECTIVE: To determine whether a polymorphism at position +3953 in exon 5 of the lL-1beta gene (IL-1beta +3953), a condition associated with an increased risk for a number of inflammatory diseases, is also involved in the development of cervical cancer. METHOD: We isolated DNA from peripheral blood in 150 women with cervical cancer and 200 healthy controls, and IL-1beta +3953 allele polymorphism was determined by polymerase chain reaction. RESULTS: Genotypes A1/A2 and A2/A2+A1/A2 were associated with increased risk of cervical cancer (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.78-4.67; P<0.001 and OR, 2.85; 95% CI, 1.77-4.6; P<0.001, respectively). The risk in a passive smoker with A2/A2 or A1/A2 genotype was increased more than 5-fold (OR, 5.69; 95% CI, 2.61-12.50; P<0.001) compared with a nonsmoker with the A1/A1 genotype. CONCLUSION: This study provides evidence of an association between lL-1beta +3953 polymorphism and risk of cervical cancer.     

Developing learning outcomes for an ideal MSc course in sports and exercise medicine

Objective: To develop learning outcomes for an ideal MSc in sports and exercise medicine.

Methods: Twenty nine learning outcomes were developed based on the learning outcomes, aims, and objectives of current sports medicine courses, occupational standards, and other related data. Using a Likert scale, the opinion of MSc/Dip course directors in the United Kingdom, Ireland, Australia, New Zealand, and South Africa as well as teachers, graduates, and students of the MSc/Dip course at the University of Nottingham were surveyed. An email questionnaire listing the 29 learning outcomes was sent to the subjects. A mixed reminder via email or mail was used. The results were treated as ordinal data, and reliability and internal consistency of the questionnaire was tested using Cronbach's coefficient α.

Results: Response rates were high (75% course directors, 79%, 54%, and 78% University of Nottingham teachers, graduates, and students respectively). The questionnaire was highly reliable (α>0.8).The total scores of all but one of the responders were above the midpoint (>87, possible range 29–145). Most course directors (>80%) agreed or strongly agreed with each of the learning outcomes, except two. Most of the other subjects also agreed or strongly agreed with the learning outcomes, with few exceptions.

Conclusion: The results suggest that there is a consensus among subjects that the final listed learning outcomes should be included in an ideal MSc in sports and exercise medicine.

     

Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome

We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2-24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C>T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.