Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.     

Non-invasive molecular imaging for preclinical cancer therapeutic development

Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development.     

Depot-medroxyprogesterone acetate in anticoagulated patients with previous hemorrhagic corpus luteum

Objective?To investigate the safety of depot-medroxyprogesterone acetate (DMPA) in women of reproductive age with prosthetic heart valves, as well as the impact of DMPA on the prevention of hemorrhagic corpus luteum in these patients with previous bleeding events.

Methods?In this prospective study we enrolled 13 patients who were receiving chronic anticoagulation for prosthetic heart valves, and who suffered from ovarian bleeding. After the initial bleeding episode(s), DMPA was initiated with the intent of preventing recurrent bleeding events by means of ovulation suppression. Follow-up included close monitoring of anticoagulation intensity, lipid profile, measurement of systolic and diastolic blood pressures and weight, and a general physical and gynecological examination.

Results?Of the participating 13 patients, one stopped DMPA after the third injection because she wanted to have a child. Among the remaining 12 women, over a mean follow-up of 39.9 months all patients were well and no hemorrhagic corpus luteum was observed. During the follow-up, anticoagulation intensity, assessed by the international normalized ratio (INR), was in the optimum therapeutic ranges at all times (range 2.5–3.5), except for values of 4.6, 5.8 and 5.9 in three patients at 9, 12 and 24 months, respectively. With regard to lipid profile, we observed a significant decrease in high-density lipoprotein cholesterol levels at 12 months, and significant increases in total cholesterol and triglyceride levels after 30 months compared to baseline serum levels. No significant changes were observed in serum low-density lipoprotein cholesterol levels. Mean body weight was higher at months 12 and 30, compared with baseline values (p?>?0.05).

Conclusion?DMPA, which is an effective contraceptive agent, can be used to prevent bleeding from the corpus luteum by means of ovulation suppression in anticoagulated patients with prosthetic heart valves. However, meticulous surveillance should be provided during the follow-up, including close monitoring of anticoagulation intensity and lipid profile.     

Oral Cancer Screening at Workplace in India��One-year Follow-up

Background:

Oral cancer remains the commonest form of cancer and cancer-related deaths among Indian males due to popularity of avoidable risk factors such as tobacco and alcohol use. A workplace oral cancer screening and tobacco cessation study was commenced on World No Tobacco Day 2007 at a chemical industry in rural Maharashtra.

Aims:

The objectives were to screen the employees for oral neoplasia and to correlate it with their tobacco consumption pattern. In addition, the objective was to provide tobacco cessation services at the workplace.

Materials and Methods:

This is an interventional cohort study among 104 employees of a chemical industrial unit in rural Maharashtra. Naked eye examination of the oral cavity was performed for all employees by a doctor irrespective of the tobacco habits at the beginning and at the end of 1 year. In between, the tobacco users were regularly examined during each follow-up.

Statistical analysis used:

Through personal interviews of the participants, data were manually recorded and were transferred to electronic data base. Data analysis was conducted in STATA™ 8.2 on intention to treat basis.

Results and Conclusions:

Among the 104 employees, 50 (48.08%) were current tobacco users at the beginning of the program. Oral precancers were seen exclusively among 20 (40%) tobacco users. After 1 year of workplace tobacco cessation intervention, 80% of oral precancers regressed. This shows that screening of the oral cavity at the workplace is effective when combined with tobacco cessation.     

Puri cation of Lovastatin from Aspergillus terreus (KM017963) and Evaluation of its Anticancer and Antioxidant Properties

Cervical cancer is the second most common malignancy in women worldwide and thus one of the leading causes of mortality in women. Lovastatin, a non polar, anticholesterol drug has previously been reported to exert antitumour activity in vitro. In the present study, lovastatin from Aspergillus terreus (KM017963) was puri ed by adsoprtion chromatography and evaluated for its anticancer and anti-oxidant properties with a human cervical cancer cell line (HeLa). Growth inhibitory and proapoptotic effects of puri ed lovastatin on HeLa cells were investigated by determining its in uence on cell numbers, mitochondrial membrane potential (MMP), DNA fragmentation and antioxidant properties in terms of hydroxy radical scavenging effects as well as levels of total reduced glutathione. Cell cycle analysis by ow cytometry (propidium iodide staining) con rmed induction of apoptotic cell death and revealed cell cycle arrest in the G0/G1 phase. Results of the study give leads for the anticancer effects of lovastatin and its potential usefulness in the chemotherapy of cervical cancer.     

Tonabersat, a gap-junction modulator: efficacy and safety in two randomized, placebo-controlled, dose-ranging studies of acute migraine

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.     

A mouse model linking viral hepatitis and salivary gland dysfunction

Objective:  Viral hepatitis is known to cause xerostomia in humans, but this has not been reported in an animal model. We report a severe, acute, highly reproducible saliva deficiency occurring in BALB/c mice as a result of experimental viral hepatitis.
Materials and Methods:  BALB/c mice, splenectomized or carrying genetic mutations to detect immunological contributions to the saliva deficiency syndrome, were infected intraperitoneally with a non-lethal dose of murine cytomegalovirus. Pilocarpine-stimulated saliva volumes were determined between 0 and 15 days after infection. Salivary gland, liver, spleen, and sera were analyzed for the presence of virus, cytokines, inflammatory infiltrates, and tissue damage.
Results:  Saliva deficiency was detectable 2 days after cytomegalovirus infection, peaked at 88% below normal by day 7, and resolved partially in all mice by 15 days postinfection as sialoadenitis increased. Neither salivary gland viral titers, sialoadenitis, splenectomy, nor systemic inflammatory markers correlated with hyposalivation severity. Elevated liver enzymes did correlate with hyposalivation, and mice genetically resistant to murine cytomegalovirus-induced hepatitis were significantly protected.
Conclusions:  Murine cytomegalovirus-induced salivary gland dysfunction is biphasic, with an acute hepatitis-associated phase and a later sialoadenitis-associated phase. Acute murine cytomegalovirus infection of BALB/c mice may provide a model for investigation of hepatitis-associated xerostomia.     

Salmonella meningitis and its complications in infants

OBJECTIVE: To review the presenting features, complications and outcome of infants with Salmonella meningitis. METHODOLOGY: Retrospective review of all cultures of cerebrospinal fluid positive for bacteria in children below 12 years of age, processed at the Department of Medical Microbiology, University of Malaya Medical Centre, Kuala Lumpur from 1973 to 1997. Records of all cases positive for Salmonella species were retrieved and studied. RESULTS: Thirteen infants aged 3 days to 9 months with Salmonella meningitis were included. The median age of onset of symptoms was 4 months. The clinical and laboratory features were similar to other causes of bacterial meningitis. Salmonella enteritidis was the commonest serotype isolated. Nine infants developed fits, six of which were difficult to control. Other complications noted were hydrocephalus (five), subdural effusions (four), empyema (three), ventriculitis (two), intracranial haemorrhage and cerebral abscess (one each). The use of ampicillin and/or chloramphenicol and inadequate duration of therapy resulted in recrudescence or relapse in five infants. The overall mortality was 18%. The presence of empyema, intracerebral abscess, ventriculitis, hydrocephalus, and intracranial haemorrhage were associated with adverse neurodevelopmental sequelae or death. More than half of those who survived had normal long-term outcome. CONCLUSION: Infants who developed neurological complications as a result of Salmonella meningitis had significant mortality and adverse long-term neurodevelopment outcome.