G-protein coupled receptors & autism -- reflections on a double-edged sword at the example of the oxytocin receptor system.

G-protein coupled receptors (GPCR) tend to desensitize/internalize when exposed to excess agonist.Previously, we have supported the argument that in the case of the oxytocin receptor (OTR), excess agonist (oxytocin, OT) at birth could be implicated with behavioural disorders of the autistic spectrum. In this review, more recent evidence for this hypothesis is summarized, and it is juxtaposed against reports where exogenous OT was found beneficial in alleviating certain undesired behaviours. Facing this dichotomy, we suggest possible in silico drug discovery approaches to mitigate undesired side effect of OT administration/OTR desensitization, especially in the light of potentially emerging agonist therapies. For this, the most important structural features of OTR are reviewed, and we highlight here the need for higher level of theory studies at the easier approachable extracellular receptor side, where loop 3(e3) and the N-terminated strain of OTR appear to offer targets of particular interest for the development of an agent that conditions the action of excess OT. Another approach, based on the development of new agonists with an improved receptor activation to receptor phosphorylation ratio, is also discussed. Finally, the issue of OTR desensitization is put into the broader context of GPCR desensitization and possible implications for behavioural disorders, and the case is made for the usefulness of computational studies in this area.

A study of use of low dose aspirin in prevention of pregnancy induced hypertension.

Forty-six nulliparous women in third trimester of pregnancy with a raised blood pressure of 30 mm Hg (systolic) or/and 15 mm Hg (diastolic) or both, over baseline values were treated with 75 mg of aspirin per day. The results are compared with another 48 age, height, weight, and gestational period matched nulliparaous women with similar condition for trial selection, who were treated as control. There is considerable more number of cases in the control group than in aspirin treated group showing subsequent rise of BP, appearance of proteinuria, and severe pre-eclamptic toxaemia. The aspirin treated group showed increased mean gestational age at termination 39.4 +/- 2.6 weeks as against 38.2 +/- 3.4, increased foetal weight 2860 +/- 552 g as against 2540 +/- 720 g. No case of neonatal haemorrhagic manifestations or congenital malformations were seen. However not much result is obtained with aspirin therapy in cases with established pregnancy induced hypertension or with proteinuria. Hence it is concluded that aspirin therapy should be given to prevent pregnancy induced hypertension. As predictability of other screening tests are not unequivocal, criterion used in this series for screening may be used.

Use of calcium antagonist (nifedipine) in premature labour.

Effectiveness of nifedipine in suppressing premature uterine activity was studied on 20 normal pregnant women who received, depending on the frequency of uterine contractions and degree of cervical dilatation, 5-10 mg nifedipine orally 8 hourly till the uterine contractions were abolished followed by 5 mg 12 hourly up to 38 weeks of gestation. Another 20 age, gravida and gestational period matched normal pregnant women received 10 mg isoxsuprine hydrochloride orally 8 hourly till the uterine contractions were abolished, followed by 10 mg 12 hourly up to 38 weeks of gestation. Successful tocolysis was observed in 85% of cases receiving nifedipine in contrast to 40% of women receiving isoxsuprine hydrochloride. The mean time from presentation to delivery and mean birth weight were 21.8 days and 2510 g respectively in isoxsuprine hydrochloride treated cases and 34.2 days and 2750 g respectively in cases treated with nifedipine. In either group there were no serious untoward effects on mother, labour and baby.

Purification and properties of a carboxymethylcellulase from phytopathogenic fungus Macrophomina phaseolina.

From the culture filtrate of Macrophomina phaseolina, two forms of carboxymethylcellulase were separated by ion-exchange chromatography and designated as CMCase-I and CMCase-II. CMCase-I was purified following a four-step procedure involving gel filtration on Sephadex G-75, Con-A Sepharose 4B affinity chromatography, fast protein liquid chromatography on mono Q anion-exchanger and on Superose 12 gel filtration. The final preparation was homogeneous by SDS-PAGE, isoelectric focussing in thin layers of polyacrylamide gels and immunoelectrophoresis. The enzyme showed optimum activity at pH 5.5 and 65 degrees C, was stable to heating at 65 degrees C for 10 min, and retained 31% of original activity after heating at 80 degrees C for 10 min. The molecular weight of the enzyme was 3.5 x 10(4) Da. A Km of 0.25 mg/ml was determined using carboxymethyl-cellulose as the substrate.