Obstetric anal sphincter injury: prospective evaluation of incidence

PURPOSE: An obstetrically damaged anal sphincter is the principal cause of the development of fecal incontinence in otherwise healthy females. Reports suggest that such damage complicates as many as 35 percent of primiparous vaginal deliveries, with 13 percent of first-time mothers becoming symptomatic. In maternity units delivering 3,000 patients annually, it would follow that 390 symptomatic patients would develop new symptoms each year. This incidence of dysfunction does not reflect current clinical practice. We have investigated this discrepancy to establish the actual incidence of anal sphincter trauma associated with childbirth. METHODS: During a six-week period, 159 females (105 primiparous and 54 para-I) were prospectively assessed postnatally using a standardized symptom questionnaire, endoanal ultrasound, and anal manometry. This group constituted 84 percent of all eligible deliveries occurring in the unit during the study period. RESULTS: One patient developed fecal urgency after this delivery; there were no reports of fecal incontinence. Anal sphincter injuries were identified ultrasonically in 6.8 percent of primiparous patients, 12.2 percent of para-I patients having vaginal deliveries, and 83 percent of patients having forceps deliveries overall. Manometric data provided confirmatory evidence, with significantly reduced maximum squeeze pressures in patients with a disrupted anal sphincter (P<0.0005). CONCLUSIONS: A symptom questionnaire is inadequate to identify anal sphincter injuries. The incidence of sphincter injury in relation to vaginal delivery has been overestimated in previous published work. This study demonstrates that the true incidence is 8.7 percent overall and that symptoms of sphincter dysfunction are uncommon this is in keeping with current clinical practice.     

Bioactive nano‐fibrous scaffold for vascularized craniofacial bone regeneration

There has been a growing demand for bone grafts for correction of bone defects in complicated fractures or tumours in the craniofacial region. Soft flexible membrane like material that could be inserted into defect by less invasive approaches; promote osteoconductivity and act as a barrier to soft tissue in growth while promoting bone formation is an attractive option for this region. Electrospinning has recently emerged as one of the most promising techniques for fabrication of extracellular matrix such as nano‐fibrous scaffolds that can serve as a template for bone formation. To overcome the limitation of cell penetration of electrospun scaffolds and improve on its osteoconductive nature, in this study, we fabricated a novel electrospun composite scaffold of polyvinyl alcohol (PVA)‐poly (ε) caprolactone (PCL)‐Hydroxyapatite based bioceramic (HAB), namely, PVA‐PCL‐HAB. The scaffold prepared by dual electrospinning of PVA and PCL with HAB overcomes reduced cell attachment associated with hydrophobic PCL by combination with a hydrophilic PVA and the HAB can contribute to enhance osteoconductivity. We characterized the physicochemical and biocompatibility properties of the new scaffold material. Our results indicate PVA‐PCL‐HAB scaffolds support attachment and growth of stromal stem cells; [human bone marrow skeletal (mesenchymal) stem cells and dental pulp stem cells]. In addition, the scaffold supported in vitro osteogenic differentiation and in vivo vascularized bone formation. Thus, PVA‐PCL‐HAB scaffold is a suitable potential material for therapeutic bone regeneration in dentistry and orthopaedics.     

Dealing with the complex drug–drug interactions: Towards mechanistic models

Unmanageable severe adverse events caused by drug‐drug interactions (DDIs), leading to market withdrawals or restrictions in the clinical usage, are increasingly avoided with the improvement in our ability to predict such DDIs quantitatively early in drug development. However, significant challenges arise in the evaluation and/or prediction of complex DDIs caused by inhibitor drugs and/or metabolites that affect not one but multiple pathways of drug clearance. This review summarizes the discussion topics at the 2013 AAPS symposium on “Dealing with the complex drug‐drug interactions: towards mechanistic models”. Physiologically based pharmacokinetic (PBPK) models, in combination with the established in vitro‐to‐in vivo extrapolations of intestinal and hepatic disposition, have been successfully applied to predict clinical pharmacokinetics and DDIs, especially for drugs with CYP‐mediated metabolism, and to explain transporter‐mediated and complex DDIs. Although continuous developments are being made towards improved mechanistic prediction of the transporter‐enzyme interplay in the hepatic and intestinal disposition and characterizing the metabolites contribution to DDIs, the prediction of DDIs involving them remains difficult. Regulatory guidelines also recommended use of PBPK modeling for the quantitative prediction and evaluation of DDIs involving multiple perpetrators and metabolites. Such mechanistic modeling approaches culminate to the consensus that modeling is helpful in predicting DDIs or quantitatively rationalizing the clinical findings in complex situations. Furthermore, they provide basis for the prediction and/or understanding the pharmacokinetics in populations like patients with renal impairment, pediatrics, or various ethnic groups where the conduct of clinical studies might not be feasible in early drug development stages and yet some guidance on management of dosage is necessary. Copyright © 2014 John Wiley & Sons, Ltd.     

Common variable immunodeficiency in an adult

Primary immunodeficiency syndromes are rarely diagnosed among adults. In this report, we describe a young male who had common variable immunodeficiency. He was treated with intravenous immunoglobulin and, on follow up, has been free of opportunistic infections.     

Prolonged hypercapnia-evoked cerebral hyperemia via K(+) channel- and prostaglandin E(2)-dependent endothelial nitric oxide synthase induction

Mechanisms for secondary sustained increase in cerebral blood flow (CBF) during prolonged hypercapnia are unknown. We show that induction of endothelial NO synthase (eNOS) by an increase in prostaglandins (PGs) contributes to the secondary CBF increase during hypercapnic acidosis. Ventilation of pigs with 6% CO(2) (PaCO(2 approximately)65 mm Hg; pH approximately 7.2) caused a approximately 2.5-fold increase in CBF at 30 minutes, which declined to basal values at 3 hours and gradually rose again at 6 and 8 hours; the latter increase was associated with PG elevation, nitrite formation, eNOS mRNA expression, and in situ NO synthase (NOS) reactivity (NADPH-diaphorase staining). Subjecting free-floating brain sections to acidotic conditions increased eNOS expression, the time course of which was similar to that of CBF increase. Treatment of pigs with the cyclooxygenase inhibitor diclofenac or the NOS inhibitor Nomega-nitro-L-arginine blunted the initial rise and prevented the secondary CBF increase during hypercapnic acidosis; neuronal NOS blockers 1-(2-trifluoromethylphenyl) imidazole and 3-bromo-7-nitroindazole were ineffective. Diclofenac abolished the hypercapnia-induced rise in cerebrovascular nitrite production, eNOS mRNA expression, and NADPH-diaphorase reactivity. Acidosis (pH approximately 7.15, PCO(2 approximately )40 mm Hg; 6 hours) produced similar increases in prostaglandin E(2) (PGE(2)) and eNOS mRNA levels in isolated brain microvessels and in NADPH-diaphorase reactivity of brain microvasculature; these changes were prevented by diclofenac, by the receptor-operated Ca(2+) channel blocker SK&F96365, and by the K(ATP) channel blocker glybenclamide. Acidosis increased Ca(2+) transients in brain endothelial cells, which were blocked by glybenclamide and SK&F96365 but not by diclofenac. Increased PG-related eNOS mRNA and NO-dependent vasorelaxation to substance P was detected as well in rat brain exposed to 6 hours of hypercapnia. PGE(2) was the only major prostanoid that modulated brain eNOS expression during acidosis. Thus, in prolonged hypercapnic acidosis, the secondary CBF rise is closely associated with induction of eNOS expression; this seems to be mediated by PGE(2) generated by a K(ATP) and Ca(2+) channel-dependent process.     

Supravalvular aortic stenosis and coronary ostial stenosis in homozygous familial hypercholesterolemia

Patients with homozygous familial hypercholesterolemia exhibit severe hypercholesterolemia, cutaneous and tendon xanthomata, and premature atherosclerosis from childhood. A rare presentation of this condition with supravalvular aortic stenosis and coronary ostial stenosis is described.