Evidence that drug flux across synthetic membranes is described by normally distributed permeability coefficients.

Over recent decades, the use of in vitro diffusion cell studies to assess skin permeability has evolved into a major research tool, providing key insights into the relationships between skin, drug and formulation. Sometimes, such studies involve synthetic membranes as this approach can yield useful inferences with respect to drug-skin partitioning and diffusion phenomena. Yet despite the popularity of such studies, it is still not at all known whether typical solute transport across synthetic barriers results in a normal distribution of permeability coefficients or alternatively some type of skewed distribution. The present study aims to shed light on this issue. To this end, five compounds (testosterone, oestradiol, corticosterone, aldosterone and adenosine) exhibiting a broad range of octanol-water partition coefficient values were selected as test penetrants. The protocol involved taking multiple replicate measurements of each drug's passive steady state flux through poly(dimethylsiloxane) membrane. Each penetrant's resultant permeability coefficient database was subjected to a Kolmogorov-Smirnov (KS) test for normality. It was found that the permeability coefficients of all five drugs were distributed in a Gaussian-normal fashion. The theoretical significance and practical impact of these findings are discussed.     

Toll-like receptor signaling inhibits structural development of the distal fetal mouse lung.

We tested the hypothesis that innate immune signaling in utero could disrupt the structural development of the fetal lung, contributing to the pathogenesis of bronchopulmonary dysplasia. Injection of Escherichia coli lipopolysaccharide (LPS) into the amniotic fluid of E15 BALB/cJ mice increased the luminal volume density of fetal mouse lungs at embryonic day (E) 17 and E18. LPS also increased luminal volume and decreased distal lung branching in fetal mouse lung explants. This effect required NF-kappaB activation and functional Toll-Like Receptor 4. Airway branching may require fibronectin-dependent epithelial-mesenchymal interactions, representing a potential target for innate immune signaling. Anti-fibronectin antibodies and LPS both blocked distal lung branching. By immunofluorescence, fibronectin localized to the clefts between newly formed airways but was restricted to peripheral mesenchymal cells in LPS-exposed explants. These data suggest that LPS may alter the expression pattern of mesenchymal fibronectin, potentially disrupting epithelial-mesenchymal interactions and inhibiting distal airway branching and alveolarization. This mechanism may link innate immune signaling with defects in structural development of the fetal lung.     

Human leukocyte antigen and adult living-donor liver transplantation outcomes: an analysis of the organ procurement and transplantation network database.

Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease.     

Deletion of aldose reductase leads to protection against cerebral ischemic injury.

Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR(-/-) brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR(-/-) brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron- and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.     

Parental perception of neonatal intensive care in public sector hospitals in South Africa.

BACKGROUND: Little is known about parental experience and decision making with regard to premature infants requiring intensive care in developing countries. We undertook this study to characterise parents' experience of physician counselling and their role in making life-support decisions for very low-birth-weight (VLBW) (birth weight < 1 501 g) infants born in South Africa's public-sector neonatal intensive care units (NICUs). METHODS: Parents of surviving VLBW infants treated in three Johannesburg-area public hospitals and attending follow-up clinics in August 2001 were interviewed regarding their experience of perinatal counselling on outcomes (pain, survival, disability), perception of actual and optimal decision making, and satisfaction with NICU communication. RESULTS: Parents of 51 infants were interviewed. Seventy-five per cent of parents reported antenatal counselling by physicians on at least one perinatal topic (severe disability, pain, death, finances or religious/moral considerations). The majority of parents (> 60%) who received counselling thought that these topics had been discussed adequately. Most parents reported that doctors had the primary decision-making role, either without consulting them (41%) or after consulting them (37%). Joint decision making was rare (14%). Parents wanted more input in life-support decisions than they reported being given. CONCLUSION: Counselling is not consistently provided in public-sector hospitals in Johannesburg. Parents of premature infants want a larger share in NICU decision making than they currently experience. Most parents were satisfied with communication later during their infant's hospitalisation. South Africa presents a unique opportunity to study the use of advanced medical technologies in a nation with marked disparities in access to care.     

Bilateral naevus of Ota: a rare manifestation in a Caucasian

The naevus of Ota (naevus fusculocoeruleus ophthalmomaxillaris) was first described by the Japanese dermatologist M. T. Ota in 1939. It has a reported incidence of 0.2% to 1% in the Japanese population. It usually occurs in the skin innervated by the first or second branch of the trigeminal nerve. The naevus comprises dermal melanocytes and is congenital or acquired during adolescence. Commonly associated lesions include scleral melanocytosis and other ocular manifestations as well as lesions of the tympanic membrane, oral and intranasal mucosa and leptomeninges. Diseases associated with Ota's naevus in rare cases are open-angle glaucomas and melanoma. The naevus of Ota in Europeans is a rare manifestation. We report the very rare case of a bilateral naevus of Ota associated with enoral melanocytosis in a white European person.     

Surgery for posterior inguinal wall deficiency in athletes

This study retrospectively evaluated the outcome for patients undergoing herniorraphy for chronic groin pain due to posterior inguinal wall deficiency, and correlated the outcome with preoperative investigation findings. There were 47 patients (with a total of 52 herniorraphies) who were contacted by phone between six and 50 months post surgery. Subjects had a diagnosis of posterior inguinal wall deficiency made on history and clinical examination. Thirty seven patients had an ultrasound scan prior to the surgery (three bilateral) with a total of 40 symptomatic groins scanned. There were 26 abnormal scans (22 posterior inguinal wall deficiency and four hernias) and 14 normal scans. Twenty nine patients had a technetium-99m bone scan with 22 having increased uptake at the symptomatic pubic tubercle, while 13 had increased uptake at other sites in the groin. Seventy seven percent of patients had a full return to sport after surgery and the average time to return to sport was four months. There was no significant difference in outcome between subjects who had an abnormal ultrasound scan on the symptomatic side and those who had a normal scan. There was a significant difference in outcome between patients who had a bone scan with increased uptake at the symptomatic pubic tubercle and those who did not (p < 0.04). Our study supports previous research that good results can be obtained with surgery when posterior inguinal wall deficiency is the sole diagnosis. Ultrasound scan does not appear to aid in predicting surgical outcome, while the role of isotope bone scanning requires further study.     

Narrowband UVB therapy for vitiligo: does the repigmentation last?

BACKGROUND: Since 1997, a number of trials have shown promising results in treating generalized vitiligo with narrowband ultraviolet B (UVB) both in adults and children. However, there is little knowledge concerning the duration and permanency of the treatment-induced repigmentation. OBJECTIVE: Our main objective was to perform a follow-up trial of successfully treated patients receiving narrowband UVB for generalized vitiligo. METHODS: We have investigated to what degree the treatment-induced repigmentation remains stable for up to 2 years post-treatment. We performed an initial open trial including 31 patients with generalized vitiligo. They received narrowband UVB thrice weekly for up to 12 months. Patients experiencing > 75% repigmentation were defined responders and were included in the follow-up trial. Responders were followed every 6 months for up to 2 years after cessation of treatment. We observed the pigmentation status and registered any changes indicating loss of pigmentation and relapse. RESULTS: Eleven of the 31 treated patients were included in the follow-up trial. Six patients had relapse and five patients had stable response 24 months after cessation of treatment. Four out of six relapses were within 6 months post-treatment. CONCLUSION: In our study population of 31 patients with generalized vitiligo, five patients (16%) experienced > 75% stable repigmentation 2 years after cessation of a treatment programme of up to 1 years narrowband UVB therapy.