Molecular mechanism of the skin permeation enhancing effect of ethanol: a molecular dynamics study

Ethanol is widely used in various pharmaceutical and cosmetic formulations in order to enhance skin penetration of active ingredients. While it is well known that ethanol partitions into the skin and enhances the permeation of both polar and nonpolar molecules, the exact mechanisms by which it enhances skin permeability are not fully understood. Several mechanisms have been proposed including lipid extraction from the stratum corneum (SC), fluidisation of SC lipid bilayer, alteration of SC protein conformation and enhancement of the drug solubility in the SC lipids. In this study, we performed molecular dynamics (MD) simulations of SC lipid bilayers comprised of an equimolar mixture of ceramides, cholesterol and free fatty acid in the presence of aqueous mixtures of ethanol. Various unrestrained MD simulations were performed in the presence of aqueous ethanol solution at molar ratios (x) ranging from x = 0 to x = 1. It was found that ethanol enhances bilayer permeability by dual actions (a) extraction of the skin lipids and (b) enhancing the mobility of lipid chains. Ethanol''s permeation enhancing effect arises from its superior ability to form hydrogen bonds with headgroup atoms of skin lipids. Further, the free energy of extraction of ceramides (CER) and fatty acids (FFA) from the lipid bilayer was studied using umbrella sampling simulations. The free energy of extraction of CER was found to be much higher compared to FFA for all ethanol concentrations which shows that CER are difficult to extract as compared to FFA. Finally, the permeation of benzoic acid drug molecules through the skin lipid bilayer is shown in presence of ethanol molecules. It was found that ethanol selectively targets the FFA of the skin lipid bilayer and extracts it out of the lipid bilayer within few microseconds. Further, ethanol penetrates inside the lipid layer and creates the channels from which drug molecules can easily cross the lipid layer. Our observations (both in unrestrained and umbrella sampling simulations) are consistent with the experimental findings reported in the literature. The simulation methodology could be used for design and testing of permeation enhancers (acting on skin SC lipid lamella) for topical and transdermal drug delivery applications.

Concentration dependent action of mechanism of ethanol on skin SC lipid barrier.     

Early postoperative voiding dysfunction after insertion of retropubic midurethral tape

Introduction and hypothesis

A significant proportion of patients develop voiding dysfunction after midurethral tape (MUT) insertion, which reduces patient satisfaction. The study’s purpose was to identify predictive factors of voiding dysfunction after a retropubic MUT procedure.

Methods

This was a retrospective study of 100 patients who underwent only a retropubic MUT procedure between January 2010 and December 2011. Early voiding dysfunction was defined when patients required a Foley catheter within 48 h. Data including demographic information, urogenital symptoms, previous surgery, preoperative uroflowmetry and urodynamic parameters were analysed using SPSS v22. Univariate analysis of all demographic variables was performed; those significant at 10 % were entered into a multivariate logistic regression.

Results

Fourteen patients required Foley catheter insertion, with a median age of 58 years (26–83 years), median BMI 28 kg/m² (20–48 kg/m2), and median parity 2 (0–4). Univariate analysis revealed peak flow rate <15 ml/s (OR 3.79; 1.07, 13.4; p?=?0.046), bladder capacity (p?=?0.044), stress incontinence versus mixed or urge incontinence (p?=?0.064) and previous surgery (OR 4.39; 1.34, 14.41; p?=?0.015) to be associated with voiding dysfunction. Multivariate analysis showed only previous pelvic floor surgery to be independently associated (OR 3.76; 1.14, 12.23, p?=?0.029).

Conclusions

Only previous pelvic-floor surgery was found to be a strong predictive factor of voiding dysfunction. The rate of voiding dysfunction was similar to those of published data. Previous studies revealed different predictive factors. A larger cohort is needed to provide a definite answer. Those with previous surgery appear to be those most at risk and pre-surgical counselling for these women could be suggested.

     

A case of poly-parasitism involving a trematode and four different nematodes in a migrant from Bihar

Reported is a case of seven-year-old, migrant from Bihar state, infested with Fasciolopsis buski Strongyloides stercoralis Ascaris lumbricoides, Trichuris trichiura and Ankylostoma duodenale in feces. Patient responded to treatment with piperazine, thiabendazole and albendazole, the importance of considering multiple and non-endemicparasite infestations in migrant of poor socio-economic background is emphasized.     

Placental pathology of recurrent spontaneous abortion: the role of histopathological examination of products of conception in routine clinical practice: a mini review

BACKGROUND: Histopathological examination of products of conception from miscarriages is part of routine clinical practice. The extent of additional clinically relevant information provided by this investigation in the setting of recurrent spontaneous abortion remains uncertain. METHODS: Review of the literature was performed to identify studies reporting on findings of histological examination of routinely obtained products of conception in the setting of recurrent spontaneous abortion. The initial search identified 312 potential references, but 300 were excluded on further examination due to lack of data on specific histopathological findings in routine products of conception specimens from patients with recurrent spontaneous abortion. The 12 included studies indicated that such examination may identify hydatidiform moles, villous dysmorphic features suggesting fetal aneuploidy, chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition and impaired trophoblast invasion. However, in most cases, morphological assessment cannot reliably determine the cause of the miscarriage or distinguish recurrent from sporadic miscarriage. Studies reporting on the use of additional immunohistochemical methods do not currently provide additional clinically useful diagnostic or prognostic information. CONCLUSION: Routine histological examination of products of conception in the setting of recurrent spontaneous abortion can provide important clinical information in a minority of cases.     

Trans-peritoneal vs. retroperitoneal robotic assisted partial nephrectomy in posterior renal tumours: need for a risk-stratified patient individualised approach. A systematic review and meta-analysis

Journal of Robotic Surgery - To systematically review world literature and compare peri-operative outcome including operating time (OT), estimated blood loss (EBL), warm ischemia time (WIT), length...     

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(−/−) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg^AQP11) that express 3×HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg^AQP11 mice and rescued renal cystogenesis in AQP11(−/−) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(−/−) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(−/−) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/−) background increased the severity of cystogenesis in AQP11(−/−) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(−/−) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(−/−) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(−/−) mice could be a key mechanism of cystogenesis in AQP11(−/−) mice.Aquaporin-11 (AQP11) is a membrane-channel protein. Although AQP11 is reported to be permeable to the water molecule,^1–3 the permeability of AQP11 to other solutes remains unclear. AQP11(−/−) mice die in the neonatal period because of renal failure and retarded growth.^4,5 Moreover, AQP11(−/−) mice develop renal cysts, suggesting that AQP11 can play a role in cystogenesis.^4,5 However, the mechanisms of cystogenesis in AQP11(−/−) mice have yet to be clarified. One of the reasons for the difficulties in investigating AQP11 has been the lack of a good antibody for detecting endogenous AQP11 in mouse tissues.Autosomal dominant polycystic kidney disease (PKD) is the most common inherited renal disorder, occurring in 1:400 to 1:1000 live births. It is characterized by gradual renal cyst development and expansion, ultimately resulting in massive kidney enlargement and ESRD. Among autosomal dominant PKD patients, 85%–90% of cases result from mutations in the PKD1 gene, whereas another 10%–15% of cases are accounted for by mutations in the PKD2 gene. PKD1 encodes polycystin-1 (PC-1), a 462-kD, 4303–amino acid integral membrane protein with 11 transmembrane domains, a long extracellular N terminus with multiple binding domains, and a short cytoplasmic C terminus that interacts with multiple proteins, including the protein product of PKD2, polycystin-2 (PC-2).⁶ PC-2 is a significantly smaller 110-kD protein with six transmembrane domains. PC-1 and PC-2 are located in the plasma membrane and cilia of renal epithelia.^6–8To enable the analyses of AQP11 in mice at the protein level in vivo, we generated AQP11 BAC transgenic mice (Tg^AQP11) that express AQP11 tagged with 3×hemagglutinin (HA) sequence at its N terminus and showed that AQP11 localizes to the endoplasmic reticulum (ER) of proximal tubule cells in vivo. Moreover, to investigate the mechanisms of cystogenesis in AQP11(−/−) mouse kidneys, we focused on PC-1 and PC-2. Impaired glycosylation processing and membrane trafficking of PC-1 in AQP11(−/−) mouse kidneys were found, which could represent a key mechanism of cyst formation in AQP11(−/−) mice.