Enhancement of In Vitro Skin Transport and In Vivo Hypoglycemic Efficacy of Glimepiride Transdermal Patches

Purpose: To utilize hydroxybutyl-β-cyclodextrin (HB-β-CD) and polyvinyl pyrrolidone (PVP) for the enhancement of the transdermal delivery of glimepiride (GMD).Methods: Matrix-type transdermal patches containing GMD, drug  coprecipitate or its inclusion complex were prepared using different gelling agents, viz, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carbopol and chitosan. In vitro skin permeation evaluation of the formulations was conducted using automated diffusion system. Selected patch formulations were assessed for hypoglycemic activity as well as for GMD plasma concentration in rats.Results: GMD- hydroxybutyl-β-cyclodextrin (HB-β-CD) binary systems (1:2 molar ratio) enhanced GMD aqueous solubility by > 10-fold. Diffusion test showed improved release of GMD-HB-β-CD inclusion complex compared with GMD alone. Maximum cumulative amounts of GMD- HB-β-CD that permeated through rat skin was 26.97 and 14.28 µg/cm2 for patches prepared with fchitosan and HPMC, respectively. Thus, GMD-chitosan  patches showed significantly higher (p < 0.05) drug permeation than GMD-HPMC after 6 h. Both chitosan and HPMC patches of GMD-HB-β-CD demonstrated substantial reduction (p < 0.05) in blood glucose level (192.67 ± 21.18 and 201 ± 15.11 mg/ dl, respectively), compared with the baseline value of 240 mg/ dl.Conclusion: Application of chitosan and HPMC transdermal patches of GMD-HB-β-CD can serve as a potential alternative to peroral GMD with improved bioavailability and patient compliance.Keywords: Glimepiride, Transdermal patch, Coprecipitate, Inclusion complex, Hydroxypropyl methylcellulose, Polyvinyl pyrrolidone, Chitosan, Skin permeatio

Aquifer potential assessment in termites manifested locales using geo-electrical and surface hydraulic measurement parameters

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. In some parts of tropical Africa, termite mound locations are traditionally used to site groundwater structures mainly in the form of hand-dug wells with high success rates. However, the scientific rationale behind the use of mounds as prospective sites for locating groundwater structures has not been thoroughly investigated. In this paper, locations and structural features of termite mounds were mapped with the aim of determining the aquifer potential beneath termite mounds and comparing the same with adjacent areas, 10 m away. Soil and species sampling, field surveys and laboratory analyses to obtain data on physical, hydraulic and geo-electrical parameters from termite mounds and adjacent control areas followed. The physical and hydraulic measurements demonstrated relatively higher infiltration rates and lower soil water content on mound soils compared with the surrounding areas. To assess the aquifer potential, vertical electrical soundings were conducted on 28 termite mounds sites and adjacent control areas. Three (3) important parameters were assessed to compute potential weights for each Vertical Electrical Sounding (VES) point: Depth to bedrock, aquifer layer resistivity and fresh/fractured bedrock resistivity. These weights were then compared between those of termite mound sites and those from control areas. The result revealed that about 43% of mound sites have greater aquifer potential compared to the surrounding areas, whereas 28.5% of mounds have equal and lower potentials compared with the surrounding areas. The study concludes that termite mounds locations are suitable spots for groundwater prospecting owing to the deeper regolith layer beneath them which suggests that termites either have the ability to locate places with a deeper weathering horizon or are themselves agents of biological weathering. Further studies to check how representative our study area is of other areas with similar termite activities are recommended

Reliability evaluation of Lithium-Ion batteries for e-mobility applications from practical and technical perspectives: A case study

Copyright: © 2021 by the authors. Evaluation of the reliability of the components of electric vehicles (EVs) has been studied by international research centers, industry, and original equipment manufacturers over the last few years. Li-ion batteries are the main sensitive component of an EV’s E-power train. In other words, the Li-ion batteries for electromobility applications are one of the main components of an EV, which should be reliable and safe over the operational lifetime of the EV. Thus, investigating how to assess the reliability of the Li-ion battery has been a highly recommended task in most European projects. Moreover, with the increase in the number of new EVs made by European car companies, there has been a competition for market acquisition by these companies to win over customers and gain more market share. This article presents a comprehensive overview of the evaluation of the reliability of Li-ion batteries from practical and technical perspectives. Moreover, a case study for assessing reliability from practical and technical perspectives has been investigated.Deanship of Scientific Research at Jouf University, Saudi Arabia (Grant No. DSR-2021-02-0309)

Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

Characterization of the Drosophila Ortholog of the Human Usher Syndrome Type 1G Protein Sans

BACKGROUND: The Usher syndrome (USH) is the most frequent deaf-blindness hereditary disease in humans. Deafness is attributed to the disorganization of stereocilia in the inner ear. USH1, the most severe subtype, is associated with mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15, and sans. Myosin VIIa, harmonin, cadherin 23, and protocadherin 15 physically interact in vitro and localize to stereocilia tips in vivo, indicating that they form functional complexes. Sans, in contrast, localizes to vesicle-like structures beneath the apical membrane of stereocilia-displaying hair cells. How mutations in sans result in deafness and blindness is not well understood. Orthologs of myosin VIIa and protocadherin 15 have been identified in Drosophila melanogaster and their genetic analysis has identified essential roles in auditory perception and microvilli morphogenesis, respectively. PRINCIPAL FINDINGS: Here, we have identified and characterized the Drosophila ortholog of human sans. Drosophila Sans is expressed in tubular organs of the embryo, in lens-secreting cone cells of the adult eye, and in microvilli-displaying follicle cells during oogenesis. Sans mutants are viable, fertile, and mutant follicle cells appear to form microvilli, indicating that Sans is dispensable for fly development and microvilli morphogenesis in the follicle epithelium. In follicle cells, Sans protein localizes, similar to its vertebrate ortholog, to intracellular punctate structures, which we have identified as early endosomes associated with the syntaxin Avalanche. CONCLUSIONS: Our work is consistent with an evolutionary conserved function of Sans in vesicle trafficking. Furthermore it provides a significant basis for further understanding of the role of this Usher syndrome ortholog in development and disease

Burden of visceral leishmaniasis in villages of eastern gedaref state, Sudan: an exhaustive cross-sectional survey.

Since December 2009, Médecins Sans Frontières has diagnosed and treated patients with visceral leishmaniasis (VL) in Tabarak Allah Hospital, eastern Gedaref State, one of the main endemic foci of VL in Sudan. A survey was conducted to estimate the VL incidence in villages around Tabarak Allah

Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

Purpose: Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. Methods: We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. Results: There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Conclusions: Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus

Protocadherin 15 suppresses oligodendrocyte progenitor cell proliferation and promotes motility through distinct signalling pathways

Oligodendrocyte progenitor cells (OPCs) express protocadherin 15 (Pcdh15), a member of the cadherin superfamily of transmembrane proteins. Little is known about the function of Pcdh15 in the central nervous system (CNS), however, Pcdh15 expression can predict glioma aggression and promote the separation of embryonic human OPCs immediately following a cell division. Herein, we show that Pcdh15 knockdown significantly increases extracellular signal-related kinase (ERK) phosphorylation and activation to enhance OPC proliferation in vitro. Furthermore, Pcdh15 knockdown elevates Cdc42-Arp2/3 signalling and impairs actin kinetics, reducing the frequency of lamellipodial extrusion and slowing filopodial withdrawal. Pcdh15 knockdown also reduces the number of processes supported by each OPC and new process generation. Our data indicate that Pcdh15 is a critical regulator of OPC proliferation and process motility, behaviours that characterise the function of these cells in the healthy CNS, and provide mechanistic insight into the role that Pcdh15 might play in glioma progression

Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome

<p>Abstract</p> <p>Background</p> <p>Recessive mutations of fibroblast growth factor 3 (FGF3) can cause LAMM syndrome (OMIM 610706), characterized by fully penetrant complete labyrinthine aplasia, microtia and microdontia.</p> <p>Methods</p> <p>We performed a prospective molecular genetic and clinical study of families segregating hearing loss linked to <it>FGF3 </it>mutations. Ten affected individuals from three large Pakistani families segregating <it>FGF3 </it>mutations were imaged with CT, MRI, or both to detect inner ear abnormalities. We also modeled the three dimensional structure of FGF3 to better understand the structural consequences of the three missense mutations.</p> <p>Results</p> <p>Two families segregated reported mutations (p.R104X and p.R95W) and one family segregated a novel mutation (p.R132GfsX26) of <it>FGF3</it>. All individuals homozygous for p.R104X or p.R132GfsX26 had fully penetrant features of LAMM syndrome. However, recessive p.R95W mutations were associated with nearly normal looking auricles and variable inner ear structural phenotypes, similar to that reported for a Somali family also segregating p.R95W. This suggests that the mild phenotype is not entirely due to genetic background. Molecular modeling result suggests a less drastic effect of p.R95W on FGF3 function compared with known missense mutations detected in fully penetrant LAMM syndrome. Since we detected significant intrafamilial variability of the inner ear structural phenotype in the family segregating p.R95W, we also sequenced <it>FGF10 </it>as a likely candidate for a modifier. However, we did not find any sequence variation, pointing out that a larger sample size will be needed to map and identify a modifier. We also observed a mild to moderate bilateral conductive hearing loss in three carriers of p.R95W, suggesting either a semi-dominant effect of this mutant allele of <it>FGF3</it>, otitis media, or a consequence of genetic background in these three family members.</p> <p>Conclusions</p> <p>We noted a less prominent dental and external ear phenotype in association with the homozygous p.R95W. Therefore, we conclude that the manifestations of recessive <it>FGF3 </it>mutations range from fully penetrant LAMM syndrome to deafness with residual inner ear structures and, by extension, with minimal syndromic features, an observation with implications for cochlear implantation candidacy.</p