Impact of variants on type-2 diabetes risk genes identified through genomewide association studies in polycystic ovary syndrome: a case–control study

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females, and is associated with altered metabolic processes in particular insulin resistance and diabetes mellitus. PCOS shares with type-2 diabetes (T2D) a number of features, including beta cell dysfunction, impaired glucose tolerance and dyslipidaemia. Recently, genomewide association studies (GWAS) have reported a number of genes with reproducible associations and susceptibilities to T2D. To address this, we examined the association between the T2D GWAS candidate genes (CDKAL1, CDKN2B, COL8A1, HHEX, IGF2BP2, KCNJ1, KCNQ1 and SLC30A8) and PCOS in Saudi women. A case–control study, includes 162 cases and 162 controls was enrolled. Genotyping was carried out by the allelic discrimination method. Our results showed that the variants including rs792837 of COL8A1, rs61873498 of KCNQ1 and rs13266634 of SLC30A8 genes to be significantly more frequent in PCOS patients than in controls. Our results suggest that COL8A1, KCNQ1 and SLC30A8, which are previously identified through GWAS as T2D-associated genes, are associated with PCOS.     

Impact of CYP3A5 and MDR-1 gene polymorphisms on the dose and level of tacrolimus among living-donor liver transplanted patients: single center experience

Aim of work: To assess the impact of Cytochrome P450 3A5 (CYP3A5) and multidrug resistance-1 gene (MDR-1) single nucleotide polymorphisms on the dose and blood level of tacrolimus among liver transplanted patients.

Patients and methods: We enrolled a prospective study of 41 liver transplanted patients. Dose-adjusted trough blood concentration (C/D ratio) was calculated. Polymerase chain reaction-restriction fragment length polymorphism followed by sequencing was done for genotyping of CYP3A5*3 (6986A?>?G).

Results: At 1 week, 1 and 3 months C/D ratio were significantly lower in CYP3A5 expressers *1/*1 patients compared to non-expressers *3/*3.

Conclusion: CYP3A5 (6986A?>?G) genotype, rather than MDR-1 (2677G?>?A/T) variant, has an impact on tacrolimus pharmacokinetics.     

Mechanism of Folding and Activation of Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P)

The proprotein convertase subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in lipid homeostasis, the unfolded protein response, and lysosome biogenesis. The protease is further hijacked by highly pathogenic emerging viruses for the processing of their envelope glycoproteins. Zymogen activation of SKI-1/S1P requires removal of an N-terminal prodomain, by a multistep process, generating the mature enzyme. Here, we uncover a modular structure of the human SKI-1/S1P prodomain and define its function in folding and activation. We provide evidence that the N-terminal AB fragment of the prodomain represents an autonomous structural and functional unit that is necessary and sufficient for folding and partial activation. In contrast, the C-terminal BC fragment lacks a defined structure but is crucial for autoprocessing and full catalytic activity. Phylogenetic analysis revealed that the sequence of the AB domain is highly conserved, whereas the BC fragment shows considerable variation and seems even absent in some species. Notably, SKI-1/S1P of arthropods, like the fruit fly Drosophila melanogaster, contains a shorter prodomain comprised of full-length AB and truncated BC regions. Swapping the prodomain fragments between fly and human resulted in a fully mature and active SKI-1/S1P chimera. Our study suggests that primordial SKI-1/S1P likely contained a simpler prodomain consisting of the highly conserved AB fragment that represents an independent folding unit. The BC region appears as a later evolutionary acquisition, possibly allowing more subtle fine-tuning of the maturation process.     

Environmentally benign first derivative synchronous spectrofluorimetry for the analysis of two binary mixtures containing duloxetine with avanafil or tadalafil in spiked plasma samples

Antidepressants can cause sexual dysfunction side effects, necessitating the co-administration of phosphodiesterase type 5 inhibitors. The simultaneous determination of these drugs in biological fluids is critical for therapeutic drug monitoring. For the first time, two binary mixtures containing duloxetine with either avanafil or tadalafil were estimated utilizing simple green spectrofluorimetric methods without the need for a previous separation step. The study was based on first derivative synchronous spectrofluorimetry in ethanol using a change in wavelength difference (∆λ) of 20 and 25 nm for the first and second combinations, respectively. Duloxetine and avanafil were estimated at 297.7 and 331 nm in their binary mixture, while duloxetine and tadalafil were determined at 290.3 and 297.7 nm, respectively. The linearity was achieved over the ranges of 0.1–1.5 μg mL⁻¹ for both duloxetine and avanafil and 0.01–0.40 μg mL⁻¹ for tadalafil, with limits of detection of 0.013, 0.022, and 0.004 μg mL⁻¹ for duloxetine, avanafil, and tadalafil, respectively. Successful application of the developed approaches was accomplished for the estimation of the two mixtures in dosage forms as well as human plasma with excellent percentage recoveries (96–103.75% in plasma), which supports their suitability for use in quality control laboratories and pharmacokinetic studies. Moreover, the adopted approaches' greenness was evidenced by applying three tools.     

Priapisme veineux: traitement et pronostic fonctionnel. A propos de 26 cas

Introduction

Priapism is a prolonged, painful and persistent erection, unrelated to sexual stimulation. The management of priapism is complex and requires various medical or surgical treatments. The authors review the aetiology, treatment and outcome of priapism.

Material and methods

26 cases of low-flow priapism were collected over a period of 23 years (1985–2007), corresponding to 22 adults and 4 children (average age: 32 years) with various types of priapism. The time to appropriate management after onset of priapism varied according to the aetiology and the time to consultation (range: 16 hours to 15 days).

Results

Complete and persistent detumescence for the first 24 hours was obtained in 84% of cases, sometimes with multiple successive procedures. No case of early recurrence was observed. 21 patients were regularly followed for a period of 3 months to 10 years (mean follow-up: 2 years). There were 9 (42.9%) successes (recovery of normal erectile function), 4 partial results (19%) and 9 (30.1%) failures (complete erectile dysfunction).

Conclusion

Low-flow priapism must be considered to be a serious andrological emergency. Medical treatment can be effective in early forms, but surgery must not be delayed to prevent permanent erectile dysfunction secondary to extensive corpora cavernosa fibrosis.     

Isolation of Beauveria species from Lebanon and evaluation of its efficacy against the cedar web-spinning sawfly, Cephalcia tannourinensis

Larvae of the cedar web-spinning sawfly, Cephalcia tannourinensis Chevin (Hymenoptera: Pamphiliidae), infected with a white fungus were collected from the Tannourine-Hadath El-Jebbeh cedar forest. Macro- and micro-morphological data based on the examination of colonies, conidiophores, and conidial shape of the fungus suggested a Beauveria species. Sequence analysis of the internal transcribed spacer regions of the isolated fungus showed that it is most closely related to isolates of B. bassiana Clade C. The present study showed that the isolated B. bassiana is a naturally occurring entomopathogenic fungus parasitizing the larvae of C. tannourinensis in Lebanon. Laboratory bioassays showed that B. bassiana caused high mortality of eggs and larvae. The infected eggs turned brownish in color, while larvae of the first instar ceased feeding and showed immobility and rigidity within 5 days and before sporulating conidial mat appeared on their cuticle. Second and third larval instars took longer time to show fungal sporulation: mortalities ranged between 85 and 100% within 7 days when treated with different conidial concentrations. The efficacy of control of C. tannourinensis using B. bassiana was higher or equal to the reference insect growth regulator, diflubenzuron, suggesting the possibility of its success as a biological control agent.     

Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of tiaprofenic acid in nonstandard HPLC organic solvents

The first straightforward lipase-catalyzed enantioselective access to enantiomerically enriched tiaprofenic acid as a versatile method in chiral separation of racemates is demonstrated. The latter was directly monitored by enantioselective HPLC using a 3,5-dimethylphenylcarbamate derivative of cellulose-based chiral stationary phase namely Chiralpak IB (the immobilized version of Chiralcel OD). Non-standard HPLC organic solvents were used as diluent to dissolve the "difficult to dissolve" enzyme substrate (the acid) and as eluent for the simultaneous enantioselective HPLC baseline separation of both substrate and product in one run without any further derivatization. The existence of a non-standard HPLC organic solvent (e.g., methyl tert-butyl ether) in the mobile phase composition is mandatory to accomplish the simultaneous enantioselective HPLC baseline separation of both substrate and product.     

Enhancing antimicrobial properties of dyed and finished cotton fabrics

1,2,3-Benzothiazole-7-thiocarboxylic acid-S-methylester (commercially known as Actigard^® AM-87) was utilized to impart cotton fabric durable antimicrobial properties. Finishing treatment was carried out under a variety of conditions. The latter were included, effect of pH, concentration of antibacterial agents, curing temperature and curing time. The effect of fabric construction, mercerization, and dyeing with different dyestuff were also investigated. The study was also extended to investigate the technical feasibility of combining antimicrobial finishing treatment in question with other finishing treatment generally carried out on cotton fabric, like soft finishing and crease recovery finishing. The treated fabrics were monitored for antimicrobial properties before and after washing. The treated fabrics were also evaluated for the physio-mechanical properties like fabric tensile strength, elongation at break (or bursting strength for knitted fabric), wettability, crease recovery angle, whiteness index and roughness. Results obtained show that, the most appropriate conditions for treatment cotton fabric with Actigard^® are: padding the cotton fabric in aqueous solution containing 6% Actigard^® at pH 5 (adjusted using formic acid) then squeezed to wet pick up of 100%, dried at 80 °C for 5 min then cured at 100 °C for 150 s. The untreated cotton fabric did not show any antimicrobial activity towards Staphylococcus aureus or Escherichia coli. Treatment of cotton fabric with Actigard^® improves its antimicrobial properties towards S. aureus or E. coli. It is also observed that, treatment of cotton fabric with Actigard^® marginally decreases fabric tensile strength, elongation at break, roughness and WI, whereas; both wettability and crease recovery angle remain practically intact. This was observed whether the fabric was pre-mercerized or not.     

Dipeptidyl nitrile inhibitors of Cathepsin L

A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.