Regulatory Aspects of Pharmaceuticals’ Exports in Gulf Cooperation Council Countries

The Gulf cooperation council (GCC) region is considered as “Emerging market” for pharmaceutical export and bilateral trade. The understanding of the regulatory requirements of this region can be beneficial for pharmaceutical export. Some incidents of the year 2008-09, like recession or economic slowdown in highly well-off and regulated market of the EU and US, raised the demand for alternate destinations for business. The regulations of Gulf countries are encouraging the import of quality generic products, which can be good news to the Indian drug manufacturers

Leaching behaviour of pendimethalin causes toxicity towards different cultivars of Brassica juncea and Brassica campestris in sandy loam soil

An experiment was conducted at the farm of Zonal Adaptive Research Station, Uttar Banga Krishi Viswavidhyalaya, Pundibari, Cooch Behar, West Bengal to evaluate the effect of pendimethalin on the yield, weed density and phytotoxicity in different varieties of rai (Brassica juncea) and yellow sarson (B. campestris var. yellow sarson) under higher soil moisture regime in Terai region of West Bengal. Pre-emergence application of pendimethalin at higher dose i.e. 1.0 kg/ha recorded higher plant mortality (30.92%) due to the presence of higher concentration of pendimethalin residue (0.292 µg/g) till the tenth day of crop age and consequently had the reduced yield (12.59 q/ha) than the dose of 0.7 kg/ha (13.33 q/ha) where plant mortality was only 12.62% due to comparatively lower level of pendimethalin residue (0.192 µg/g). Although the application of pendimethalin at the rate of 1.0 kg/ha was able to control weed more efficiently (18.96/m2) than the dose of 0.7 kg/ha (30.41/m2) and subsequent lower doses. The herbicide leached down to the root zone resulting in phytotoxicity towards crop. Yellow sarson group (Brassica campestris) showed more susceptibility than rai (Brassica juncea) group against pendimethalin application at higher doses

Effectiveness of en masse versus two-step retraction:a systematic review and meta-analysis

Abstract Background This review aims to compare the effectiveness of en masse and two-step retraction methods during orthodontic space closure regarding anchorage preservation and anterior segment retraction and to assess their effect on the duration of treatment and root resorption. Methods An electronic search for potentially eligible randomized controlled trials and prospective controlled trials was performed in five electronic databases up to July 2017. The process of study selection, data extraction, and quality assessment was performed by two reviewers independently. A narrative review is presented in addition to a quantitative synthesis of the pooled results where possible. The Cochrane risk of bias tool and the Newcastle-Ottawa Scale were used for the methodological quality assessment of the included studies. Results Eight studies were included in the qualitative synthesis in this review. Four studies were included in the quantitative synthesis. En masse/miniscrew combination showed a statistically significant standard mean difference regarding anchorage preservation − 2.55 mm (95% CI − 2.99 to − 2.11) and the amount of upper incisor retraction − 0.38 mm (95% CI − 0.70 to − 0.06) when compared to a two-step/conventional anchorage combination. Qualitative synthesis suggested that en masse retraction requires less time than two-step retraction with no difference in the amount of root resorption. Conclusions Both en masse and two-step retraction methods are effective during the space closure phase. The en masse/miniscrew combination is superior to the two-step/conventional anchorage combination with regard to anchorage preservation and amount of retraction. Limited evidence suggests that anchorage reinforcement with a headgear produces similar results with both retraction methods. Limited evidence also suggests that en masse retraction may require less time and that no significant differences exist in the amount of root resorption between the two methods

Experimental Induction of Paromomycin Resistance in Antimony-Resistant Strains of L. donovani: Outcome Dependent on In Vitro Selection Protocol

Paromomycin (PMM) has recently been introduced for treatment of visceral leishmaniasis in India. Although no clinical resistance has yet been reported, proactive vigilance should be warranted. The present in vitro study compared the outcome and stability of experimental PMM-resistance induction on promastigotes and intracellular amastigotes. Cloned antimony-resistant L. donovani field isolates from India and Nepal were exposed to stepwise increasing concentrations of PMM (up to 500 µM), either as promastigotes or intracellular amastigotes. One resulting resistant strain was cloned and checked for stability of resistance by drug-free in vitro passage as promastigotes for 20 weeks or a single in vivo passage in the golden hamster. Resistance selection in promastigotes took about 25 weeks to reach the maximal 97 µM inclusion level that did not affect normal growth. Comparison of the IC50 values between the parent and the selected strains revealed a 9 to 11-fold resistance for the Indian and 3 to 5-fold for the Nepalese strains whereby the resistant phenotype was also maintained at the level of the amastigote. Applying PMM pressure to intracellular amastigotes produced resistance after just two selection cycles (IC50 = 199 µM) compared to the parent strain (IC50 = 45 µM). In the amastigote-induced strains/clones, lower PMM susceptibilities were seen only in amastigotes and not at all in promastigotes. This resistance phenotype remained stable after serial in vitro passage as promastigote for 20 weeks and after a single in vivo passage in the hamster. This study clearly demonstrates that a different PMM-resistance phenotype is obtained whether drug selection is applied to promastigotes or intracellular amastigotes. These findings may have important relevance to resistance mechanism investigations and the likelihood of resistance development and detection in the field

Purification and Characterization of a Novel Chlorpyrifos Hydrolase from Cladosporium cladosporioides Hu-01

Chlorpyrifos is of great environmental concern due to its widespread use in the past several decades and its potential toxic effects on human health. Thus, the degradation study of chlorpyrifos has become increasing important in recent years. A fungus capable of using chlorpyrifos as the sole carbon source was isolated from organophosphate-contaminated soil and characterized as Cladosporium cladosporioides Hu-01 (collection number: CCTCC M 20711). A novel chlorpyrifos hydrolase from cell extract was purified 35.6-fold to apparent homogeneity with 38.5% overall recovery by ammoniumsulfate precipitation, gel filtration chromatography and anion-exchange chromatography. It is a monomeric structure with a molecular mass of 38.3 kDa. The pI value was estimated to be 5.2. The optimal pH and temperature of the purified enzyme were 6.5 and 40°C, respectively. No cofactors were required for the chlorpyrifos-hydrolysis activity. The enzyme was strongly inhibited by Hg2+, Fe3+, DTT, β-mercaptoethanol and SDS, whereas slight inhibitory effects (5–10% inhibition) were observed in the presence of Mn2+, Zn2+, Cu2+, Mg2+, and EDTA. The purified enzyme hydrolyzed various organophosphorus insecticides with P-O and P-S bond. Chlorpyrifos was the preferred substrate. The Km and Vmax values of the enzyme for chlorpyrifos were 6.7974 μM and 2.6473 μmol·min−1, respectively. Both NH2-terminal sequencing and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometer (MALDI-TOF-MS) identified an amino acid sequence MEPDGELSALTQGANS, which shared no similarity with any reported organophosphate-hydrolyzing enzymes. These results suggested that the purified enzyme was a novel hydrolase and might conceivably be developed to fulfill the practical requirements to enable its use in situ for detoxification of chlorpyrifos. Finally, this is the first described chlorpyrifos hydrolase from fungus

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes

The study of atmospheric ice-nucleating particles via microfluidically generated droplets

Ice-nucleating particles (INPs) play a significant role in the climate and hydrological cycle by triggering ice formation in supercooled clouds, thereby causing precipitation and affecting cloud lifetimes and their radiative properties. However, despite their importance, INP often comprise only 1 in 10³–10⁶ ambient particles, making it difficult to ascertain and predict their type, source, and concentration. The typical techniques for quantifying INP concentrations tend to be highly labour-intensive, suffer from poor time resolution, or are limited in sensitivity to low concentrations. Here, we present the application of microfluidic devices to the study of atmospheric INPs via the simple and rapid production of monodisperse droplets and their subsequent freezing on a cold stage. This device offers the potential for the testing of INP concentrations in aqueous samples with high sensitivity and high counting statistics. Various INPs were tested for validation of the platform, including mineral dust and biological species, with results compared to literature values. We also describe a methodology for sampling atmospheric aerosol in a manner that minimises sampling biases and which is compatible with the microfluidic device. We present results for INP concentrations in air sampled during two field campaigns: (1) from a rural location in the UK and (2) during the UK’s annual Bonfire Night festival. These initial results will provide a route for deployment of the microfluidic platform for the study and quantification of INPs in upcoming field campaigns around the globe, while providing a benchmark for future lab-on-a-chip-based INP studies

Drug Resistance in Eukaryotic Microorganisms

Eukaryotic microbial pathogens are major contributors to illness and death globally. Although much of their impact can be controlled by drug therapy as with prokaryotic microorganisms, the emergence of drug resistance has threatened these treatment efforts. Here, we discuss the challenges posed by eukaryotic microbial pathogens and how these are similar to, or differ from, the challenges of prokaryotic antibiotic resistance. The therapies used for several major eukaryotic microorganisms are then detailed, and the mechanisms that they have evolved to overcome these therapies are described. The rapid emergence of resistance and the restricted pipeline of new drug therapies pose considerable risks to global health and are particularly acute in the developing world. Nonetheless, we detail how the integration of new technology, biological understanding, epidemiology and evolutionary analysis can help sustain existing therapies, anticipate the emergence of resistance or optimize the deployment of new therapies