Fecal Pharmacokinetics and Gut Microbiome Effects of Oral Omadacycline Versus Vancomycin in Healthy Volunteers.

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. RESULTS: Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P < .05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. CONCLUSIONS: Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. CLINICAL TRIALS REGISTRATION: NCT06030219.

Trend of risk and correlates of under-five child undernutrition in Bangladesh: an analysis based on Bangladesh Demographic and Health Survey data, 2007-2017/2018.

OBJECTIVES: The objectives of this study are to identify the trend of undernutrition risk among under-five children (U5C) in Bangladesh and the trend of its correlates. DESIGN: Multiple cross-sectional data sets from different time points were used. SETTING: Nationally representative Bangladesh Demographic and Health Surveys (BDHSs) were conducted in 2007, 2011, 2014 and 2017/2018. PARTICIPANTS: In the BDHSs, the sample sizes for ever-married women (age: 15-49 years) were 5300 in 2007, 7647 in 2011, 6965 in 2014 and 7902 in 2017/2018. OUTCOMES: Extant indicators of undernutrition (stunted, wasted and underweight) have been considered as the outcome variables. MATERIALS AND METHODS: Descriptive statistics, bivariate analysis and factor loadings from factor analysis have been used to determine the prevalence of undernutrition over the years and find the trend of risk and its correlates. RESULTS: Risks of stunting among the U5C were 41.70%, 40.67%, 36.57% and 31.14%; that of wasting were 16.94%, 15.48%, 14.43% and 8.44%; and that of underweight were 39.79%, 35.80%, 32.45% and 22.46% in 2007, 2011, 2014 and 2017/2018, respectively. From the factor analysis, it has been found that the top five potential correlates of undernutrition are the wealth index, the education of the father and mother, the frequency of antenatal visits during pregnancy, the father's occupation and/or the type of place of residence in the last four consecutive surveys. CONCLUSION: This study helps us gain a better understanding of the impact of the top correlates on child undernutrition. To accelerate the reduction of child undernutrition more by 2030, Government and non-government organisations should focus on improving education and household income-generating activities among poor households and raising awareness among women about the importance of receiving antenatal care during pregnancy.

Clinical Characteristics and Predictors of Mortality in Elderly Patients Hospitalized with COVID-19 in Bangladesh: A Multicenter, Retrospective Study.

Purpose: Elderly patients are at high risk of fatality from COVID-19. The present work aims to describe the clinical characteristics of elderly inpatients with COVID-19 and identify the predictors of in-hospital mortality at admission. Materials and Methods: In this retrospective, multicenter cohort study, we included elderly COVID-19 inpatients (n = 245) from four hospitals in Sylhet, Bangladesh, who had been discharged between October 2020 and February 2021. Demographic, clinical, and laboratory data were extracted from hospital records and compared between survivors and nonsurvivors. We used univariable and multivariable logistic regression analysis to explore the risk factors associated with in-hospital death. Principal Results. Of the included patients, 202 (82.44%) were discharged and 43 (17.55%) died in hospital. Except hypertension, other comorbidities like diabetes, chronic kidney disease, ischemic heart disease, and chronic obstructive pulmonary disease were more prevalent in nonsurvivors. Nonsurvivors had a higher prevalence of leukocytosis (51.2 versus 30.7; p=0.01), lymphopenia (72.1 versus 55; p=0.05), and thrombocytopenia (20.9 versus 9.9; p=0.07). Multivariable regression analysis showed an increasing odds ratio of in-hospital death associated with older age (odds ratio 1.05, 95% CI 1.01-1.10, per year increase; p=0.009), thrombocytopenia (OR = 3.56; 95% CI 1.22-10.33, p=0.019), and admission SpO2 (OR 0.91, 95% CI 0.88-0.95; p=0.001). Conclusions: Higher age, thrombocytopenia, and lower initial level of SpO2 at admission are predictors of in-hospital mortality in elderly patients with COVID-19.

Multi-country surveillance of Clostridioides difficile demonstrates high prevalence of spores in non-healthcare environmental settings.

BACKGROUND: C. difficile spores are frequently isolated from hospital and non-healthcare settings but a worldwide analysis has not been done. The study objectives were to assess C. difficile spore contamination in the hospital and non-healthcare environments across a variety of countries. METHODS: Field studies assessed hospital vs. non-healthcare C. difficile spore contamination in hospitals, non-healthcare buildings, outdoor environments, and shoes. Swabs were cultured anaerobically for C. difficile and typed using PCR-fluorescent ribotyping. C. difficile contamination by swabbing area and geographic locations were compared. FINDINGS: A total of 7,857 unique samples were collected primarily from the USA (89%) in addition to 9 other countries. The global prevalence of C difficile from environmental samples was 25.3% and did not differ between countries. In USA based studies, C. difficile contamination rates were similar for healthcare buildings (23.2%), non-healthcare buildings (23.4%), and outdoor spaces (24.7%). Floor samples had significantly higher (p < 0.001) C. difficile contamination rate (46.5%) followed by non-floor samples (21.1%), and bathrooms (15.3%). In a comparison of USA to other country samples, C. difficile contamination rates were similar for USA samples (21.5%) compared to rest of world samples (22.3%; p = 0.61). The most common ribotypes included F014-020 (15.7%), F106 (12.6%), F010 (8.9%), F027 (8.8%), and F002 (8.1%) and did not differ significantly between USA and non-USA samples. Finally, 546 of 1,218 (44.8%) shoe soles swabbed from the USA were contaminated with C. difficile spores. INTERPRETATION: This large surveillance study of several countries demonstrated high prevalence of toxigenic C. difficile in non-healthcare environments with high contamination rates from floors and shoe soles.

Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial.

BACKGROUND: This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection. The primary objectives were to assess clinical cure rates and adverse events (AEs). Secondary objectives were to evaluate plasma/fecal pharmacokinetics, microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) with ibezapolstat. METHODS: This single-arm, open-label, phase 2a study enrolled adults with C. difficile infection at 4 US centers. Patients received ibezapolstat 450 mg orally every 12 hours for 10 days and followed for an additional 28 days to assess study objectives. RESULTS: Ten patients with a mean (standard deviation [SD]) age of 49 [15] years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233 to 578 ng/mL while mean (SD) fecal levels were 416 (494) µg/g stool by treatment day 3 and >1000 µg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy, which was maintained after completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (mean change [SD], -10.0% [4.8%]; P = .04) with a concomitantly increased proportion of Firmicutes phylum (+14.7% [5.4%]; P = .009). Compared with baseline, total primary bile acids decreased by a mean (SD) of 40.1 (9.6) ng/mg stool during therapy (P < .001) and 40.5 (14.1) ng/mg stool after completion of therapy (P = .007). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). CONCLUSIONS: In this phase 2a study, 10 of 10 patients achieved SCC, demonstrated favorable pharmacokinetics, minimal AEs, and beneficial microbiome and bile acids results. These results support continued clinical development.

Asymptomatic RT-PCR positive COVID-19 patients in orthopaedic pre-operative evaluation during the peak of the second wave.

Introduction: Asymptomatic COVID-19 patients are the most challenging and feared obstacles in resuming these surgical procedures. The purpose of this study was to evaluate the proportion of asymptomatic carriers detected by RT-PCR in pre-operative orthopaedic evaluation during the peak of the second wave. Methods: 514 asymptomtomatic COVID-19 patients, negative for TOCC (Travel, Profession, Cluster, Contact) risk factors were observed retrospectively. A nasopharyFngeal RT-PCR test was obtained 48 to 72 h before the surgery in all cases. Possible risk factors for a positive test was identified. Results: The detected asymptomatic COVID-19 infection rate during the peak of the second wave among the pre-operative orthopaedic patients was 12.3%. Younger age, female gender, longer duration of admission to RT-PCR test interval were found to be significant (p= < 0.05) risk factors for asymptomatic RT-PCR to be positive. The hazard ratio (HR) for being asymptomatic RT-PCR positive was 4.3 (p = 0. 025), while the RT-PCR was performed at 14 days, but the HR increased to 9.2 (p = 0.049) when the test was performed after 45 days. Conclusion: According to our findings, pre-operative testing to rule out COVID-19 should be regarded as a critical step in preventing the disease clusters in hospitals.

Chlorination Treatment of Meta-Aramid Fibrids and Its Effects on Mechanical Properties of Polytetramethylene Ether Glycol/Toluene Diisocyanate (PTMEG/TDI)-Based Polyurethane Composites.

Meta-aramid fibrids (MAF) have attracted much attention. However, it is difficult for this high mechanical performance fiber to form sufficient interface adhesion between the MAF and polyurethane (PU) matrix due to the chemical inertness of its surface. Thus, the surface activity of MAF should be improved to obtain a high-performance MAF/PU composite. A novel methodology to modify the surface of MAF with a sodium dichloroisocyanurate solution (DCCNa) was developed to obtain chlorinated MAF (MAFC) in this study. A series of MAFC/PU composites was prepared by in situ polymerization processes. The results of Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) demonstrated that the chlorine-contained chemical groups were introduced onto the MAF surfaces after chlorination. Dynamic contact angle analysis (DCAA) revealed that the surface wettability and the surface free energy of the MAFC were significantly improved, which allowed for strong chemical bonding to PU. Scanning electron microscopy (SEM) showed a uniform distribution of MAFC and good interfacing bonding between the MAFC and PU. With the incorporation of 1.5 wt% MAFC into the polyurethane matrix, the tensile and tear strength values of MAFC/PU were 36.4 MPa and 80.1 kN·m-1 respectively, corresponding to improvements of approximately 43.3% and 21.1%, as compared to those of virgin PU as 25.4 MPa and 66.1 kN·m-1, respectively.

Investigation on the Preparation and Properties of CMC/magadiite Nacre-Like Nanocomposite Films.

The layered hydrated sodium salt-magadiite (MAG), which has special interpenetrating petals structure, was used as a functional filler to slowly self-assemble with sodium carboxy-methylcellulose (CMC), in order to prepare nacre-like nanocomposite film by solvent evaporation method. The structure of prepared nacre-like nanocomposite film was characterized by Scanning Electron Microscope (SEM) and X-ray diffraction (XRD) analysis; whereas, it was indicated that CMC macromolecules were inserted between the layers of MAG to increase the layer spacing of MAG by forming an interpenetrating petals structure; in the meantime, the addition of MAG improved the thermal stability of CMC. The tensile strength of CMC/MAG was significantly improved compared with pure CMC. The tensile strength of CMC/MAG reached the maximum value at 1.71 MPa when the MAG content was 20%, to maintaining high transparency. Due to the high content of inorganic filler, the flame retarding performance and the thermal stability were also brilliant; hence, the great biocompatibility and excellent mechanical properties of the bionic nanocomposite films with the unique interpenetrating petals structure provided a great probability for these original composites to be widely applied in material research, such as tissue engineering in biomedical research.

Preparation and Characterization of Magadiite⁻Magnetite Nanocomposite with Its Sorption Performance Analyses on Removal of Methylene Blue from Aqueous Solutions.

The magadiite⁻magnetite (MAG⁻Fe3O4) nanocomposite has great potential applications in the field of biomaterials research. It has been used as a novel magnetic sorbent, prepared by co-precipitation method. It has the dual advantage of having the magnetism of Fe3O4 and the high adsorption capacity of pure magadiite (MAG). MAG⁻Fe3O4 was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM). The results showed that Fe3O4 nanoparticles were deposited on the interlayer and surface of magadiite. MAG⁻Fe3O4 was treated as an adsorbent for methylene blue (MB) removal from aqueous solutions. The adsorption properties of MAG⁻Fe3O4 were investigated on methylene blue; however, the results showed that the adsorption performance of MAG⁻Fe3O4 improved remarkably compared with MA and Fe3O4. The adsorption capacity of MAG⁻Fe3O4 and the removal ratio of methylene blue were 93.7 mg/g and 96.2%, respectively (at 25 °C for 60 min, pH = 7, methylene blue solution of 100 mg/L, and the adsorbent dosage 1 g/L). In this research, the adsorption experimental data were fitted and well described using a pseudo-second-order kinetic model and a Langmuir adsorption isotherm model. The research results further showed that the adsorption performance of MAG⁻Fe3O4 was better than that of MAG and Fe3O4. Moreover, the adsorption behavior of MB on MAG⁻Fe3O4 was investigated to fit well in the pseudo-second-order kinetic model with the adsorption kinetics. The authors also concluded that the isothermal adsorption was followed by the Langmuir adsorption isotherm model; however, it was found that the adsorption of the MAG⁻Fe3O4 nanocomposite was a monolayer adsorption.

Effects on the Mechanical Properties of Nacre-Like Bio-Hybrid Membranes with Inter-Penetrating Petal Structure Based on Magadiite.

Rigid biological systems are increasingly becoming a source of inspiration for the fabrication of the advanced functional materials due to their diverse hierarchical structures and remarkable engineering properties. As a bionic biomaterial with a clear layered structure, excellent mechanical properties, and interesting rainbow colors, nacre has become one of the most attractive models for novel artificial materials design. In this research paper, the tough and strong nacre-like bio-hybrid membranes with an interpenetrating petals structure were fabricated from chitosan (CS) and magadiite (MAG) clay nanosheets through the gel-casting self-assembling method. The analyses from X-ray diffraction (XRD), scanning electron microscope (SEM), and observations of water droplets on membranes indicated that the nacre-like hybrid membranes had a layered compact structure. Fourier transforms infrared spectroscopy (FTIR) analyses suggested that the CS molecular chains formed chemical bonds and hydrogen bonds with MAG layers. The inter-penetrating petal layered structure had a good effect on the mechanical properties of a nacre-like bio-hybrid membranes and the tensile strength of the hybrid membranes could reach at 78.6 MPa. However, the transmission analyses of the results showed that the hybrid membranes still had a certain visible light transmittance. Finally, the hybrid membranes possessed an intriguing efficient fire-shielding property during exposure to the flame of alcohol burner. Consequently, the great biocompatibility and excellent mechanical properties of the bio-hybrid membranes with the special interpenetrating petals structure provides a great opportunity for these composites to be widely applied in biomaterial research.

Research on 5-fluorouracil as a drug carrier materials with its in vitro release properties on organic modified magadiite.

The magadiite (MAG) was modified by cetyltrimethyl ammonium-Bromide (CTAB) and then further modified by Chitosan (CS) which is called organic modified-magadiite as magadiite-cetyltrimethyl ammonium bromide (MAG-CTAB) and magadiite-cetyltrimethyl ammonium bromide-Chitosan (MAG-CTAB-CS), respectively, in this research study. The MAG, MAG-CTAB, and MAG-CTAB-CS were used as 5-Fluorouracil (5-FU) drug carrier materials; the drug carrier's materials were marked as magadiite-5-Fluorouracil (MAG/5-FU), magadiite-cetyltrimethyl ammonium bromide-5-Fluorouracil (MAG-CTAB/5-FU), and magadiite-cetyltrimethyl ammonium bromide-Chitosan (MAG-CTAB-CS/5-FU). X-ray diffraction(XRD, Flourier transform infrared spectrometry (FTIR) and scanning electron microscopy (SEM) results were shown that 5-Fluorouracil was combined with carrier materials through physical apparent adsorption, ion exchange, chemical bond, hydrogen bond, and electrostatic interaction. The drug carriers in vitro release behavior in simulated gastric fluids (SGF，pH = 1.35) and intestinal fluids (SIF，pH = 7.40) were investigated. The drug loading capacity and accumulated release ration were as follows the order: MAG-CTAB-CS/5-FU > MAG-CTAB/5-FU > MAG/5-FU. The drug loading capacity of MAG-CTAB-CS/5-FU was 162.29 mg/g, 48 h later the drug accumulated release ratio was 61.24%, and the release amount was 97.52 mg/g for 24 h. Korsmeyer-Peppas model and First order model were found to be suitable to describe the vitro release behavior of 5-Fluorouracil. This would be an economically viable and efficient method for the preparation of advanced drug delivery system.

Adsorption Analyses of Phenol from Aqueous Solutions Using Magadiite Modified with Organo-Functional Groups: Kinetic and Equilibrium Studies.

Organically-modified magadiite (MAG⁻CTAB⁻KH550) was synthesized via ion-exchange method and condensation reaction in the presence of pure magadiite (MAG), cetyltrimethylammonium bromide (CTAB) and γ-aminopropyltriethoxysilane (KH550) in aqueous solution in this research. This new adsorbent material was studied using scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier transforms infrared spectroscopy (FTIR), and N2 adsorption/desorption isotherms process. It was found that the MAG⁻CTAB⁻KH550 has high Brunaur-Emmet-Teller (BET) specific surface area and mesoporous pore size distribution which enhanced its ability to remove phenol in aqueous solution; and, the value of pH has a relatively large impact on the adsorption behavior of the sorbent. Finally, the adsorptive behavior of the mesoporous material on phenol was followed pseudo-second-order kinetic adsorption model. In contrast, the adsorption equilibrium isotherm was better performed Langmuir isotherm model than the Freundlich isotherm model; in addition, the results also showed that the MAG⁻CTAB⁻KH550 had a better adsorption capacity and removal efficiency than MAG.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

Proteomic analysis of the protective effects of aqueous bark extract of Terminalia arjuna (Roxb.) on isoproterenol-induced cardiac hypertrophy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Aqueous bark extract of Terminalia arjuna (TA) has been in use as an ethnomedicine for cardiovascular ailments in the Indian subcontinent for centuries. Studies using hemodynamic, ROS scavenging and anti-inflammatory parameters in animal models have shown its anti-atherogenic, hypotensive, inotropic, anti-inflammatory effects. However, details analysis on its effects on established molecular and cell biological markers are a prerequisite for its wider acceptance to the medical community. AIMS OF THE STUDY: To test the efficacy of TA extract in ameliorating cardiac hypertrophy induced by ISO in rats. METHODS: Cardiac hypertrophy was induced by ISO (5mg/kg/day s.c. for 14 days) in rats and a standardized aqueous extract of TA stem bark was orally administered by gavage. Total RNA and protein were isolated from control, ISO, ISO plus TA and TA treated rat hearts and analyzed for the transcripts for the markers of hypertrophy, signaling kinases, transcription factors and total protein profile. RESULTS: TA extract reversed the induction of fetal genes like ß-myosin heavy chain, skeletal α-actin and brain natriuretic peptide in hypertrophic rat hearts. While ISO slightly increased the level of phospho-ERK, TA repressed it to about one third of the base line level. Survival kinase Akt, ER stress marker Grp78 and epigenetic regulator HDAC5 were augmented by ISO and TA restored them by various extents. ISO administration moderately increased the transcription factor NFκB binding activity, while coadministration of TA further increased it. AP-1 binding activity was largely unchanged by ISO treatment but it was upregulated when administered along with TA. MEF2D binding activity was increased by ISO and TA restored it to the baseline level. Global proteomic analysis revealed that TA treatment restored a subset of proteins up- and down-regulated in the hypertrophied hearts. Amongst those restored by TA were purinergic receptor X, myosin light chain 3, tropomyosin, and kininogen; suggesting a nodal role of TA in modulating cardiac function. CONCLUSIONS: This study for the first time reveals that TA partially or completely restores the marker mRNAs, signaling kinases, transcription factors and total protein profile in rat heart, thereby demonstrating its efficacy in preventing ISO-induced cardiac hypertrophy.

Novel Series of Dihydropyridinone P2X7 Receptor Antagonists.

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.

We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.

Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead.

A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.

3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models.

The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.

Hereditary multiple exostoses causing cord compression.

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the presence of multiple osseous prominences. It can occur sporadically or within families (22 - 56%). Two genes, EXT1 and EXT2 located respectively at 8q24 and 11p11-p12, have been isolated to cause HME. It can cause gross deformity of limbs and growth disturbance which is quite a common complication. Malignant transformation to chondrosarcoma can also occur. Neurological presentations are rare and usually happened due to direct compression of a peripheral nerve or nerve root or less often the spinal cord. This case is possibly the first case of HME described from Bangladesh, presented with dorsal cord compression. Decompression was done and the complaints of myelopathy were improved.

Persistence of avian influenza viruses in various artificially frozen environmental water types.

Background. This study investigates the viable persistence of avian influenza viruses (AIVs) in various types of artificially frozen environmental water and evaluates the feasibility of similar occurrence taking place in nature, and allowing for prolonged abiotic virus survival, with subsequent biotic viral recirculation. Methods. Fresh, brackish, and salty water, taken in Japan from aquatic biotopes regularly visited by migratory waterfowl, were seeded with AIVs. We monthly monitored the viability of the seeded viruses in the frozen state at -20°C and -30°C, for 12 months. We also monitored virus viability following repeatedly induced freezing and thawing. Results. The viruses exhibited considerable viable persistence all along that period of time, as well as during freezing-thawing cycles. Appreciable, yet noncrucial variances were observed in relation to some of the parameters examined. Conclusions. As typical waterborne pathogens of numerous northerly aquatic birds, AIVs are innately adapted to both the body temperature of their hosts (40°C to 42°C) and, presumably, to subzero temperatures of frozen lakes (down to -54°C in parts of Siberia) occupied and virus-seeded by subclinically infected birds, prior to freezing. Marked cryostability of AIVs appears to be evident. Preservation in environmental ice has significant ecophylogenetic and epidemiological implications, potentially, and could account for various unexplained phenomena.