Congenital chloride diarrhea: A rare cause of recurrent polyhydramnios

Congenital chloride diarrhea (CCD) is a rare, inherited disorder. Our case was a preterm neonate who presented with severe watery diarrhoea since Day 2 of life. There was maternal history of polyhydramnios and dilated bowel loops. The diagnosis of CCD was confirmed by mutation analysis. The infant is 9 months corrected age, on salt and potassium supplementation, with age-appropriate milestones. The diagnosis of CCD must be made early to prevent life-threatening fluid and electrolyte imbalance

International Journal of Chemical and Physical Sciences Binary Phase Diagramand Thin Film Coatings of Bimetallic Oxides using Bis(N-isopropylsalicylaldimine)M(II) M = Co, Ni and Zn as a Single Source Precursor for Thermal Chemical Vapor Deposition Binary

Abstract The metal Schiff base complexes of bis(N-isopropylsalicylaldimine)coblt(II), bis(N-isopropylsalicylaldimine)nickel(II) and bis (N-isopropylsalicylaldimine

Synthesis, x-ray crystal structures and biological evaluation of some mono- and bi-cyclic 1,3-diazetidin-2-ones: non-natural β -lactam analogues

Mono- and bi-cyclic 1,3-diazetidin-2-ones (aza-β -lactams) are synthesised and evaluated as non-natural analogues of β -lactams. The aza-β -lactams are designed on the principle that their reaction with active site serine hydroxy will form a carbamoyl-enzyme intermediate that is sluggish to hydrolysis. The synthesis of racemic mono- and bi-cyclic aza-β -lactams is carried out starting from pyrimidinone 18 which is transformed to the densely functionalised substrate 20. The chemical reactivity of tricarbonyl 20 for selective functional group manipulation was first assessed and then it was transformed to amino alcohol 24. Cyclisation of 24 affords aza-carbapenams and its homologation followed by aldol cyclisation provides access to aza-carbacephams. The X-ray structures of aza-carbapenam 35 and aza-carbacepham 42 suggest that the structural requirements for biological activity in β -lactams are fulfilled. An unexpected ozonolysis product, phenol 52 resolves spontaneously during crystallisation and its crystal structure was also determined. The biological activity of the novel mono- and bi-cyclic aza-β -lactams was evaluated with potent gram-positive bacterial strain, Bacillus subtilis and compared with β -lactam antibiotics, ampicillin and penicillin G. Of the 19 aza-β -lactams tested, eight compounds show inhibition better than the standards while another eight are of comparable activity. This study shows that aza-β -lactams represent a novel and non-natural lead towards serine peptidase inhibitors

INTERNATIONAL JOURNAL OF PHARMACY & LIFE SCIENCES Screening of potential efficacy of dietary ginger on ethanol induced oxidative stress in rat cardiac tissue: A study on changes in basic metabolic profiles

Abstract The present study was premeditated to examine the possible mechanisms where by ginger (Zingiber officinale) could protect cardiac tissue from alcohol toxicity in rats. The carbohydrate metabolic profiles like total carbohydrates, pyruvate, total proteins, free amino acids and lactate levels were measured in heart tissue. The total carbohydrates, pyruvate, and total proteins were significant declined while free amino acids, lactate levels were significant increased in alcohol intoxicated rats. Whereas with ginger (200 mg/kg body weight) treatment shown significant increase in the total carbohydrates, total proteins and pyruvate levels, whereas free amino acids, lactate levels were significant drop in the cardiac tissues. From the present study, we conclude that ginger protects the heart tissue from alcohol toxicity in rats, this may be due to the presence of many bioactive compounds in ginger

Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria

Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress

Wdpcp, a PCP Protein Required for Ciliogenesis, Regulates Directional Cell Migration and Cell Polarity by Direct Modulation of the Actin Cytoskeleton

Planar cell polarity (PCP) regulates cell alignment required for collective cell movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question of the role of the cilium in PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and collective cell movement, but the underlying mechanism is unknown. Here we show Wdpcp can regulate PCP by direct modulation of the actin cytoskeleton. These studies were made possible by recovery of a Wdpcp mutant mouse model. Wdpcp-deficient mice exhibit phenotypes reminiscent of Bardet-Biedl/Meckel-Gruber ciliopathy syndromes, including cardiac outflow tract and cochlea defects associated with PCP perturbation. We observed Wdpcp is localized to the transition zone, and in Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the transition zone, indicating Wdpcp is required for recruitment of proteins essential for ciliogenesis. Wdpcp is also found in the cytoplasm, where it is localized in the actin cytoskeleton and in focal adhesions. Wdpcp interacts with Sept2 and is colocalized with Sept2 in actin filaments, but in Wdpcp-deficient cells, Sept2 was lost from the actin cytoskeleton, suggesting Wdpcp is required for Sept2 recruitment to actin filaments. Significantly, organization of the actin filaments and focal contacts were markedly changed in Wdpcp-deficient cells. This was associated with decreased membrane ruffling, failure to establish cell polarity, and loss of directional cell migration. These results suggest the PCP defects in Wdpcp mutants are not caused by loss of cilia, but by direct disruption of the actin cytoskeleton. Consistent with this, Wdpcp mutant cochlea has normal kinocilia and yet exhibits PCP defects. Together, these findings provide the first evidence, to our knowledge, that a PCP component required for ciliogenesis can directly modulate the actin cytoskeleton to regulate cell polarity and directional cell migration

Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies

Radiation effects on MHD flow past an impulsively started infinite isothermal vertical plate

63-67MHD (Magneto hydrodynamics) flow past an impulsively started infinite vertical isothermal plate in the presence of thermal radiation is studied here. The fluid considered is a gray, absorbing-emitting radiation but a non-scattering medium. It is observed that for an increase in radiation parameter N, there is a fall in the velocity or temperature