Binding of small molecules at interface of protein-protein complex - A newer approach to rational drug design.

Protein-protein interaction is a vital process which drives many important physiological processes in the cell and has also been implicated in several diseases. Though the protein-protein interaction network is quite complex but understanding its interacting partners using both in silico as well as molecular biology techniques can provide better insights for targeting such interactions. Targeting protein-protein interaction with small molecules is a challenging task because of druggability issues. Nevertheless, several studies on the kinetics as well as thermodynamic properties of protein-protein interactions have immensely contributed toward better understanding of the affinity of these complexes. But, more recent studies on hot spots and interface residues have opened up new avenues in the drug discovery process. This approach has been used in the design of hot spot based modulators targeting protein-protein interaction with the objective of normalizing such interactions.

Comparative Study of Prevalence of Cataract at High Altitude and Kathmandu Valley.

BACKGROUND: Cataract is the leading cause of avoidable blindness in the world. Many etiological and risk factors for age related cataract has been documented. The present study is conducted to compare the prevalence of cataract at high altitude and Kathmandu valley.Many etiological and risk factors for age related cataract has been documented. METHODS: A cross sectional comparative study was conducted at Jomsom, Kagbeni, Jharkot and Muktinath of Mustang district and Balaju and Jawalakhel of Kathmandu valley of Nepal in 2009 to 2011 . There were 222 participants at Mustang and186 participants at Kathmandu. The prevalence of cataract was studied among the Tibetans and Thakali population at Mustang and Tibetans at Jawalakhel and Thakali population at Balaju of Kathmandu valley. RESULTS: Prevalence of cataract at high altitude was 31.5% and 10.2% at Kathmandu valley. The prevalence of cataract is 4.05 times more at high altitude as compared to Kathmandu valley (p value < 0.001). CONCLUSIONS: The prevalence of cataract was significantly high at high altitude as compared to lower altitude.

Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.

Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

Interactome analysis and design of inhibitors against selected protein targets of Ser/Thr protein kinase (STPK) signaling pathways in Mycobacterium tuberculosis H37Rv.

Tuberculosis continues to be a major cause of mortality worldwide despite significant advances in chemotherapy and development of the BCG vaccine. Although curable, the tuberculosis treatment period (6-9 months) presents many concerns, including patient noncompliance and the development of drug toxicity and drug resistance. This study aimed to understand the protein-protein interactions of key proteins involved in the Mycobacterium tuberculosis STPK signal transduction pathway (such as PknB, PknE, and PstP); in addition, we attempted to identify promising leads for the inhibition of protein-protein interactions. Interactome analyses revealed the interactions of these protein targets with several other proteins, including PknG and PbpA. Drug-like candidates were screened based on Lipinski's rule of five and the absorption digestion metabolism excretion toxicity. Molecular docking of the target proteins with the selected ligands identified cryptolepine HCl to be a common molecule interacting with all protein targets (with a good docking score). The generation of a pharmacophore model for cryptolepine HCl revealed three pharmacophoric regions: aromatic hydrocarbon, hydrogen bond acceptor, and hydrogen bond donor, which play important roles in its interaction with the protein targets. Therefore, cryptolepine HCl appears to be a promising drug candidate for further optimization and validation against M. tuberculosis.

Resistive Index of Intrarenal Artery in Evaluation of Diabetic Nephropathy.

Diabetes mellitus is one of the systemic diseases affecting the kidneys. Diabetic nephropathy is a serious microvascular complication of diabetes mellitus. It is the most important,cause of death in type I diabetic patients, of whom 30%-40% eventually develop end-stage renal failure and 40% of type II diabetics are at risk of developing diabetic nephropathy. So, diagnosis of diabetic nephropathy is paramount for the survivability of the diabetic patients not only because of the consequences of renal progression but also because of the strong association with the risk of developing cardiovascular disease. A total number of 53 subjects were enrolled in this present cross sectional study in the department of Radiology and Imaging, Bangabandhu Sheikh Mujib Medical University (BSMMU) in collaboration of Nephrology and Medicine of the same institution during two years (2011-13) aim to evaluate the diagnostic usefulness of renal resistive index (RI) by duplex Doppler ultrasonography for detection of renal dysfunction in diabetic patients. Clinically diagnosed diabetic patients having diabetic nephropathy referred to the department of Radiology and Imaging in BSMMU for ultrasonography of Kidneys, Ureters and Bladder (KUB) region or whole abdomen were selected as sample. Biochemical reports (Serum creatinine and Urinary albumin) and the RI value of intrarenal artery were correlated and analyzed. Only those patients biochemically were diagnosed as having diabetic nephropathy was included. Those with incomplete data, hydro nephrosis and renal calculus were excluded. Both the kidneys were visualized by commercially available real time scanner (GE Voluson) equipped with a curvilinear transducer operating at 3.5 MHz First Gray scale ultrasonography was done followed by Color Doppler of intra renal artery and then RI was measured. Majority (45.3%) patients were in 6th decade with the mean age was of 52.66±7.4 years and ranging from 38 to 65 years in patients. Male was found to be 54.7% of diabetic patients with male to female ratio 1.2:1. Resistive index of (≥ 0.7) was found in 73.6% patients with diabetes with the mean resistive index of 0.71±0.04. Positive correction between resistive index with serum creatinine (r=0.581, p<0.01) and albuminuria (r-0.725, p<0.01) were observed. It can be concluded that Resistive Index measured by duplex Doppler ultrasonography is useful diagnostic modality for detection of renal dysfunction in diabetic nephropathy patients. Resistive Index has value in identifying diabetic patients who are developing nephropathy and can be used as an additional diagnostic tool. Also it is well correlated with Serum Creatinine and Albuminuria which are the biochemical parameters to diagnose diabetic nephropathy.

Effective control of hypertension in adults with chronic kidney disease.

INTRODUCTION: Adequate control of hypertension in Chronic Kidney Disease patients is difficult to achieve. This study was designed to analyze the adequacy of Hypertension control in adults with CKD using different classes of antihypertensive drugs. METHODS: A cross-sectional observational study was done that included 85 patients with CKD admitted to our Medicine Department over a period of two years (2006-2008 A.D.). Presence of CKD was defined as glomerular filtration rate <60 ml/min per 1.73 m2 for more than three months or presence of albuminuria (albumin:creatinine ratio >30ug/mg). Adequate blood pressure control was defined as systolic blood pressure less than or equals to 130 and diastolic blood pressure less than or equals to 80 mm Hg. Data and Statistical analysis was done using SPSS Version 12 for Windows. RESULTS: Of all the CKD patients, 51.4% required three Anti-Hypertensive drugs combination for the effective control of Hypertension, while only 21% of CKD patients with hypertension was controlled on two drugs. CONCLUSION: Adequate control of blood pressure in CKD patient was shown to be most effective on combination of three antihypertensive drugs. A poor control was seen on patients taking less than three antihypertensive drugs.

Visual outcome of conventional extracapsular cataract extraction with posterior chamber intraocular lens implantation versus manual small-incision cataract surgery.

BACKGROUND: an effective method for cataract surgery should be identified to combat cataract blindness. AIM: to study the surgical outcome of conventional extracapsular cataract extraction versus manual small-incision cataract surgery. MATERIALS AND METHODS: a randomized clinical trial was carried out including one hundred eyes (88 patients) which were divided into two groups using systematic randomization: groups of conventional extracapsular cataract extractionwith posterior chamber intraocular lens (ECCE with PCIOL) implantation and manual small-incision cataract surgery (MSICS). The postoperative parameters/variables studied were the unaided and best-corrected visual acuity and astigmatism. STATISTICS: epi info 2000 version statistical software was used for data analysis and calculation of relative risk, 95% CI and p value. The p value of less than 0.05 was considered as significant. RESULTS: in the immediate postoperative period, unaided visual acuity of =or> 6/18 was achieved in 24 subjects in MSICS group versus 7 in ECCE with PCIOL group (RR=2.05, 95% CI= 1.44 - 2.94, p = 0.0002), whereas the same at 6 - 8 weeks postoperatively was found in 28 and 22 subjects in those groups respectively (RR=1l.27, 95% CI=0.86-1.89, p=0.23). The astigmatism of =or> 2 at6 - 8 weeks was found in 35 and 17 subjects from the conventional and MSICS groups respectively ( R=2.28, 95% CI= 1.39-3.73, p=0.0002). CONCLUSION: both MSICS and conventional ECCE with PCIOL are safe and effective techniques for treatment of cataract patients. A more rapid recovery of good vision can be achieved with MSICS than with conventional ECCE with PCIOL in the immediate postoperative period.

Thrombocytosis in intensive care.

We conducted a retrospective study of platelet count in 226 patients admitted for critical care over a 5-month period, to explore the incidence of thrombocytosis and its relation to admission category, duration of ICU stay and outcome. Our findings indicate that thrombocytosis is not rare in ICU patients. At least one platelet count greater than 450x10(9) litre(-1) was found in 21.7% of patients and was associated with lower ICU mortality (P=0.003), lower hospital mortality (P=0.006), but longer duration of ICU stay (P<0.0001). Thrombocytosis may serve as an independent predictor of favourable outcome in ICU patients.

Toxicity of antibiotics and antifungals on cultured human corneal cells: effect of mixing, exposure and concentration.

Toxic effects of topical drugs may be masked by manifestations of the disease they cure. The toxicity of drug mixtures has not been thoroughly studied. We therefore investigated cytopathic effects on primary cultures of human corneal cells of six topical antimicrobials singly and in combinations of any two, to determine the combined toxicity ranking and the interaction between duration of exposure and concentration. Preconfluent cultures were exposed to fixed dilutions of single drugs, or to equal-dilution mixtures of two drugs, for 7 and 14 days. Diminishing concentrations of single drugs were applied sequentially to cultures for 14 days. The number of metabolically competent cells was assessed by measuring hexosaminidase and total protein. Toxic effects depended on substance, concentration and exposure. The scale of toxicity determined for single drugs after 7 days of exposure was: gentamicin > econazole > or = methicillin > or = clotrimazole > or = miconazole > or = chloramphenicol. After 14 days this order changed: in particular chloramphenicol showed a highly increased toxicity. The order of diminishing effects was: gentamicin > chloramphenicol > or = methicillin > miconazole > econazole > clotrimazole. A clear reduction in cytopathic effects was observed when drug concentration was decreased progressively only in cultures treated with gentamicin or methicillin. All drug combinations were more toxic than their components at equal dilution. Combinations containing chloramphenicol ranked most toxic overall, those containing econazole least. A tapering off combination regime did not improve cell survival. These in vitro toxicity data complement clinical studies and suggest ways in which topical drugs can be chosen to minimise toxic effects to corneal surface.

[Erythrocytosis in a 4 year-old child: diagnostic, prognostic, therapeutical problems]. / Erythrocytose pure chez un enfant de 4 ans: problèmes diagnostiques, pronostiques, thérapeutiques.

BACKGROUND: Pure erythrocytosis is rare in children. This report describes such a case. CASE REPORT: A 4 year-old boy was admitted because erythrocytosis had been found routinely before adenoidectomy. He was born in Guatemala, was adopted just after his birth, and had been living in France since that age. Clinical examination was normal. His hemogram showed: erythrocytes: 8,800,000/mm3; hemoglobin: 20.1 g/dl; hematocrit: 66.8%; reticulocytes: 262,000/mm3; platelets: 200,000/mm3; leukocytes: 6,800/mm3. The patient had been given iron salts for the past 3 months without an earlier hemogram. Total red cell mass was 1200 ml (N: 600). The myelogram was normal as was the leukocyte alkaline phosphatases, serum lysozyme and vitamin B12. Blood ferritin was low (3.5 ng/ml). In vitro cultures of erythroid precursors were normal, as was the karyotype of myeloid cells. Blood erythropoietin concentration was 20-293 mU/ml (N:4-14). All the causes of secondary polycythemia were eliminated by appropriate investigations. The patient was treated by phlebotomy in aliquots of 25 ml/kg, twice a month, for 10 months, and was given iron therapy. At the end of treatment, his hemoglobin was 14 g/dl and his hematocrit was 45%. Both progressively increased again one year later, requiring new phlebotomies. The patient was followed for 4 years but no cause for this erythrocytosis was found; it was probably congenital in origin. CONCLUSION: This case of pure erythrocytosis was associated with elevated erythropoietin production. Whether this high secretion is related to receptor dysfunction remains to be determined.

Nepal: a potentially explosive situation.

PIP: 90% of Nepal's population is engaged in agriculture; the rural children lack all modern amenities and facilities, and boys are given preference over girls, who do not attend school. In urban populations, girls and boys are treated equally; however, 150,000 children, aged 7 to 16 years, work in carpet factories in unhygienic conditions. 52.71% are illiterate; 47.29% are dropouts. Others work as domestic servants, dishwashers in restaurants, or ragpickers. Many fortunate children do attend schools, which are numerous and filled to capacity. But thousands of Nepalese girls are sold to brothels in Bombay, Calcutta, and other parts of India; upon their return home, they bring human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) with them, as do thousands of male adult migrant workers. A government agency, AIDS Prevention and Control Programme, and about 50 nongovernmental organizations (NGOs) are collaborating to help persons who are infected with HIV or suffering from AIDS. Caritas works with two of the NGOs on a mass education program, prevention, and rehabilitation of HIV-positive women. Although government statistics indicate there are 133 identified cases of HIV in Nepal, the World Health Organization estimates the number of people there who are infected with HIV to be 10,000.^ieng

[Palpebral edema with fever and Streptococcus sanguis septicemia]. / Oedème palpébral fébrile et septicémie à Streptococcus sanguis.

A case of facial cellulitis complicated by regional thrombophlebitis and septicemia is reported in a 6 year-old girl. Streptococcus sanguis, a bacterial agent, unusually responsible for cellulitis, was isolated from 5 blood cultures. This child had no immunosuppression or endocarditis or dental infection. She had been previously given a non-steroidal anti-inflammatory agent, which was potentially responsible for the diffusion of infection.

Group A streptococcal cellulitis-adenitis in a patient with acquired immunodeficiency syndrome.

A rapidly enlarging left inguinal adenitis, with positive groove sign, and fever, chills, malaise, hypotension, headache, scarlatiniform rash, choleroid diarrhea, and proteinuria developed in an homosexual man who was positive for human immunodeficiency virus. The needle aspiration of the inguinal mass showed group A beta-hemolytic streptococci and the blood cultures were negative, suggesting group A streptococcal cellulitis-adenitis with toxic strep syndrome. Treatment with penicillin and surgical drainage was successful. Bacterial infections associated with defective humoral immunity appear to be common in patients with acquired immunodeficiency syndrome (AIDS), and some of these infections have a remarkable extensive and lethal evolution. Therefore streptococcal adenitis should be considered in any patient with AIDS or AIDS-related syndrome in whom rapidly enlarging inguinal nodes develop.

Pyoderma gangrenosum with pulmonary involvement.

A 60-year-old woman had a typical pyoderma gangrenosum with monoclonal IgA gammopathy and atrophic gastritis. Two years after the onset of her skin disease, she had evidence of pulmonary abscesslike involvement. Corticosteroid therapy led to healing of skin and lung diseases. This case stresses the multisystemic manifestations of neutrophilic dermatoses with special attention to pulmonary involvement.

Gardez moi en bonne sante: Prise en charge de l'enfant entre 0 et 5 ans: manuel a l'usage des agents des centres de sante

Le jeune enfant est un etre particulierement fragile. Pour lui assurer une croissance et un developpement harmonieux; pour le proteger au maximum contre les maladies et les accidents; de nombreuses mesures doivent etre prises. Ces mesures sont developpees dans le present manuel