Assessment of the impact of on-site sanitation systems on groundwater pollution in two diverse geological settings--a case study from India.

On-site sanitation has emerged as a preferred mode of sanitation in cities experiencing rapid urbanization due to the high cost involved in off-site sanitation which requires conventional sewerages. However, this practice has put severe stress on groundwater especially its quality. Under the above backdrop, a study has been undertaken to investigate the impact of on-site sanitation on quality of groundwater sources in two mega cities namely Indore and Kolkata which are situated in two different geological settings. The parameters for the studies are distance of groundwater source from place of sanitation, effect of summer and monsoon seasons, local hydro-geological conditions, and physico-chemical parameters. NO(3) and fecal coliform concentrations are considered as main indexes of pollution in water. Out of many conclusions which can be made from this studies, one major conclusion is about the influence of on-site sanitation on groundwater quality is minimal in Kolkata, whereas it is significant in Indore. This difference is due to the difference in hydrogeological parameters of these two cities, Kolkata being on alluvium quaternary and Indore being on Deccan trap of Cretaceous to Paleogene age.

Multicenter evaluation of individual donor nucleic acid testing (NAT) for simultaneous detection of human immunodeficiency virus -1 & hepatitis B & C viruses in Indian blood donors.

BACKGROUND & OBJECTIVE: India has a high prevalence of HIV-1, hapatitis C and B virus (HCV and HBV) in the blood donors but has yet to implement nucleic acid testing (NAT) in blood screening. We undertook a multicentre evaluation of blood donor testing by NAT for simultaneous detection of HIV-1, HBV and HCV in a single tube and also to determine the feasibility of NAT implementation in India's low volume setting. METHODS: A total of 12,224 unlinked samples along with their serological results were obtained from representative eight blood banks in India and were individually manually tested by the Procleix Ultrio Assay (Chiron Corp. Emeryville, CA) for simultaneous detection of HIV-1, HCV, and HBV. RESULTS: Of the 12,224 samples tested, 209 (1.71%) were seroreactive. One hundred thirty three samples (1.09%) were reactive by Ultrio assay, 84 samples were seroreactive but NAT non reactive. There were eight NAT yield cases: 1 HIV, 1 HIV-HCV co-infection, and 6 HBV. INTERPRETATION & CONCLUSION: Our observed NAT yield for all three viruses was 1 in 1528 (0.065%). We estimate NAT could interdict 3272 infectious donations a year among our approximate 5 million annual donations.

Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.

We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.

Structure determination and conformation analysis of symmetrical dimers.

Conformational and stereochemical analysis of six new symmetrical dimers was performed using proton-proton vicinal coupling measured from (1)H NMR and (13)C satellites of (1)H NMR signals, natural abundance (13)C-edited nuclear overhauser effect (NOE) experiments, comprehensive NOE analysis and molecular modeling. The (13)C satellite analysis and (13)C-edited NOE experiments were carried out to extract spectral information between equivalent protons. Molecular modeling was applied for estimations of three-dimensional parameters of the studied dimers, which were subsequently used to generate a set of theoretical NOE for each possible conformation. The J-coupling, (13)C-edited NOE and quantitative NOE analyses showed the predominance of gauche conformation for three dimers, whereas a mixture of gauche and anti conformations (45:55) for three other dimers was established by quantitative NOE analysis. X-ray crystallographic study confirmed the stereochemistry of one of the dimers and revealed a discrepancy in conformation stability between liquid and solid states.

Observation of stimulated emission at high gyroharmonics: basis for a synchrotron resonance maser.

First experimental observations are reported on stimulated coherent synchrotron radiation from highly relativistic electrons in a strong magnetic field. The experiment employed a quasioptical millimeter-wave resonator and a 6-MeV electron beam gyrating in a field of up to 25 kG. Coherent radiation at 54 GHz, corresponding to the 11th gyroharmonic, was observed and characterized. These observations demonstrate the possibility of a synchrotron resonance maser.

Farnesyl protein transferase inhibition: a novel approach to anti-tumor therapy. the discovery and development of SCH 66336.

Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to non-cytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are currently in clinical evaluation. This review focuses on FPT inhibitors in clinical trials and concentrates on the benzocycloheptapyridine class, with details on the discovery and development of SCH 66336, currently in Phase II clinical trials.

High-resolution LC/MS for analysis of minor components in complex mixtures: negative ion ESI for identification of impurities and degradation products of a novel oligosaccharide antibiotic.

High-resolution mass spectrometry has been routinely used for structural confirmation and identification; however, it has mostly been applied to relatively pure samples. Exact mass measurement of minor components such as impurities, degradation products or metabolites in complex mixtures has been difficult without prior separation and isolation. Here we report the utilization of on-line liquid chromatography in combination with high-resolution mass spectrometry for the identification of impurities and base degradation products of Sch 27899, a member of the everninomicin class of antibiotics. Nine Sch 27899-related impurities and degradation products were detected by negative ion electrospray ionization using a magnetic sector mass spectrometer. Exact mass measurements were obtained at a resolution of 5000 using polyethylene glycol (PEG) sulfates as internal standards. Corresponding elemental compositions were determined within a 2 ppm error tolerance and structures were proposed for all components.

Ziracin, a novel oligosaccharide antibiotic.

Ziracin is produced by Micromonospora carbonacea and is highly active against Gram-positive bacteria. In particular it is highly active against methicillin resistant staphylococci and vancomycin resistant enterococci. Ziracin, C71H97NO38Cl2, contains two orthoester linkages, a nitro sugar, a methylene dioxy group, two aromatic ester residues and thirty five centres of assymmetries. In this paper a brief description of the structural elucidation of ziracin is presented along with the chemical modification of the antibiotic which has led to the identification of several potent antibacterials.

Putrescine, DNA, RNA and protein contents in human uterine, breast and rectal cancer.

AIMS: To find out the status of DNA, RNA and protein in human uterine, ovarian, breast and rectal carcinoma. MATERIAL AND METHODS: In this prospective study, patients of age group between late thirties and late fifties suffering from uterine, ovarian, breast and rectal cancer were taken as subjects of the present study. The total number of cases studied for each cases was ten. Pieces of human carcinomatous tissues of above mentioned cases were taken along with surrounding normal tissues. From the tissue samples, putrescine is separated by the method of Herbst et al, DNA analysed by Diphenylamine method, RNA by Orcinol method and protein by Biuret method. RESULTS: Tissue content of putrescine rises simultaneously with that of DNA, RNA and protein in carcinomatous growths as above in comparison to their respective adjacent normal tissue, the differences being statistically highly significant. CONCLUSIONS: Increase in DNA, RNA and protein concentration may be a pre-requisite for increased synthesis of putrescine in carcinomatous tissue and thereby the concentration of other di- and poly-amines.

Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity.

Introduction of bromine at the 10-position of 3-bromo-8-chloro-benzocycloheptapyridine analogues of type 3 results in formation of atropisomeric compounds of type (+/-)-1 and (+/-)-2 that are easily separable at room temperature on a ChiralPak AD column providing pure atropisomers, (+)-1, (-)-1, and (+)-2, (-)-2, respectively. Evaluation of the FPT activity of these atropisomers revealed that compounds (+)-1 and (+)-2 were more potent in the FPT enzyme and cellular assay than their (-)-isomer counterparts. Compounds (+)-1 and (+)-2 were found to inhibit FPT processing in COS cells at low micro molar range. They were also found to have excellent cellular antitumor activity. Evaluation of compound (+)-1 and (+)-2 in DLD-tumor model in nude mice revealed that they were efficacious, inhibiting tumor growth by 55 and 63% at 50 mpk, respectively.

Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships.

Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.

Chemical modifications and structure activity studies of ziracin and related everninomicin antibiotics.

Chemical modifications of eveminomicin antibiotics, particularly ziracin (1), were carried out to study the SARs as well as the chemical properties of this class of compounds. Use of allyl ether group for protection and selective deprotection of phenolic groups provided access to a variety of novel analogs of the title compounds, some of which exhibited the same high in vitro potency as the parent compounds.

Analysis of Gaussian beam and Bessel beam driven laser accelerators.

This paper presents a comparison of Gaussian and Bessel beam driven laser accelerators. The emphasis is on the vacuum beat wave accelerator (VBWA), employing two laser beams of differing wavelengths to impart a net acceleration to particles. Generation of Bessel beams by means of circular slits, holographic optical elements, and axicons is outlined and the image space fields are determined by making use of Huygens' principle. Bessel beams-like Gaussian beams-experience a Guoy phase shift in the vicinity of a focal region, resulting in a phase velocity that exceeds c, the speed of light in vacuo. In the VBWA, by appropriate choice of parameters, the Guoy phases of the laser beams cancel out and the beat wave phase velocity equals c. The particle energy gain and beam quality are determined by making use of an analytical model as well as simulations. The analytical model--including the v x B interaction--predicts that for equal laser powers Gaussian and Bessel beams lead to identical energy gains. However, three-dimensional, finite-emittance simulations, allowing for detuning, transverse displacements, and including all the electromagnetic field components, show that the energy gain of a Gaussian beam driven VBWA exceeds that of a Bessel beam driven VBWA by a factor of 2-3. The particle beam emerging from the interaction is azimuthally symmetric and collimated, with a relatively small angular divergence. A table summarizing the ratios of final energies, acceleration lengths, and gradients for a number of acceleration mechanisms is given.

Synthesis of C-11 methyl-substituted benzocycloheptapyridine inhibitors of farnesyl protein transferase.

[formula: see text] Synthesis of C-11 methyl-substituted benzocycloheptylpyridine tricyclic compounds has been achieved via two different methods. Methylation of C-11 has been effected by treatment of amine 4 with BuLi followed by Mel quenching. In a similar procedure, introduction of a C-11 substituent with concomitant rearrangement of the exocyclic double bond has been carried out. Potent farnesyl protein transferase inhibitors have been synthesized using the above methodologies.

Effect of thymectomy on serum gonadotrophins and testosterone concentration.

There is controversy about the relationship between thymic secretion and secretion of gonadotrophins and testosterone. One group of scientists reported that thymus is stimulatory to gonadotrophins and testosterone secretion, and according to other group thymic secretion is inhibitory to gonadotrophins and testosterone secretion. So we tried to observe what exactly happens to serum gonadotrophins and testosterone level following thymectomy. Thymectomy was performed in prepubertal animals and after 45 days of their operation serum gonadotrophins were measured by ELISA technique and serum testosterone was measured by RIA technique. The present study reveals a significant fall in serum FSH level along with significant rise in serum LH and testosterone level in male albino rats following thymectomy in comparison to that of sham thymectomized rats. It appears that thymus has an inhibitory influence on LH secreting gonadotrophs which has been withdrawn following thymectomy and as a result there occurs an increase in serum LH level. This LH stimulates interstitial cells of leydig and cause thereby an increase in serum testosterone level. The result also gives an indication that among the gonadotrophs in pituitary, one type is concerned with the secretion of LH while some gonadotrophs are concerned with secretion of FSH only; and the thymus possibly maintains the FSH secreting gonadotrophs intact at least till the age of puberty. Thymectomy may cause some disorganization of FSH secreting gonadotrophs which results in the fall in serum FSH level in thymectomized animals in comparison to that of sham thymectomized animal group.

Interaction of a novel GDP exchange inhibitor with the Ras protein.

Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit tumorigenic Ras function may be useful in the treatment of Ras-related tumors. The interaction of a novel GDP exchange inhibitor (SCH-54292) with the Ras-GDP protein was studied by NMR spectroscopy. The binding of the inhibitor to the Ras protein was enhanced at low Mg2+ concentrations, which enabled the preparation of a stable complex for NMR study. To understand the enhanced inhibitor binding and the increased GDP dissociation rates of the Ras protein, the conformational changes of the Ras protein at low Mg2+ concentrations was investigated using two-dimensional 1H-15N HSQC experiments. The Ras protein existed in two conformations in slow exchange on the NMR time scale under such conditions. The conformational changes mainly occurred in the GDP binding pocket, in the switch I and the switch II regions, and were reversible. The Ras protein resumed its regular conformation after an excess amount of Mg2+ was added. A model of the inhibitor in complex with the Ras-GDP protein was derived from intra- and intermolecular NOE distance constraints, and revealed that the inhibitor bound to the critical switch II region of the Ras protein.

(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent.

We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.