Expedient synthesis of sulfinamides from sulfonyl chlorides.
Sulfinamides were synthesized from sulfonyl chlorides using a procedure involving in situ reduction of sulfonyl chlorides. The reaction is broad in scope and easy to perform.
Amides↗
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Bioequivalence of two tablet formulations of nadolol using single and multiple dose data: assessment using stereospecific and nonstereospecific assays.
Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state.
Adult↗
Carboxymethyl cellulose as a new heterobifunctional ligand carrier for affinity precipitation of proteins.
Affinity precipitation is a technique that imparts selectivity to the widely used primary purification step of precipitation of proteins from crude extracts. Hetero-bifunctional affinity precipitation involves use of reversibly soluble/insoluble polymers that can be used as backbones to conjugate affinity ligands for specific separations. A variety of such polymers have been reported in literature. In this work we report development of carboxymethyl cellulose (CM cellulose) as a cheap, readily available and versatile reversibly soluble polymer system. Available CM cellulose as sodium salt could be quantitatively precipitated from its aqueous solution in presence of about 50 mM calcium and 7.2% w/v polyethylene glycol-4000, and could be resolubilised in the working buffer in absence of calcium, polyethylene glycol or both. Effectiveness of the CM cellulose-calcium-polyethylene glycol system was demonstrated by purifying lactate dehydrogenase from porcine muscle extract using covalently conjugated Cibacron blue dye-ligand. By careful choice of conditions that suppressed non-specific interactions, the system was shown to be an effective affinity precipitation polymer system inspite of the polyelectrolytic nature of CM cellulose. Up to 23 fold purification of the enzyme from crude extarct was obtained in one single precipitation sequence.
Animals↗
Non-dopaminergic neurons expressing dopamine synthesis enzymes: differentiation and functional significance.
The development and functional significance of neurons in the arcuate nucleus expressing tyrosine hydroxylase and/or aromatic L-amino acid decarboxylase were studied in rat fetuses, neonates, and adults using immunocytochemical (single and double immunolabeling of tyrosine hydroxylase and aromatic L-amino acid decarboxylase) methods with a confocal microscope and computerized image analysis, HPLC with electrochemical detection, and radioimmunological analysis. Single-enzyme neurons containing tyrosine hydroxylase were first seen on day 18 of embryonic development in the ventrolateral part of the arcuate nucleus. Neurons expressing only aromatic L-amino acid decarboxylase or both enzymes of the dopamine synthesis pathway were first seen on day 20 of embryonic development, in the dorsomedial part of the nucleus. On days 20-21 of embryonic development, dopaminergic (containing both enzymes) neurons amounted to less than 1% of all neurons expressing tyrosine hydroxylase and/or aromatic L-amino acid decarboxylase. Nonetheless, in the ex vivo arcuate nucleus and in primary neuron cultures from this structure, there were relatively high leveLs of dopamine and L-dihydroxyphenylalanine (L-DOPA), and these substances were secreted spontaneously and in response to stimulation. In addition. dopamine levels in the arcuate nucleus in fetuses were sufficient to support the inhibitory regulation of prolactin secretion by the hypophysis, which is typical of adult animals. During development, the proportion of dopaminergic neurons increased, reaching 38% in adult rats. Specialized contacts between single-enzyme tyrosine hydroxylase-containing and aromatic L-amino acid decarboxylase-containing neurons were present by day 21 of embryonic development; these were probably involved in transporting L-DOPA from the former neurons to the latter. It was also demonstrated that the axons of single-enzyme decarboxylase-containing neurons projected into the median eminence, supporting the secretion of dopamine into the hypophyseal portal circulation. Thus, dopamine is probably synthesized in the arcuate nucleus not only by dopaminergic neurons, but also by neurons expressing only tyrosine hydroxylase or aromatic L-amino acid decarboxylase.
Animals↗
A randomized, double-blind, placebo-controlled trial of interferon-alpha and amantadine versus interferon-alpha alone in the treatment of patients with chronic hepatitis C.
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Adult↗
Metal chelate affinity precipitation of RNA and purification of plasmid DNA.
The affinity of metal chelates for amino acids, such as histidine, is widely used in purifying proteins, most notably through six-histidine 'tails'. We have found that metal affinity interactions can also be applied to separation of single-stranded nucleic acids through interactions involving exposed purines. Here we describe a metal affinity precipitation method to resolve RNA from linear and plasmid DNA. A copper-charged copolymer of N-isopropyl acrylamide (NIPAM) and vinyl imidazole (VI) is used to purify plasmid from an alkaline lysate of E. coli. The NIPAM units confer reversible solubility on the copolymer while the imidazole chelates metal ions in a manner accessible to interaction with soluble ligands. RNA was separated from the plasmid by precipitation along with the polymer in the presence of 800 mM NaCl. Bound RNA could be recovered by elution with imidazole and separated from copolymer by a second precipitation step. RNA binding showed a strong dependence on temperature and on the type of buffer used.
Acrylamides↗
Hepatic steatosis in hepatitis C virus genotype 3 infection: does it correlate with body mass index, fibrosis, and HCV risk factors?
Hepatic steatosis is a recognized feature of hepatitis C viral infection, particularly in genotype 3. The demographics and the associations contributing to moderate to severe steatosis in genotype 3 are not very well studied. The aim of this study is to determine the demographics and association of steatosis with fibrosis, obesity, diabetes, lipid levels, and risk factors among patients with hepatitis C virus (HCV) genotype 3. Two hundred ninety-three consecutive HCV patients (genotype 1, n = 218; genotype 2, n = 43; genotype 3, n = 32) at our institution were studied retrospectively. Demographic information such as height, weight, genotype, risk factors, serum cholesterol and triglyceride, and liver biopsy was collected. Steatosis was graded using the Brunt classification. HCV genotype 3-infected patients were younger (P < 0.04) and had lower serum cholesterol levels (P < 0.02) compared to nongenotype 3 patients. Moderate to severe steatosis was more prevalent in HCV genotype 3 patients (P < 0.001) with intravenous drug abuse as a risk factor (P = 0.04). Genotype 3 was the independent predictor of steatosis in all patients. There was no statistical association between grade of steatosis and body mass index, fibrosis, necroinflammation, or hyperlipidemia when only HCV genotype 3 patients were included in the multivariate logistic model. Hepatic steatosis is a feature of genotype 3. Patients with HCV genotype 3 are younger and have lower serum cholesterol levels. Genotype 3 is the independent predictor for steatosis in HCV patients. HCV genotype 3 patients with moderate to severe steatosis are more likely to have intravenous drug use as a risk factor.
Arizona↗
Hepatitis C virus recurrence in living donor liver transplant recipients.
Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) is a universal phenomenon. Recent reports have suggested an earlier and more aggressive recurrence in the living donor liver transplant (LDLT) population. The aim of this study was to compare the histological recurrence of HCV after LDLT versus deceased donor transplantation (DDT). Twenty-nine patients underwent LT for HCV-related end-stage liver disease at our institution between April 2001 and March 2003 (42 months). Twenty patients underwent DDT, and nine patients LDLT. Laboratory data were collected on a weekly to biweekly basis and HCV PCR was performed before LT and 3-4 months and yearly post-LT. Liver biopsies were performed as needed and per institutional protocol at 7 days, at 4 months, and yearly thereafter. All biopsies were evaluated by a single pathologist and scored for rejection (Banff score) and chronic hepatitis (Ishak score system). The predominant genotype in the DDT and LDLT groups was genotype 1 (DDT = 70%, LDLT = 79%). HCV RNA titers pre-LT and 3-4 months after LT did not differ. The incidence of rejection was higher in the DDT group (P < 0.05). There was a trend toward improved Ishak stage and grade in the LDLT group at 4 and 12 months post-LT, however, this trend did not reach statistical significance. No histological difference in the recurrence or severity rate was observed at 4 or 12 months post-LT in the DDT group vs. the LDLT group.
Adult↗
One-pot microwave assisted preparation of pyrazoloquinazolinone libraries.
The novel solution-phase synthesis of an array of biologically relevant pyrazoloquinazolinones in a simple microwave driven one pot procedure is revelaed. Transformations are carried out in good to excellent yield by condensation of alpha-cyano-ketones and 2-hydrazino-benzoic acids. Subsequent microwave irradiation affords pyrazoloquinazolinones with six points of potential diversification. The protocol described represents a very attractive solution phase procedure for the rapid generation of arrays of such functionalized cores, further demonstrating the growing importance of economic and enabling complexity generating chemistries in the lead discovery arena.
Chemistry, Organic↗
The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization.
The sterile alpha motif (SAM) domain is a novel protein module of approximately 70 amino acids that is found in a variety of signaling molecules including tyrosine and serine/threonine protein kinases, cytoplasmic scaffolding and adaptor proteins, regulators of lipid metabolism, and GTPases as well as members of the ETS family of transcription factors. The SAM domain can potentially function as a protein interaction module through the ability to homo- and hetero-oligomerize with other SAM domains. This functional property elicits the oncogenic activation of chimeric proteins arising from translocation of the SAM domain of TEL to coding regions of the betaPDGF receptor, Abl, JAK2 protein kinase and the AML1 transcription factor. Here we describe the 2.0 A X-ray crystal structure of a SAM domain homodimer from the intracellular region of the EphA4 receptor tyrosine kinase. The structure reveals a mode of dimerization that we predict is shared amongst the SAM domains of the Eph receptor tyrosine kinases and possibly other SAM domain containing proteins. These data indicate a mechanism through which an independently folding protein module can form homophilic complexes that regulate signaling events at the membrane and in the nucleus.
Amino Acid Sequence↗
Site-specific PEGylation of native disulfide bonds in therapeutic proteins.
Native disulfide bonds in therapeutic proteins are crucial for tertiary structure and biological activity and are therefore considered unsuitable for chemical modification. We show that native disulfides in human interferon alpha-2b and in a fragment of an antibody to CD4(+) can be modified by site-specific bisalkylation of the two cysteine sulfur atoms to form a three-carbon PEGylated bridge. The yield of PEGylated protein is high, and tertiary structure and biological activity are retained.
Alkylation↗
Use of GFP tags to monitor localization of different luciferases in E. coli.
The utility of the green fluorescent protein (GFP) as a probe to monitor protein localization in living cells is gaining a great deal of attention. In this study, to understand the localization of luciferases in E. coli, we have attached GFP tags at both the N- and the C-terminus of firefly luciferase (FF-Luc)(from Pyrocoelia miyako) and of red (RE-Luc) and green (GR-Luc) bioluminescence-emitting luciferases (from Phrixothrix railroad-worms), respectively. There was no significant change in the bioluminescence emission spectrum for any of the three luciferases following the tagging with GFP at either the N- or C-terminus, confirming the absence of energy transfer between one another. Using confocal imaging microscopy, we observed that all three luciferases expressed in the E.coli cultured at 37 degrees C tend to aggregate and are seen to localize in the poles, thus confirming their poor folding properties. In contrast, in the E.coli cultured at 18 degrees C FF-Luc was found to be highly expressed in the soluble form when compared to RE-Luc and GR-Luc. These results support our previous finding that the folding properties of FF-Luc and RE/GR-Luc are totally different.
Cytosol↗
Topics in penile dermatology.
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Balanitis↗
Moderate preputial dysplasia in a young child.
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Adult↗
The hypothesis of age-associated neovasculopathy with recurrent bleeding.
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Age Factors↗
Complete pathological response to chemotherapy for non-small cell lung cancer demonstrated by gamma camera positron emission tomography.
We report the case history of a 61-year-old female smoker who presented with an inoperable T2N2M0 squamous cell carcinoma of the right upper lobe bronchus. This was staged by computed tomography (CT), positron emission tomography (PET) using a modified dual-headed gamma camera, and mediastinoscopy. She then underwent three cycles of cisplatin-containing chemotherapy. After the chemotherapy, CT demonstrated a residual 10 mm mass in the right upper lobe and a considerable reduction in size of the mediastinal lymphadenopathy. Functional tumour imaging with PET showed no abnormality, suggesting that there was no remaining viable tumour. At right upper lobectomy a complete pathological response was confirmed. We discuss PET, the potential new applications of gamma camera technology, and the use of cisplatin-containing chemotherapy in non-small cell lung cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Primary intraosseous carcinoma of the mandible--a case report and review of the literature.
BACKGROUND: Squamous cell carcinoma arising within bone is a rare lesion and is only seen essentially in the jaw bones. METHODS: A case of primary intraosseous carcinoma arising in the mandible is reported in a 60-year-old female patient. Twenty-eight cases of primary intraosseous carcinoma published in the literature, till date, are reviewed. RESULTS: The mean age of the patients at the time of diagnosis was 53 years and the male: female ratio was 2.2:1. The posterior mandible was the predominant site. Fourteen of 28 patients presented with routine dental disorders, while eight patients complained of swelling, four of severe pain and three had sensory disturbances. The incidence of lymphadenopathy was 10 (34.481%) out of the 29 cases reviewed here. Wide surgical excision is accepted as the treatment of choice. CONCLUSION: The most common presenting symptom of these tumours is swelling and persistent pain in the jaw. Hence, in making a diagnosis one is likely to consider benign dental conditions. The importance of considering intraosseous carcinoma as a possibility in all cases of persistent pain and swelling in the jaw is emphasized so that suitable treatment can be instituted early.
Carcinoma, Squamous Cell↗
Evidence-based incorporation of serum sodium concentration into MELD.
BACKGROUND & AIMS: Serum sodium (Na) concentrations have been suggested as a useful predictor of mortality in patients with end-stage liver disease awaiting liver transplantation. METHODS: We evaluated methods to incorporate Na into model for end-stage liver disease (MELD), using a prospective, multicenter database specifically created for validation and refinement of MELD. Adult, primary liver transplant candidates with end-stage liver disease were enrolled. RESULTS: Complete data were available in 753 patients, in whom the median MELD score was 10.8 and sodium was 137 mEq/L. Low Na (<130 mEq/L) was present in 8% of patients, of whom 90% had ascites. During the study period, 67 patients (9%) died, 243 (32%) underwent transplantation, 73 (10%) were withdrawn, and 370 were still waiting. MELD score and Na, at listing, were significant (both, P < .01) predictors of death within 6 months. After adjustment for MELD score and center, there was a linear increase in the risk of death as Na decreased between 135 and 120 mEq/L. A new score to incorporate Na into MELD was developed: "MELD-Na" = MELD + 1.59 (135 - Na) with maximum and minimum Na of 135 and 120 mEq/L, respectively. In this cohort, "MELD-Na" scores of 20, 30, and 40 were associated with 6%, 16%, and 37% of risk of death within 6 months of listing, respectively. If this new score were used to allocate grafts, it would affect 27% of the transplant recipients. CONCLUSIONS: We demonstrate an evidence-based method to incorporate Na into MELD, which provides more accurate survival prediction than MELD alone.
Analysis of Variance↗