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Biomedical subjects

A N Shah

Publications and source records attributed to A N Shah.

At least 19 recordsLinked to original sources
PubMed2001

Molecular cloning and sequence analysis of the complestatin biosynthetic gene cluster.

Streptomyces lavendulae produces complestatin, a cyclic peptide natural product that antagonizes pharmacologically relevant protein-protein interactions including formation of the C4b,2b complex in the complement cascade and gp120-CD4 binding in the HIV life cycle. Complestatin, a member of the vancomycin group of natural products, consists of an alpha-ketoacyl hexapeptide backbone modified by oxidative phenolic couplings and halogenations. The entire complestatin biosynthetic and regulatory gene cluster spanning ca. 50 kb was cloned and sequenced. It consisted of 16 ORFs, encoding proteins homologous to nonribosomal peptide synthetases, cytochrome P450-related oxidases, ferredoxins, nonheme halogenases, four enzymes involved in 4-hydroxyphenylglycine (Hpg) biosynthesis, transcriptional regulators, and ABC transporters. The nonribosomal peptide synthetase consisted of a priming module, six extending modules, and a terminal thioesterase; their arrangement and domain content was entirely consistent with functions required for the biosynthesis of a heptapeptide or alpha-ketoacyl hexapeptide backbone. Two oxidase genes were proposed to be responsible for the construction of the unique aryl-ether-aryl-aryl linkage on the linear heptapeptide intermediate. Hpg, 3,5-dichloro-Hpg, and 3,5-dichloro-hydroxybenzoylformate are unusual building blocks that repesent five of the seven requisite monomers in the complestatin peptide. Heterologous expression and biochemical analysis of 4-hydroxyphenylglycine transaminon confirmed its role as an aminotransferase responsible for formation of all three precursors. The close similarity but functional divergence between complestatin and chloroeremomycin biosynthetic genes also presents a unique opportunity for the construction of hybrid vancomycin-type antibiotics.

Base Sequence↗
PubMed2001

Gender-related differences in acute rehabilitation lengths of stay, charges, and functional outcomes for a matched sample with spinal cord injury: a multicenter investigation.

OBJECTIVE: To examine the effects of gender on length of stay (LOS), treatment costs, and outcomes by using a matched sample of patients with spinal cord injury (SCI). DESIGN: A 2 x (15 x 3) mixed, block design was used retrospectively to analyze the impact of gender on subjects matched for age, American Spinal Injury Association (ASIA) motor impairment classification, and level of neurologic injury. SETTING: Twenty medical centers in the federally sponsored Spinal Cord Injury Model Systems project. PARTICIPANTS: One thousand seventy-four adult patients with SCI admitted between 1988 and 1998 were assessed at acute-care admission, inpatient rehabilitation admission, and inpatient rehabilitation discharge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: ASIA motor index and FIM instrument admission, discharge, and efficiency scores; rehabilitation LOS and medical care charges; and discharge disposition. RESULTS: Analysis revealed no gender-related differences in FIM motor scores on admission and discharge. No differences in FIM motor efficiencies or daily change were observed. No significant differences were found for ASIA motor scores on acute-care admission and rehabilitation discharge. No differences in acute rehabilitation LOS and charges were observed. No gender-related differences were seen in the likelihood of discharge to an institutional setting. CONCLUSION: Gender was not a significant factor in functional outcome of SCI patients after acute rehabilitation.

Activities of Daily Living↗
PubMed2001

Hypertensive.

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Adult↗
PubMed2001

Malakoplakia of the kidney--a case report.

Malakoplakia is a rare disease expressed as a special type of inflammatory reaction to infection with various bacteria and fungi. We present a case of renal malakoplakia in a 30-year-old female patient. The symptoms were not characteristic enough for making the ture diagnosis preoperatively. A preoperative diagnosis of renal cell carcinoma was made in this case.

Adult↗
PubMed2000

Cloning, nucleotide sequence, and heterologous expression of the biosynthetic gene cluster for R1128, a non-steroidal estrogen receptor antagonist. Insights into an unusual priming mechanism.

R1128 substances are anthraquinone natural products that were previously reported as non-steroidal estrogen receptor antagonists with in vitro and in vivo potency approaching that of tamoxifen. From a biosynthetic viewpoint, these polyketides possess structurally interesting features such as an unusual primer unit that are absent in the well studied anthracyclic and tetracyclic natural products. The entire R1128 gene cluster was cloned and expressed in Streptomyces lividans, a genetically well developed heterologous host. In addition to R1128C, a novel optically active natural product, designated HU235, was isolated. Nucleotide sequence analysis of the biosynthetic gene cluster revealed genes encoding two ketosynthases, a chain length factor, an acyl transferase, three acetyl-CoA carboxylase subunits, two cyclases, two oxygenases, an amidase, and remarkably, two acyl carrier proteins. Feeding studies indicate that the unusual 4-methylvaleryl side chain of R1128C is derived from valine. Together with the absence of a dedicated ketoreductase, dehydratase, or enoylreductase within the R1128 gene cluster, this suggests a functional link between fatty acid biosynthesis and R1128 biosynthesis in the engineered host. Specifically, we propose that the R1128 synthase recruits four subunits from the endogenous fatty acid synthase during the biosynthesis of this family of pharmacologically significant natural products.

Anthraquinones↗
PubMed1999

Kinetic analysis of the actinorhodin aromatic polyketide synthase.

Type II polyketide synthases (PKSs) are bacterial multienzyme systems that catalyze the biosynthesis of a broad range of natural products. A core set of subunits, consisting of a ketosynthase, a chain length factor, an acyl carrier protein (ACP) and possibly a malonyl CoA:ACP transacylase (MAT) forms a "minimal" PKS. They generate a poly-beta-ketone backbone of a specified length from malonyl-CoA derived building blocks. Here we (a) report on the kinetic properties of the actinorhodin minimal PKS, and (b) present further data in support of the requirement of the MAT. Kinetic analysis showed that the apoACP is a competitive inhibitor of minimal PKS activity, demonstrating the importance of protein-protein interactions between the polypeptide moiety of the ACP and the remainder of the minimal PKS. In further support of the requirement of MAT for PKS activity, two new findings are presented. First, we observe hyperbolic dependence of PKS activity on MAT concentration, saturating at very low amounts (half-maximal rate at 19.7 +/- 5.1 nM). Since MAT can support PKS activity at less than 1/100 the typical concentration of the ACP and ketosynthase/chain length factor components, it is difficult to rule out the presence of trace quantities of MAT in a PKS reaction mixture. Second, an S97A mutant was constructed at the nucleophilic active site of the MAT. Not only can this mutant protein support PKS activity, it is also covalently labeled by [(14)C]malonyl-CoA, demonstrating that the serine nucleophile (which has been the target of PMSF inhibition in earlier studies) is dispensible for MAT activity in a Type II PKS system.

Acyl Carrier Protein↗
PubMed1998

A newly recognized entity: intraductal "oncocytic" papillary neoplasm of the pancreas.

Intraductal papillary-mucinous tumors of the pancreas are increasingly recognized, and their characteristic endoscopic and radiological features are well reported in the literature in recent years. Oncocytic features in these tumors are uncommon and unrecognized. Intraductal oncocytic papillary neoplasm is a distinct pancreatic tumor and is a recently recognized entity. We report a case of a 69-yr-old patient who presented with symptoms mimicking pancreatitis, resulting in delay in the diagnosis of her pancreatic tumor. She underwent a successful Whipple's procedure and subsequently has remained well. The resected specimen showed an intraductal oncocytic papillary-mucinous neoplasm. The entity is new and the literature information is inadequate at present to judge the biological behavior of this tumor. We discuss this recently recognized entity.

Aged↗
PubMed1998

Prevalence of Helicobacter pylori in peptic ulcer patients in greater Rochester, NY: is empirical triple therapy justified?

OBJECTIVES: Among patients with peptic ulcer disease, the prevalence of Helicobacter pylori has been reported to range from 80% to 90%. Thus empirical cost-effective therapy has been suggested. We surveyed patients with peptic ulcer disease in Rochester, NY. METHODS: From two teaching hospitals all patients who had duodenal ulcers (DU) and/or gastric ulcers (GU) on esophagogastroduodenoscopy (EGD) with antral biopsy for histology for H. pylori and for rapid urease (CLO) test were included in the study. We examined a total of 160 patients with DU and 145 patients with GU, age range 18-92 yr, obtaining clinical data, race, medication profile, and history of use of nonsteroidal antiinflammatory drugs (NSAIDs). An ulcer was defined if the lesion with loss of mucosal integrity was > or = 0.5 cm, with apparent depth. H. pylori was considered present if CLO test and/or histology were positive for H. pylori. To confirm the reliability of nonuse of NSAIDs, we randomly checked blood samples of 90 such patients from the ambulatory clinic for the presence of salicylates. To identify the sensitivity of the CLO test, we performed a serology test for H. pylori antibody in 100 subjects to compare the CLO test results. Also, 500 CLO test results were compared to the histology results for H. pylori. RESULTS: Among 160 DU patients, 16 were NSAID users with negative H. pylori and excluded from the prevalence study. Of the remaining 144 patients with DU, H. pylori was present in 88 patients (61%). When these data were analyzed according to race, H. pylori was present in 54 (52%) of 104 whites compared to 34 of 40 (85%) nonwhites (blacks, Hispanics, Asians) (p < 0.01). Among 145 GU patients 18 were NSAID users with negative H. pylori and excluded from the prevalence analysis. Of the remaining 127 patients with GU, H. pylori was present in 87 patients (61%). Among them, H. pylori was present in 46 of 87 (53%) whites, whereas 31 of 40 nonwhites (78%) were H. pylori-positive (p < 0.01). Antral histology and CLO test for H. pylori were in agreement in 92% of cases. Serology and CLO test for H. pylori were in agreement in 87% of cases. None of the randomly screened patients, including 16 ulcer patients with negative H. pylori, showed presence of salicylate in blood. CONCLUSION: In greater Rochester, NY, where the majority of our patients with EGD were whites, the prevalence of H. pylori among ulcer patients was lower compared to other regions, particularly among whites. This suggests that an additional causative factor or factors for peptic ulcers may be present. Hence, empirical antibiotic therapy of ulcer patients without confirming the presence of H. pylori may not be justified.

Adolescent↗
PubMed1997

Thermodynamic characterization of the reversible, two-state unfolding of maltose binding protein, a large two-domain protein.

The folding and stability of maltose binding protein (MBP) have been investigated as a function of pH and temperature by intrinsic tryptophan fluorescence, far- and near-UV circular dichroism, and high-sensitivity differential scanning calorimetric measurements. MBP is a monomeric, two-domain protein containing 370 amino acids. The protein is stable in the pH range of 4-10.5 at 25 degrees C. The protein exhibits reversible, two-state, thermal and guanidine hydrochloride-mediated denaturation at neutral pH. The thermostability of MBP is maximal at pH 6, with a Tm of 64.9 degrees C and a deltaHm of 259.7 kcal mol(-1). The linear dependence of deltaHm on Tm was used to estimate a value of deltaCp of 7.9 kcal mol(-1) K(-1) or 21.3 cal (mol of residue)(-1) K(-1). These values are higher than the corresponding deltaCp's for most globular proteins studied to date. However, the extrapolated values of deltaH and deltaS (per mole of residue) at 110 degrees C are similar to those of other globular proteins. These data have been used to show that the temperature at which a protein undergoes cold denaturation depends primarily on the deltaCp (per mol of residue) and that this temperature increases with an increase in deltaCp. The predicted decrease in stability of MBP at low temperatures was experimentally confirmed by carrying out denaturant-mediated unfolding studies at neutral pH at 2 and 28 degrees C.

Bacterial Proteins↗
PubMed1996

A wandering spleen. Detection by In-111 leukocyte imaging.

A wandering spleen is a rare condition characterized by splenic malposition due to congenital maldevelopment or laxity of the supporting ligamentous structures that usually fixate the anatomical position of the spleen. The diagnosis is often difficult to make clinically. In this report, a case is described in which an In-111 oxime labeled leukocyte scan was helpful in making a diagnosis of a wandering spleen.

Adult↗
PubMed1996

Parathyroid adenomas: accurate detection and localization with Tc-99m sestamibi SPECT.

PURPOSE: To evaluate the ability to detect and localize parathyroid adenomas with technetium-99m sestamibi single photon emission computed tomography (SPECT). MATERIALS AND METHODS: Forty-seven adult patients underwent Tc-99m sestamibi SPECT. Early (15-30 minutes after injection) and delayed (2-4 hours after injection) images were acquired. Thirty-three patients were examined for initial parathyroid surgery; the remaining 14, for repeat surgery because of persistent or recurrent hyperparathyroidism. SPECT reprojection images viewed in a rotating cine-display mode were read independently by two nuclear medicine physicians who were blinded to the results of other localization studies. Thirty-seven patients underwent subsequent neck exploration. SPECT findings were compared with surgical and histopathologic findings. RESULTS: In the 37 patients who underwent surgery, parathyroid adenomas were confirmed in 34 (92%) and hyperplasia in three (8%). In 31 patients, adenomas were correctly detected and localized with early SPECT images (sensitivity, 91%). In contrast, the sensitivity of delayed SPECT images was 74% (25 of 34 patients) for detection and 32% (11 of 34 patients) for localization. Early SPECT images were significantly better for localization (P < .001) and detection (P = .03). CONCLUSION: For Tc-99m sestamibi parathyroid imaging, early SPECT images were the most accurate in the detection and localization of parathyroid adenomas.

Adenoma↗
PubMed1996

A survey of sunbathing practices on three Connecticut State beaches.

In order to analyze sunbathing practices, a survey was conducted during the summer of 1995 on three Connecticut state beaches, with 1,003 interviews completed. The majority (65.8%) of respondents were women. Almost 70% of respondents were visiting the beach to get or maintain a tan. While the intended beach stay averaged four hours, only 55.7% of respondents were using sunscreen, 6.9% were sitting under shade, 12.7% were wearing hats, and 17.1% were wearing clothes other than a bathing suit. More than half (55%) of the sunscreen used had a sun protection factor of less than 15. Children were provided with greater protection than adults. The survey indicates the need for greater educational efforts to motivate protective behavior. Primary-care physicians could have an important role in these efforts.

Adolescent↗