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Biomedical subjects

V Mohan

Publications and source records attributed to V Mohan.

At least 37 records · Page 2Linked to original sources
PubMed1998

Biophysical and antisense properties of oligodeoxynucleotides containing 7-propynyl-, 7-iodo- and 7-cyano-7-deaza-2-amino-2'-deoxyadenosines.

The synthesis of 7-propynyl-, 7-iodo- and 7-cyano-7-deaza-2-amino-2'-deoxyadenosines is described. The nucleosides were synthesized, functionalized into the phosphoramidites and incorporated into oligodeoxynucleotides. Spectroscopic melting experiments against complementary RNA showed increases of 3-4 degreesC per modification for single substitutions and smaller increases per incorporation for multiple substitutions relative to unmodified control sequences. The 7-propyne and 7-iodo nucleosides were incorporated into antisense sequences targeting the 3'-UTR of murine C- raf mRNA. Both nucleosides demonstrated substitution-dependent potency. The sequences with three and four substitutions of the 7-propyne-7-deaza-2-amino-2'-deoxyadenosine exhibited a 2-3-fold increase in potency over unmodifed controls.

Animals↗
PubMed1998

Antibodies to pancreatic islet cell antigens in diabetes seen in Southern India with particular reference to fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a type of diabetes secondary to tropical chronic non-alcoholic pancreatitis. Little is known about the aetiopathogenesis of FCPD. We studied glutamic acid decarboxylase antibodies (GAD-Ab) and islet cell antibodies (ICA) in patients with FCPD and compared the results with Type 1 (insulin dependent) diabetes mellitus, Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic subjects in Southern India. The prevalence of GAD-Ab was 7.0% (95% Confidence Interval (CI) 1.9-17.2) in FCPD, 47.5% (CI 31.4-64.0) in Type 1 (p < 0.001 compared to FCPD), 5.6% (CI 1.5-13.9) in Type 2 (non-significant (NS) compared to FCPD) and 0% in controls. The prevalence of ICA was 6.3% (CI 1.2-17.4) in FCPD, 53.8% (CI 37.1-70.0) in Type 1 (p < 0.001 compared to FCPD), 9.9% (CI 4.0-19.4) in Type 2 (NS compared to FCPD) and 4.7% (CI 0.4-16.1) in controls. The data suggest that in FCPD, the frequency of auto-antibodies is low and its aetiology is probably not linked to autoimmunity in the majority of the patients.

Adult↗
PubMed1998

Fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a unique form of diabetes secondary to chronic pancreatitis seen in developing countries of the world associated with either overt protein-calorie malnutrition or, more likely, with deficiency of certain micronutrients. FCPD affects young individuals and runs an aggressive course to reach the endpoints of diabetes, pancreatic calculi and exocrine pancreatic dysfunction (steatorrhoea) in the majority of cases. There are characteristic features of FCPD radiologically, ultrasonographically, on endoscopic retrograde cholangiopancreatography and on histopathology which distinguish it from chronic pancreatitis of other aetiologies seen in temperate zones, e.g. alcoholic chronic pancreatitis. Although a secondary form of diabetes, specific diabetes-related complications like retinopathy and nephropathy do occur in FCPD. There appears to be a high risk of developing pancreatic carcinoma. Although the aetiology of FCPD is still unclear, the role of micronutrient (antioxidant) deficiency is emerging as a possible aetiological or predisposing factor. The contribution of genetic factors and environmental toxins, e.g. cyanogenic glycosides or other nutritional/toxic factors, merit further study. Studies on FCPD, a good model of a secondary form of diabetes, could lead to improved understanding of other primary forms of diabetes as well. If the underlying aetiological factors are identified, it may also be possible to prevent this type of diabetes.

Adult↗
PubMed1998

Oral pancreatic enzyme therapy in the control of diabetes mellitus in tropical calculous pancreatitis.

CONCLUSION: Pancreatic enzyme supplementation therapy conducted during a 6 mo period produces better control of diabetes, improvement in nutrition, and overall improvement in quality of life in patients with tropical calculous pancreatitis. BACKGROUND: Tropical calculous pancreatitis is characterized by abdominal pain, pancreatic calculi, and diabetes. The diabetes in insulin resistant. The brittle diabetes may be owing to defective glucagon secretion and erratic absorption of nutrients. METHODS: Patients with tropical calculous pancreatitis with diabetes and chronic pancreatitis were studied for fasting and postprandial plasma glucose, glycosylated hemoglobin, serum cholesterol, triglycerides, and calcium, liver function, and plasma C-peptide. All patients were given Creon and evaluated for quality of life. RESULTS: Clinical parameters of the patients showed considerable improvement at the end of the trial. Abdominal pain, steatorrhea, and sense of well being improved. There was a significant reduction in postprandial plasma glucose and glycosylated hemoglobin.

Administration, Oral↗
PubMed1998

Lack of association between serum sialic acid levels and retinopathy in Type 2 diabetic patients.

Sialic acid, an acetylated derivative of neuraminic acid, is reported to be a marker of micro- and macrovascular complications in diabetic subjects. The purpose of this study was to investigate the association of serum sialic acid and diabetic retinopathy. Serum sialic acid levels were measured in healthy non-diabetic control subjects, Type 2 diabetic patients without retinopathy (No DR), Type 2 diabetic patients with non-proliferative diabetic retinopathy (NPDR) and Type 2 diabetic patients with proliferative diabetic retinopathy (PDR). There was no significant difference in the serum sialic acid levels between the study groups (controls, 2.1 mmol/l; No DR, 2.5 mmol/l; NPDR, 2.2 mmol/l and PDR, 2.3 mmol/l). These results suggest that there is no association between serum sialic acid levels and diabetic retinopathy.

Adult↗
PubMed1998

The opening of a single base without perturbations of neighboring nucleotides: a study on crystal B-DNA duplex d(CGCGAATTCGCG)2.

In this work we explore the possibility of the opening of a single base without perturbation of its neighboring nucleotides. Low energy base opening into the grooves can be accomplished by rotation of the relevant backbone and glycosidic bond torsion angles. The pathway has been determined by identifying zeta torsion angle as the reaction coordinate together with the accompanying geometric requirement that guides the displacement of other torsion angles. Our study on Dickerson dodecamer duplex d(CGCGAATTCGCG)2 showed that all bases with normal equilibrium zeta can be rotated by approximately 30 degrees, corresponding to approximately 3.5A base displacement, towards the major groove. Such an opening extent is comparable with estimated amplitudes of local angular motions in DNA bases from NMR experiments, which might facilitate proton exchange. The computed base opening energy barrier is also comparable with measured base pair opening enthalpy. These results indicate possible relevance of the pathway studied in this work with experimentally observed base pair opening process. Our analysis also showed a preference for base opening along the major groove and an abnormal opening behavior for bases with unusual equilibrium zeta torsion angle.

Base Composition↗
PubMed1998

Osteonecrosis of the humeral head treated by core decompression.

Core decompression is one treatment used for symptomatic osteonecrosis of the humeral head. The purpose of this report was to examine the long term outcome of this procedure. Sixty-three shoulders in 43 patients who underwent a core decompression for humeral head osteonecrosis were followed up from 2 to 20 years (mean, 10 years). None of these patients had responded to nonoperative treatment before core decompression. Results of core decompression according to preoperative Ficat and Arlet stage revealed Stage I disease had 15 of 16 (94%) successful outcomes and Stage II had 15 of 17 (88%) successful outcomes. Stage III had 16 of 23 (70%) successful results and Stage IV had one of seven (14%) successful result. Core decompression of the shoulder is a safe procedure with few recognized complications and can be performed on an outpatient basis. The procedure has been successful for Stages I, II, and III osteonecrosis in terms of early relief of pain and increased function.

Activities of Daily Living↗
PubMed1998

Lipoprotein(a) is an independent risk factor for coronary artery disease in NIDDM patients in South India.

OBJECTIVE: Asian Indians have been reported to have very high prevalence rates of coronary artery disease (CAD) in the absence of traditional risk factors. Recently, elevated levels of lipoprotein(a) [Lp(a)] have been reported to be associated with premature CAD in migrant Asian Indians. However, there are very little data regarding Lp(a) in CAD patients from the Indian subcontinent and virtually none in individuals with NIDDM. The objective of this study was to assess the role of Lp(a) as a marker for CAD in South Indian NIDDM patients. RESEARCH DESIGN AND METHODS: We estimated serum Lp(a) in 100 control subjects, 100 NIDDM patients without CAD, and 100 NIDDM patients with CAD. Lp(a) values were transformed into natural logarithms. Statistical analysis included Student's t test, one-way analysis of variance, and chi2 test. Multiple logistic regression analysis was used to identify associations with CAD. RESULTS: Lp(a) levels were significantly higher in NIDDM patients with CAD compared with NIDDM patients without CAD and control subjects (geometric mean 24.6, 15.1, and 19.4 mg/dl, respectively, P < 0.05). Results of logistic regression analysis showed that Lp(a), age, and HDL were associated with CAD. In NIDDM patients with CAD, there was no correlation between Lp(a) and serum cholesterol, triglyceride, or HDL cholesterol levels, but there was a weak association with LDL cholesterol and systolic blood pressure. CONCLUSIONS: The data suggests that serum Lp(a) is an independent risk factor for CAD in NIDDM patients in South India.

Biomarkers↗
PubMed1998

Multifocal osteonecrosis.

OBJECTIVE: To study demographic, clinical, and radiographic staging patterns in patients with multifocal osteonecrosis to facilitate earlier diagnosis and optimize treatment. METHODS: Multifocal osteonecrosis was defined as disease of 3 or more anatomic sites. Patients were characterized demographically, which included disease associations, corticosteroid and other agent usage, presenting joints, and symptomatology. Radiographically, patients were evaluated with plain radiographs and magnetic resonance imaging (MRI) scans of all joints to determine the presenting stage of the lesions. RESULTS: We found that 32 of 1056 (3%) osteonecrosis patients under our care had multifocal disease. Associated factors included systemic lupus erythematosus (13 patients), inflammatory bowel disease (5 patients), malignancy (4 patients), and renal transplantation (3 patients). Thirty of the 32 patients (94%) had a history of corticosteroid therapy, with the other 2 patients found to have a coagulopathy. All 32 patients had bilateral femoral head involvement and 30 of 32 had bilateral knee involvement, with the other 2 having only left knee lesions. Osteonecrosis was also seen in the shoulder (28 patients), ankle (8 patients), and 3 other sites. Overall, 201 sites were involved (6.3 per patient). The majority of joints presented in a pre-collapse stage (77%). Patients most commonly presented with hip or multiple joint symptoms (22 patients, 69%). In 8 patients, the knee was the sole presenting symptomatic joint and the ankle and shoulder were the sole presenting symptomatic joints in one patient each. CONCLUSION: In patients with a diagnosis of osteonecrosis and complaints in other joints, these other areas should be fully evaluated with plain radiographs and, if inconclusive, with MRI. In patients with osteonecrosis not involving the femoral head, the patient's hips should be radiographically evaluated regardless of whether the patient is symptomatic. Patients diagnosed with osteonecrosis of the knee, shoulder, or ankle should have other joints evaluated, as such patients have multifocal disease roughly 50% of the time.

Adrenal Cortex Hormones↗
PubMed1997

The influence of antisense oligonucleotide-induced RNA structure on Escherichia coli RNase H1 activity.

The ability of Escherichia coli RNase H1 to hydrolyze structured substrates containing antisense oligonucleotides preannealed to a 47-mer RNA was compared with its ability to hydrolyze unstructured substrates containing antisense oligonucleotides duplexed with 13-mer RNA. These results demonstrate that when antisense oligonucleotides were bound to structured RNA, the resultant duplexes were cleaved at rates significantly slower than when the same oligonucleotides were bound to unstructured oligoribonucleotides. Structured substrates exhibited fewer cleavage sites, and each cleavage site was cleaved less rapidly than in unstructured substrates. Furthermore, the enzymatic activity of E. coli RNase H1 for the structured substrates was most affected when the cleavage sites corresponding to the enzymatically most active sites on the unstructured substrates were blocked in the structured substrates. Molecular modeling suggests that the observed ablation of RNase H activity was due to the steric hindrance of the enzyme by the structured RNA, i.e. steric interference of the phosphate groups on the substrate and/or the binding site of the enzyme. When chimeric oligonucleotides composed of a five-base deoxynucleotide sequence flanked by chemically modified nucleotides were bound to structured RNA, the resultant duplexes were even worse substrates for RNase H. These results offer further insights into the role of antisense-induced RNA structure on RNase H activity and may facilitate the design of effective antisense oligonucleotides.

Base Sequence↗
PubMed1997

Clinical profile of lean NIDDM in South India.

The majority (> 80%) of patients with non insulin dependent diabetes mellitus (NIDDM) present in Europe and America are obese. In developing countries like India, most NIDDM (> 60%) are non-obese and many are actually lean with a body mass index (BMI) of < 18.5 and are referred to as 'lean NIDDM'. This paper compares the clinical profile of a cohort of 347 lean NIDDM, with a group of 6274 NIDDM of ideal body weight (IBW) and 3252 obese NIDDM attending a diabetes centre at Madras in South India. The lean NIDDM who constituted 3.5% of all NIDDM patients seen at our centre, had more severe diabetes and an increased prevalence of retinopathy (both background and proliferative), nephropathy and neuropathy. Although a larger percentage of the lean NIDDM patients were treated with insulin, 47% of the males and 53% of the females were still on oral hypoglycaemic agents even after a mean duration of diabetes of 9.2 +/- 8.1 years. Studies of GAD antibodies, islet cell antibodies (ICA) and fasting and stimulated C-peptide estimations done in a small subgroup of the lean NIDDM showed that they were distinct from IDDM patients. More studies are needed on metabolic, hormonal and immunological profile of lean NIDDM seen in developing countries like India.

Adult↗
PubMed1997

Vibrational analysis of phosphorothioate DNA: II. The POS group in the model compound dimethyl phosphorothioate [(CH3O)2(POS)]-.

The results of Raman and Infrared (IR) spectroscopic investigations on the vibrational modes of dimethyl phosphorothioate (DMPS) anion, [(CH3O)2(POS)]-, are reported. Ab initio calculations of the vibrational modes, the IR and Raman spectra and the interatomic force constants of DMPS were performed. A normal mode calculation was performed and the results were used to calculate the potential energy distribution for the vibrational modes. This analysis shows that in DMPS the P-S stretching mode has a frequency of about 630 cm-1 and an angle bending mode involving the sulfur atom has a frequency of about 440 cm-1. The proposed vibrational mode assignments will serve as marker bands in the conformational studies of phosphorothioate oligonucleotides which play a central role in the novel antisense therapeutic paradigm.

DNA↗
PubMed1997

Analysis of islet regenerating (reg) gene polymorphisms in fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes associated with tropical chronic calcific pancreatitis, seen mostly in developing countries. FCPD is likely to be a multifactorial disease with both environmental and genetic components. The reg 1A gene encodes a protein associated with regeneration of pancreatic islets and has a sequence identical to that of pancreatic stone protein. Since FCPD is associated with both diabetes and pancreatitis, we tested the hypothesis that FCPD may be the result of mutations in the coding regions of the reg 1A gene. Restriction length polymorphisms (RFLPs) and possible sequence variants of the reg 1A gene were studied by RFLP analysis, looking for single-stranded conformational polymorphisms (SSCPs) and direct nucleotide sequencing. In 20 patients with FCPD and 20 control subjects, no RFLPs were detected using 10 restriction enzymes. In 50 patients with FCPD and 50 control subjects, no SSCP variants were detected. Finally, direct nucleotide sequencing of the reg 1A gene from 30 patients with FCPD did not show any differences from the published human reg 1A gene sequence. In conclusion, it seems unlikely that mutations in the coding region of the reg 1A gene are a common cause of FCPD.

Calcinosis↗
PubMed1996

2'-O-aminopropyl ribonucleotides: a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides.

Oligonucleotides containing 2'-O-aminopropyl-substituted RNA have been synthesized. The 2'-O-(aminopropyl)adenosine (APA), 2'-O-(aminopropyl)cytidine (APC), 2'-O-(aminopropyl)-guanosine (APG), and 2'-O-(aminopropyl)uridine (APU) have been prepared in high yield from the ribonucleoside, protected, and incorporated into an oligonucleotide using conventional phosphoramidite chemistry. Molecular dynamics studies of a dinucleotide in water demonstrates that a short alkylamine located off the 2'-oxygen of ribonucleotides alters the sugar pucker of the nucleoside but does not form a tight ion pair with the proximate phosphate. A 5-mer with the sequence ACTUC has been characterized using NMR. As predicted from the modeling results, the sugar pucker of the APU moiety is shifted toward a C3'-endo geometry. In addition, the primary amine rotates freely and is not bound electrostatically to any phosphate group, as evidenced by the different sign of the NOE between sugar proton resonances and the signals from the propylamine chain. Incorporation of aminopropyl nucleoside residues into point-substituted and fully modified oligomers does not decrease the affinity for complementary RNA compared to 2'-O-alkyl substituents of the same length. However, two APU residues placed at the 3'-terminus of an oligomer gives a 100-fold increase in resistance to exonuclease degradation, which is greater than observed for phosphorothioate oligomers. These structural and biophysical characteristics make the 2'-O-aminopropyl group a leading choice for incorporation into antisense therapeutics. A 20-mer phosphorothioate oligonucleotide capped with two phosphodiester aminopropyl nucleotides targeted against C-raf mRNA has been transfected into cells via electroporation. This oligonucleotide has 5-10-fold greater activity than the control phosphorothioate for reducing the abundance of C-raf mRNA and protein.

Exonucleases↗
PubMed1996

Hydration of single-stranded phosphodiester and phosphorothioate oligodeoxyribonucleotides.

Infrared spectroscopy was used to identify hydration-sensitive structural differences between single- stranded phosphorothioate (PS) and phosphodiester (PO) oligodeoxyribonucleotides. Spectra were recorded in the mid-infrared region, 500-1800 cm-1, at relative humidities between 0 and 98%; the PS and PO spectra are substantially different. The hydration effects on spectral bands in these single-stranded oligodeoxyribonucleotides is markedly different from such behavior in double- and triple-stranded oligodeoxyribonucleotides. A strong absorption occurs at 656 cm-1 in the phosphorothioate sample which is completely absent from the PO spectra. Gravimetric measurements were carried out on one PS and one PO sample to monitor and confirm hydration. The calculated BET adsorption constants [Brunauer, S., Emmett, RH. and Teller, E. (1938) J. Am. Chem. Soc., 60, 309-319] are 1.2 and 1.4 water molecules per nucleotide in the first hydration layer of PS and PO respectively. While the gravimetric data indicate that the single-stranded oligodeoxyribonucleotides hydrate very similarly to duplex DNA, the mid-infrared conformational marker bands are strikingly different from those observed for duplex DNA. In particular, the Vas of the phosphate group (PO2) at 1222 cm-1 in the single-stranded PO spectra is independent of relative humidity.

Base Sequence↗
PubMed1996

Abnormal antioxidant status in impaired glucose tolerance and non-insulin-dependent diabetes mellitus.

A total of 105 subjects with impaired glucose tolerance were classified into two groups, 51 subjects with plasma glucose > 11.1 mmol l-1 in one of the blood samplings during OGTT, but at 2 h being less than < 11.1 mmol l-1 were classified as early hyperglycaemics. Fifty-four cases were classified as true IGT, with fasting plasma glucose < 7.8 mmol l-1 and post plasma glucose level between 7.8 and 11.1 mmol l-1. Age and sex matched groups of normals (healthy adults) and NIDDM cases without symptomatic secondary complications were also included in the study. Lipid peroxidation (LPO) product in plasma, erythrocyte, and erythrocyte cell membrane were found to be significantly elevated (p < 0.001) in IGT, early hyperglycaemia and diabetes mellitus while glycosylated haemoglobin was also higher. Antioxidant enzymes superoxide dismutase and catalase were significantly lower in red blood cells obtained from IGT and early hyperglycaemic groups. They were closer to the levels showed in NIDDM confirming that antioxidant deficiency is already present in subjects classified as impaired glucose tolerant. Among the antioxidant scavengers, reduced glutathione (GSH) and ascorbic acid are reduced by 15% and 20% in IGT and NIDDM, respectively. We conclude that antioxidant status is poor in both IGT and NIDDM, suggesting an overlap of frank diabetic state in those classified as IGT. It is possible that antioxidant therapy might retard progression from IGT to NIDDM.

Adult↗