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1.  Transcription enhancer factor 1 interacts with a basic helix-loop-helix zipper protein, Max, for positive regulation of cardiac alpha-myosin heavy-chain gene expression. 
Molecular and Cellular Biology  1997;17(7):3924-3936.
The M-CAT binding factor transcription enhancer factor 1 (TEF-1) has been implicated in the regulation of several cardiac and skeletal muscle genes. Previously, we identified an E-box-M-CAT hybrid (EM) motif that is responsible for the basal and cyclic AMP-inducible expression of the rat cardiac alpha-myosin heavy chain (alpha-MHC) gene in cardiac myocytes. In this study, we report that two factors, TEF-1 and a basic helix-loop-helix leucine zipper protein, Max, bind to the alpha-MHC EM motif. We also found that Max was a part of the cardiac troponin T M-CAT-TEF-1 complex even when the DNA template did not contain an apparent E-box binding site. In the protein-protein interaction assay, a stable association of Max with TEF-1 was observed when glutathione S-transferase (GST)-TEF-1 or GST-Max was used to pull down in vitro-translated Max or TEF-1, respectively. In addition, Max was coimmunoprecipitated with TEF-1, thus documenting an in vivo TEF-1-Max interaction. In the transient transcription assay, overexpression of either Max or TEF-1 resulted a mild activation of the alpha-MHC-chloramphenicol acetyltransferase (CAT) reporter gene at lower concentrations and repression of this gene at higher concentrations. However, when Max and TEF-1 expression plasmids were transfected together, the repression mediated by a single expression plasmid was alleviated and a three- to fourfold transactivation of the alpha-MHC-CAT reporter gene was observed. This effect was abolished once the EM motif in the promoter-reporter construct was mutated, thus suggesting that the synergistic transactivation function of the TEF-1-Max heterotypic complex is mediated through binding of the complex to the EM motif. These results demonstrate a novel association between Max and TEF-1 and indicate a positive cooperation between these two factors in alpha-MHC gene regulation.
PMCID: PMC232245  PMID: 9199327
2.  A Type-II First Branchial Cleft Anomaly Presenting as a Post-Auricular Salivary Fistula: A Rare Presentation 
First branchial cleft anomalies are rare with the average age of presentation as 19 years. There is an average delay of 3.5 years between initial presentation and adequate treatment due to diagnostic dilemma. A very rare variant of first branchial cleft anomaly presenting as a post-auricular salivary fistula is reported. A 12-year-old girl presented with a history of intermittent watery discharge, more so at the time of meals from a right post-auricular opening for last 3 years. Computed tomography sialography revealed a fistulous tract connecting the sub segmental duct of the parotid gland extending along the pre-tragus region in subcutaneous plane up to mastoid tip after passing inferior to external auditory canal. Superficial parotidectomy with identification of facial nerve branches was carried out for excision of the tract. Histopathology revealed sinus tract comprising of ectodermal components and acini of the parotid gland. We classified our case into work's type-2 based on anatomical location at an angle of mandible, its relationship to parotid gland and facial nerve and previous history of ear discharge. To the best of our knowledge, this is the first case of its type to be reported.
PMCID: PMC3952286  PMID: 24669347
Branchial cleft fistula; First branchial anomaly; Salivary fistula
3.  Constipation is not associated with an increased rate of findings on colonoscopy: results from a national endoscopy consortium 
Endoscopy  2010;42(3):10.1055/s-0029-1243843.
Background and study aims
There are no definite guidelines regarding colonoscopic evaluation for the indication of constipation, a common gastrointestinal complaint. The aim of our study was to determine the risk of finding significant lesions in patients undergoing colonoscopy for the indication of constipation alone compared with constipation with another indication or average-risk screening.
Patients and methods
A retrospective review of the Clinical Outcomes Research Initiative database was carried out for colonoscopies undertaken between 1 January 2000 and 30 June 2003. A total of 41,775 index colonoscopies performed for the indications of average-risk screening, constipation only or constipation with another indication were identified. Logistic regression analyses were performed for constipation alone versus constipation with another indication, and for constipation alone versus average-risk screening.
Constipation alone did not show any increased risk of significant findings on colonoscopy. Constipation and the presence of another indication, however, had a statistically significant increased risk of a significant finding on colonoscopy. The indication of constipation alone had a lower risk of significant findings on colonoscopy compared with average-risk screening. Variations in the definition of constipation used was a limitation of the study.
Colonoscopy for constipation alone has a lower yield for significant findings compared with average-risk screening and constipation with another indication; hence, colonoscopy should not be done for constipation alone.
PMCID: PMC3846169  PMID: 20101567
4.  Semi-mechanistic Population Pharmacokinetic Model of Multivalent Trastuzumab Emtansine in Patients with Metastatic Breast cancer 
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.
PMCID: PMC3745717  PMID: 22968044
5.  A Review of Controversies in the Management of Colorectal Cancers 
The Indian Journal of Surgery  2012;74(3):221-227.
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Due to a higher incidence of CRC in the western hemisphere a significant amount of research was carried out and majority of the controversies could be resolved as far as management of CRC is concerned. Recently a number of significant advances were made in the field of CRC related to surgery, systemic therapy and radiotherapy. During the last decade we have witnessed introduction of minimally invasive surgery, incorporation of more effective newer chemotherapeutic regimes and targeted therapies and refinements in radiotherapy protocols. The demographics and clinical picture of CRC seems to be different in developing countries and there is paucity of CRC related studies from developing countries. In-order to update the practicing surgeons a review of conventional controversies of CRC surgery was performed and an update on the recent developments in the field of CRC was also presented in this article.
PMCID: PMC3397187  PMID: 23730048
Colorectal cancer; Controversies; Management; Total mesorectal excision
6.  Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy 
Leukemia  2011;26(6):1356-1364.
Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-positive DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3Lys685 acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3Tyr705 phosphorylation with minimal effect on STAT3Ser727 and JAK2 tyrosine activity. pSTAT3Tyr705-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3Tyr705-negative DLBCLs. This cytotoxicity was associated with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3Lys685 acetylation but prevented STAT3Tyr705 phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells. These studies provide the rationale for targeting STAT3-positive DLBCL tumors with HDAC inhibitors.
PMCID: PMC3625618  PMID: 22116549
lymphoma; HDAC3; LBH589; STAT3; Mcl-1
8.  Wound Induced Tanscriptional Regulation of Benzylisoquinoline Pathway and Characterization of Wound Inducible PsWRKY Transcription Factor from Papaver somniferum 
PLoS ONE  2013;8(1):e52784.
Wounding is required to be made in the walls of the green seed pod of Opium poppy prior exudation of latex. To withstand this kind of trauma plants regulate expression of some metabolites through an induced transcript level. 167 unique wound-inducible ESTs were identified by a repetitive round of cDNA subtraction after 5 hours of wounding in Papaver somniferum seedlings. Further repetitive reverse northern analysis of these ESTs revealed 80 transcripts showing more than two fold induction, validated through semi-quantitative RT-PCR & real time expression analysis. One of the major classified categories among identified ESTs belonged to benzylisoquinoline transcripts. Tissue specific metabolite analysis of benzylisoquinoline alkaloids (BIAs) in response to wounding revealed increased accumulation of narcotine and papaverine. Promoter analysis of seven transcripts of BIAs pathway showed the presence of W-box cis-element with the consensus sequence of TGAC, which is the proposed binding site for WRKY type transcription factors. One of the Wound inducible ‘WRKY’ EST isolated from our subtracted library was made full-length and named as ‘PsWRKY’. Bacterially expressed PsWRKY interacted with the W-box element having consensus sequence TTGACT/C present in the promoter region of BIAs biosynthetic pathway genes. PsWRKY further activated the TYDC promoter in yeast and transiently in tobacco BY2 cells. Preferential expression of PsWRKY in straw and capsule and its interaction with consensus W-box element present in BIAs pathway gene transcripts suggest its possible involvement in the wound induced regulation of BIAs pathway.
PMCID: PMC3559656  PMID: 23382823
9.  Safety and efficacy of donepezil hydrochloride in patients with mild to moderate Alzheimer's disease: Findings of an observational study 
Indian Journal of Psychiatry  2012;54(4):337-343.
Alzheimer's disease (AD), a progressive brain disorder, is the most common cause of dementia among the elderly. Donepezil hydrochloride is a potent, reversible, and highly selective inhibitor of acetylcholinesterase (AChE). It is chemically distinct from other cholinesterase (ChE) inhibitors which are effective in the treatment of AD.
To evaluate the safety and efficacy of donepezil hydrochloride therapy over a 12 weeks period in patients with mild to moderate AD in Indian population.
Materials and Methods:
In this post-marketing study, patients with mild to moderate AD received oral donepezil hydrochloride 5 mg/day for 4 weeks followed by 10 mg/day for 8 weeks. Patients were assessed 4 times weekly for cognition on ‘Mini Mental Status Examination (MMSE) scale’, and function on ‘Activities of Daily Living (ADL) index’. Clinicians and caregivers assessment of safety and efficacy was assessed on a 5-point rating scale.
One hundred and seventy two of one hundred and eighty two patients completed 12 weeks of study period. MMSE score significantly improved (P<0.0001) from 16.72 at baseline to 19.77 after 12 weeks, and there was significant improvement (P<0.05) in ADL index in 13 of 17 domains after 12 weeks. Caregivers and clinicians rated the therapy as very good to good in >80% and >90% patients, respectively. Adverse events were consistent with the known pharmacological and safety profile of donepezil.
Donepezil is well tolerated in Indian patients with mild to moderate AD with significant improvement in cognition and function.
PMCID: PMC3554965  PMID: 23372236
Alzheimer's; cognition; dementia; donepezil
10.  Pharmacognostical, phytochemical and pharmacological evaluation for the antipyretic effect of the seeds of Saraca asoca Roxb. 
To conduct a systemic evaluation of the medicinal value of seeds which include macroscopic and microscopic characterization, physiochemical evaluation, preliminary phytochemical screening and experimental antipyretic activity.
Saraca asoca seed was studied for pharmacognostical, phytochemical and other recommended methods for standardizations. Also, the acetone extract of the seeds was evaluated for acute toxicity study and antipyretic activity using Brewer's yeast induced pyrexia in Wistar rats at oral doses of 300 mg/kg and 500 mg/kg.
After phytochemical screening, the acetone extract showed the presence of saponin, tannins and flavonoids which inhibit pyrexia. The therapeutic efficacy achieved at both the dose levels of the research drug and standard drug aspirin (100 mg/kg) showed significant (P<0.01) antipyretic activity when compared to the control group. The highly significant antipyretic effect exhibited at the dose of 500 mg/kg was also found to be sustainable in nature.
The antipyretic effect of the acetone extract showed significant results in rats at the dose of 500 mg/kg after following the standard pharmacognostical and phytochemical methods.
PMCID: PMC3609231  PMID: 23569847
Antipyretic; Saraca asoca; Seed; Pharmacognosy; Acetone extract
11.  Role of magnesium sulfate in neuroprotection in acute ischemic stroke 
To study the effect of intravenous magnesium sulfate infusion on clinical outcome of patients of acute stroke.
Materials and Methods:
Sixty consecutive cases of acute ischemic stroke hospitalised within 24 h of an episode of stroke were taken as subjects. All subjects underwent a computed tomography head, and those found to have evidence of bleed/space-occupying lesions were excluded from the study. The subjects taken up for the study were divided into two groups of 30 subjects each. Both the groups received the standard protocol management for acute ischemic stroke. Subjects of Group 1 additionally received intravenous magnesium sulfate as initial 4 g bolus dose over 15 min followed by 16 g as slow infusion over the next 24 h. In all the subjects of the two study groups, serum magnesium levels were estimated at the time of admission (Day 0), Day 1 and Day 2 of hospitalization using an atomic absorption spectrometer.
Statistical Analysis Used:
Scandinavian stroke scores were calculated on Day 3, day of discharge and Day 28. Paired t-test was employed for comparison of stroke scores on Day 3, day of discharge and Day 28 within the same group and the unpaired t-test was used for the intergroup comparison, i.e. comparison of stroke scores of control group with corresponding stroke scores of magnesium group.
Comparison of stroke scores on Day 3 and day of discharge, on the day of discharge and Day 28 and on Day 3 and Day 28 in the magnesium group produced a t-value of 5.000 and P <0.001, which was highly significant. However, the comparison of the mean stroke scores between the magnesium and the control groups on Day 3, day of discharge and Day 28 yielded a P-value of >0.05, which was not significant.
The study failed to document a statistical significant stroke recovery in spite of achieving a significant rise in serum magnesium level, more than that necessary for neuroprotection, with an intravenous magnesium sulfate regime.
PMCID: PMC3424793  PMID: 22919188
Ischemic stroke; magnesium sulfate; neuroprotection
12.  Need for a national epilepsy control program 
This article briefly outlines the proposed national epilepsy control program. The content of the article is based on four meetings held by invitation of the Ministry of Health. Invitees by ministry – Drs. D. C. Jain, M. Gourie Devi, V. Saxena, S. Jain, P. Satish. Chandra, M. Gupta, K. Bala, V. Puri, K. S. Anand, S. Gulati, S. Johri, P. S. Chandra, M. Behari, K. Radhakrishnan, D. Bachani. Presentations were made by Dr. M. Tripathi.The program will involve all neurologists across the country in teaching and training at state levels and a central monitoring committee.
PMCID: PMC3345606  PMID: 22566719
Control; epilepsy; India; national; program
13.  Effect of Antimicrobial Peptide, Nisin, on the Reproductive Functions of Rats 
ISRN Veterinary Science  2012;2011:828736.
Our previous studies have demonstrated that naturally occurring peptide, Nisin possess antibacterial activity and did not interfere with rabbit vaginal mucosa. In this study, the reproductive toxicity of the Nisin in male rats was evaluated. Rats were fed orally with Nisin (10, 25, and 50 mg/kg/day) for 13 weeks. No treatment related mortality was observed. The body weight gain, food consumption and serum biochemical parameters were at par with the control group. Histomorphology of the selected reproductive (testis, epididymis, ventral prostate, and seminal vesicle) and nonreproductive (liver and kidney) tissues was observed to be normal. There was no treatment-related increase or decrease in the expression of testis-specific genes (c-Kit, GATA-1, and HILS-1) and the activity levels of epididymal α-glucosidase, ventral prostate alkaline phosphatase (AlP), liver alanine aminotransferase (AlAT) and aspartate aminotransferase (AAT). Fructose and lactic acid levels in the seminal vesicles also remained unchanged. These studies suggest that Nisin did not affect the normal physiology of these organs. In addition, no adverse effects were observed on the reproductive performance of Nisin-treated male rats and their offspring. In conclusion, the current studies support our earlier studies, which demonstrated suitability of Nisin as a safe and effective microbicide.
PMCID: PMC3658505  PMID: 23738116
14.  Giant cell arteritis presenting as macular choroidal ischaemia 
Eye  2010;25(1):121-123.
PMCID: PMC3144651  PMID: 21072065
16.  Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death 
Cell Death & Disease  2011;2(11):e231-.
The ATP-dependent ClpQY protease system in Plasmodium falciparum is a prokaryotic machinery in the parasite. In the present study, we have identified the complete ClpQY system in P. falciparum and elucidated its functional importance in survival and growth of asexual stage parasites. We characterized the interaction of P. falciparum ClpQ protease (PfClpQ) and PfClpY ATPase components, and showed that a short stretch of residues at the C terminus of PfClpY has an important role in this interaction; a synthetic peptide corresponding to this region antagonizes this interaction and interferes with the functioning of this machinery in the parasite. Disruption of ClpQY function by this peptide caused hindrance in the parasite growth and maturation of asexual stages of parasites. Detailed analyses of cellular effects in these parasites showed features of apoptosis-like cell death. The peptide-treated parasites showed mitochondrial dysfunction and loss of mitochondrial membrane potential. Dysfunctioning of mitochondria initiated a cascade of reactions in parasites, including activation of VAD–FMK-binding proteases and nucleases, which resulted in apoptosis-like cell death. These results show functional importance of mitochondrial proteases in the parasite and involvement of mitochondria in programmed cell death in the malaria parasites.
PMCID: PMC3223699  PMID: 22113196
Plasmodium; ClpQY machinery; mitochondria; programmed cell death
17.  Effect of potassium channel openers on intraocular pressure in rabbits 
Indian Journal of Pharmacology  2011;43(3):357-358.
PMCID: PMC3113396  PMID: 21713049
18.  Dual Ectopic Thyroid: A Case Report with Review of Literature 
Iranian Journal of Radiology  2011;8(1):29-32.
The ectopic thyroid gland is a rare entity which is mostly found along the line of descent of the thyroid gland. Most of the patients present with midline swelling and usually seek medical attention. Dual ectopic thyroid gland is even rarer. The clinical examination and different imaging modalities establish its diagnosis. Radionuclide studies are highly sensitive and specific in demonstrating the functional tissues in patients with ectopic thyroid, thereby guiding further management. The authors reported a case of ectopic thyroid gland in a girl with midline neck swelling initially, subsequently lost to follow-up. She again presented with enlarged swelling after a period of three years with dual ectopic thyroid in the neck region on thyroid scan. Thyroid scintigraphy demonstrated that progression in the size of ectopic glands was due to neglect in treatment.
PMCID: PMC3522407  PMID: 23329913
Dual Ectopic Thyroid; Tc-99m Pertechnetate Scan; Subclinical Hypothyroidism
19.  Evaluation of Factors Contributing to Excessive Nitrate Accumulation in Fodder Crops Leading to Ill-Health in Dairy Animals 
Toxicology International  2011;18(1):22-26.
A study was conducted to estimate nitrate content in commonly used fodder crops, viz., berseem (Trifolium alexandrinum), bajra (Pennisetum glaucum), maize (Zea mays), oats (Avena sativa), sorghum (Sorghum vulgare) and toriya (Brassica napus), collected from the fields of different villages of Punjab and farms of the university, and to evaluate the factors associated with nitrate accumulation in these crops. The nitrate level was highest in sorghum on dry matter basis, followed by oats and toriya, berseem, maize and bajra. The nitrate content was also determined in fodder samples harvested from young and mature stages and in different parts of plants. The stem part of forages had higher content than leaves; however, concentrations were low in mature crops as compared to immature ones. The environmental and soil factors associated with it are discussed and correlated with the experimental findings.
PMCID: PMC3052579  PMID: 21430916
Dairy animals; fertilizers; fodder crops; nitrate
20.  Isolated Bilateral Trigeminal Neuropathy in Sarcoidosis Presenting with Neurotrophic Corneal Ulcers 
Sarcoidosis is a multisystem granulomatous disease that may affect various organs. Nevertheless, involvement of the trigeminal nerve is exceedingly uncommon. This report presents a rare case of isolated bilateral trigeminal neuropathy presenting with neurotrophic corneal ulcers. The patient was treated with topical chloramphenicol and lubricants, as well as botulinum toxin injection to the upper eyelid to induce ptosis. Our case illustrates the importance of recognizing that bilateral corneal ulceration might be a manifestation of sarcoidosis. Physicians should be aware of this rare association, when treating sarcoidosis patients with eye related symptoms.
PMCID: PMC3661453  PMID: 23861615
sarcoidosis; trigeminal neuropathy; neurotrophic ulcers
23.  Orbital myiasis in a case of invasive basal cell carcinoma 
Oman Journal of Ophthalmology  2009;2(1):41-42.
PMCID: PMC3018106  PMID: 21234224
24.  Pharmacognostical investigation roots of Monochoria vaginalis presl 
Ancient Science of Life  2008;28(2):7-9.
The present study deals with the macroscpical, microscopical and preliminary phytochemical investigation on Monochoria vaginalis P. The transverse section shows in the root, the presence of cork, cortex, xylem, phloem, pith etc. The diagnostic features of the roots are the presence of fibers associated with vessels, calcium oxalates, and xylem vessel which will help in the identification and authentification process of the drug. Preliminary phytochemical work of the alcoholic extract showed the presence of glycosides, flavonoids and tannins.
PMCID: PMC3336351  PMID: 22557303
25.  Chorioretinal Vascular Oxygen Tension in Spontaneously Breathing Anesthetized Rats 
Ophthalmic Research  2007;39(2):103-107.
To establish baseline and variability of oxygen tension (PO2) measurements in the choroid, retinal arteries, capillaries, and veins of spontaneously breathing anesthetized rats and determine the effect of a moderate surgical procedure on the chorioretinal PO2.
Our previously established optical section phosphorescence imaging technique was utilized to measure PO2 in the chorioretinal vasculatures. Imaging was performed in 29 spontaneously breathing rats under ketamine/xylazine anesthesia. In 7 rats, blood was drawn using a surgically implanted femoral arterial catheter and analyzed to determine the systemic arterial PO2. The PO2 measurements in 22 rats without surgery (group 1) and 7 surgically instrumented rats (group 2) were statistically compared. The intrasubject variability was calculated by the average standard deviation (SD) of repeated measurements.
The average systemic arterial PO2 was 52 ± 7 mm Hg (mean ± SD) in group 2. In group 1, the average PO2 measurements in the choroid, retinal arteries, capillaries, and veins were 50 ± 11, 40 ± 5, 39 ± 6, and 30 ± 5 mm Hg, respectively. No statistically significant PO2 differences in any of the chorioretinal vasculatures were found between the two groups (p > 0.4). The intrasubject variability was 3 mm Hg in the choroid, retinal arteries, capillaries, and veins.
Chorioretinal PO2 measurements in spontaneously breathing anesthetized rats have a relatively low variability, indicating that PO2 changes due to various physiological alterations can be reliably assessed.
PMCID: PMC2883832  PMID: 17284937
Choroid; Oxygen; Retina

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