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1.  Anatomical Variations of Brachial Artery - Its Morphology, Embryogenesis and Clinical Implications 
Background: Accurate knowledge of variation pattern of the major arteries of upper limb is of considerable practical importance in the conduct of reparative surgery in the arm, forearm and hand however brachial artery and its terminal branches variations are less common.
Aim: Accordingly the present study was designed to evaluate the anatomical variations of the brachial artery and its morphology, embryogenesis and clinical implications.
Materials and Methods: In an anatomical study 140 upper limb specimens of 70 cadavers (35 males and 35 females) were used and anatomical variations of the brachial artery have been documented.
Results: Accessory brachial artery was noted in eight female cadavers (11.43%). Out of eight cadavers in three cadavers (4.29%) an unusual bilateral accessory brachial artery arising from the axillary artery and it is continuing in the forearm as superficial accessory ulnar artery was noted. Rare unusual variant unilateral accessory brachial artery and its reunion with the main brachial artery in the cubital fossa and its variable course in relation to the musculocutaneous nerve and median nerve were also noted in five cadavers (7.14%).
Conclusion: As per our knowledge such anatomical variations of brachial artery and its terminal branches with their relation to the surrounding structures are not reported in the modern medical literature. An awareness of such a presence is valuable for the surgeons and radiologists in evaluation of angiographic images, vascular and re-constructive surgery or appropriate treatment for compressive neuropathies.
PMCID: PMC4316237  PMID: 25653931
Entrapment neuropathy; Median nerve; Paraesthesia
2.  Neuroimaging and clinical features in type II (late-onset) Alexander disease 
Neurology  2014;82(1):49-56.
To describe the imaging and clinical features in type II (late-onset) Alexander disease (AxD).
We retrospectively identified all cases of type II AxD evaluated at Mayo Clinic, Rochester from January 1996 to February 2012. Clinical and neuroimaging data abstracted from the record included age at onset of symptoms, age at diagnosis, first symptom, neurologic symptoms, physical/neurologic findings on examination, genetic testing and/or biopsy (if performed), and MRI findings.
Thirteen patients with type II AxD were identified. Median age at onset was 38 years (range: 12–63). Five patients were female. Eleven of 13 patients had atrophy of the medulla while all 13 had medullary T2 hyperintensity. In 7 patients, these brainstem regions showed patchy enhancement. Five subjects had T2 signal change in the middle cerebellar peduncle, with associated contrast enhancement in 4 subjects. Eleven of 12 patients with T2 fluid-attenuated inversion recovery (FLAIR) imaging had pial FLAIR signal change in the medulla. Nine of 12 patients with spinal cord imaging had cord atrophy, and 3 of 9 of these evaluated with contrast had cervical cord enhancement.
Our study confirms prior reports of atrophy and signal change of the medulla and spinal cord in late-onset AxD. We expand on previous imaging studies by identifying middle cerebellar peduncle and pial FLAIR signal changes as important diagnostic clues. Variable patchy enhancement may occur in regions of T2 hyperintensity, leading to diagnostic uncertainty. In addition, we demonstrate that previously emphasized clinical features such as palatal tremor may not be common. We affirm that age at onset predicts clinical phenotype and imaging findings.
PMCID: PMC3873623  PMID: 24306001
3.  Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery 
Recent progresses in the field of Induced Pluripotent Stem Cells (iPSCs) have opened up many gateways for the research in therapeutics. iPSCs are the cells which are reprogrammed from somatic cells using different transcription factors. iPSCs possess unique properties of self renewal and differentiation to many types of cell lineage. Hence could replace the use of embryonic stem cells (ESC), and may overcome the various ethical issues regarding the use of embryos in research and clinics. Overwhelming responses prompted worldwide by a large number of researchers about the use of iPSCs evoked a large number of peple to establish more authentic methods for iPSC generation. This would require understanding the underlying mechanism in a detailed manner. There have been a large number of reports showing potential role of different molecules as putative regulators of iPSC generating methods. The molecular mechanisms that play role in reprogramming to generate iPSCs from different types of somatic cell sources involves a plethora of molecules including miRNAs, DNA modifying agents (viz. DNA methyl transferases), NANOG, etc. While promising a number of important roles in various clinical/research studies, iPSCs could also be of great use in studying molecular mechanism of many diseases. There are various diseases that have been modeled by uing iPSCs for better understanding of their etiology which maybe further utilized for developing putative treatments for these diseases. In addition, iPSCs are used for the production of patient-specific cells which can be transplanted to the site of injury or the site of tissue degeneration due to various disease conditions. The use of iPSCs may eliminate the chances of immune rejection as patient specific cells may be used for transplantation in various engraftment processes. Moreover, iPSC technology has been employed in various diseases for disease modeling and gene therapy. The technique offers benefits over other similar techniques such as animal models. Many toxic compounds (different chemical compounds, pharmaceutical drugs, other hazardous chemicals, or environmental conditions) which are encountered by humans and newly designed drugs may be evaluated for toxicity and effects by using iPSCs. Thus, the applications of iPSCs in regenerative medicine, disease modeling, and drug discovery are enormous and should be explored in a more comprehensive manner.
PMCID: PMC4313779
iPSC; reprogramming; pluripotency; differentiation; disease modeling; drug discovery; gene therapy
4.  Antibiotic Resistance in Uropathogenic E. Coli Strains Isolated from Non-Hospitalized Patients in Pakistan 
Purpose: To study multidrug-resistance in Uropathogenic E. Coli (UPEC) isolated from non-hospitalized patients.
Materials and Methods: Altogether, 250 bacterial samples were collected from non-hospitalized patients. Their identifications were done on basis of Gram-staining, colony morphology, biochemical testing and PCR. Susceptibility testing was performed by using standard protocols which were recommended by CLSI.
Statistical analysis: For comparisons, statistical analysis was performed by using software, Graphpad Prism 5.0
Results: In total, 32% (n = 80) of the isolates were identified as E. Coli strains and their susceptibility patterns for different antibiotics were determined. The data indicated least resistance against tazocin [(TZP) -1.25%], amikacin [(AK) -1.8%], tigecycline [(TGC)- 2.5%] and nitrofurantoin [(F) -3.75%]. For both minocycline (MH) and sulzone (SUL), resistance rate was 5%, for gentamicin (CN), it was 16.25%, while higher resistances were observed against cephalothine [(KF)- 70%], cefotaxime [(CTX) -58.5%], ceftazidime [(CAZ)- 57.5%], cefepime [(FEP) -55%], cefuroxime and cefixime [(CXM) (CFM)- 53.75 %]. Resistance against ciprofloxacin (CIP) was 57.5%, for norfloxacine (NOR), it was 52.5% and incase of sparfloxacin (SPX), it remained 55%. High percentage of the isolates were resistant to cotrimoxazole [(SXT) -86%] and Amoxicillin [AMX-CLA (AMC)- 76%]. No resistance against meropenem (MEM) was observed.
Conclusion: Highest level of drug-resistance was observed against trimethoprim-sulfamethoxazole (TMP-SMZ) among clinical isolates of uropathogenic E. Coli collected from non-hospitalized patients.
PMCID: PMC4225882  PMID: 25386430
Antibiotic susceptibility; Beta-lactamase; Cotrimoxazole; E. Coli; Plasmids; UPEC
5.  PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction 
Aging (Albany NY)  2014;6(10):835-851.
Dietary restriction (DR) increases life span and delays the onset of age-related diseases across species. However, the molecular mechanisms have remained relatively unexplored in terms of gene regulation. In C. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robust genetic regulator of DR, although little is known about how it regulates gene expression. We profiled the transcriptome and miRNAome of an eat-2 mutant, a genetic surrogate of DR, by Next Generation sequencing and find that most of the miRNAs are upregulated in the young-adult worms, none significantly downregulated. Interestingly, PHA-4 can potentially regulate the expression of most of these miRNA genes. Remarkably, many of the PHA-4-regulated genes that are induced during DR are also targets of the PHA-4-upregulated miRNAs, forming a large feed-forward gene regulatory network. The genes targeted by the feed-forward loops (FFLs) are enriched for functions related to ubiquitin-mediated decay, lysosomal autophagy, cellular signalling, protein folding etc., processes that play critical roles in DR and longevity. Together our data provides a framework for understanding the complex and unique regulatory network employed during DR, suggesting that PHA-4 employs such FFLs to fine-tune gene expression and instil robustness in the system during energy crisis.
PMCID: PMC4247386  PMID: 25504288
microRNA; dietary restriction; PHA-4/FOXA; Transcription factor; miRNA; feed forward loops; aging
6.  Antigenotoxic Effect of Curcumin and Carvacrol against Parathion Induced DNA Damage in Cultured Human Peripheral Blood Lymphocytes and Its Relation to GSTM1 and GSTT1 Polymorphism 
Journal of Toxicology  2014;2014:404236.
In recent years, the use of organophosphorus pesticides has been extensively increased and these compounds signify a major class of agricultural pesticides today. We studied antigenotoxic potential of curcumin and carvacrol against the parathion induced DNA damage in cultured peripheral blood lymphocytes using sister chromatid exchanges as a biomarker of genotoxicity. Heparinised fresh blood from healthy individuals was treated with 2.5 μg/mL concentration of parathion in presence of curcumin and carvacrol in order to observe the antigenotoxic potential of both curcumin and carvacrol. Significant reduction (P < 0.05) was observed in the frequencies of SCEs in presence of 10 μg/mL and 15 μg/mL concentrations of curcumin as compared to parathion exposed sample. Similarly carvacrol had significant (P < 0.05) antigenotoxic effect at the concentrations of 2.5 μg/mL and 5.0 μg/mL against the parathion. We also studied the effect of GSTT1 and GSTM1 on genotoxicity of parathion and antigenotoxic potential of curcumin and carvacrol. We did not observe any significant effect (P > 0.05) of GSTT1 and GSTM1 polymorphism on genotoxicity of parathion and antigenotoxic potential of curcumin and carvacrol.
PMCID: PMC4195395  PMID: 25328519
7.  Development of Novel Elastic Vesicle-Based Topical Formulation of Cetirizine Dihydrochloride for Treatment of Atopic Dermatitis 
AAPS PharmSciTech  2013;14(4):1284-1293.
Cetirizine is a piperazine-derived second-generation antihistaminic drug recommended for treatment of pruritus associated with atopic dermatitis. The present investigation encompasses development of a nanosized novel elastic vesicle-based topical formulation of cetirizine dihydrochloride using combination of Phospholipon® 90G and edge activators with an aim to have targeted peripheral H1 antihistaminic activity. The formulation was optimized with respect to phospholipid/drug/charge inducer ratio along with type and concentration of edge activator. The optimized formulation was found to be satisfactory with respect to stability, drug content, entrapment efficiency, pH, viscosity, vesicular size, spreadability, and morphological characteristics. The ex vivo permeation studies through mice skin were performed using Franz diffusion cell assembly. It was found that the mean cumulative percentage amount permeated in 8 h was almost twice (60.001 ± 0.332) as compared to conventional cream (33.268 ± 0.795) and aqueous solution of drug (32.616 ± 0.969), suggesting better penetration and permeation of cetirizine from the novel vesicular delivery system. Further, therapeutic efficacy of optimized formulation was assessed against oxazolone-induced atopic dermatitis in mice. It was observed that the developed formulation was highly efficacious in reducing the itching score (4.75 itches per 20 min) compared to conventional cream (9.75 itches per 20 min) with profound reduction in dermal eosinophil count and erythema score. To conclude, a novel vesicular, dermally safe, and nontoxic topical formulation of cetirizine was successfully developed and may be used to treat atopic dermatitis after clinical investigation.
PMCID: PMC3840784  PMID: 23959702
atopic dermatitis; cetirizine; elastic vesicles; oxazolone; topical
8.  Extraction and purification of C-phycocyanin from Spirulina platensis (CCC540) 
In this study a simple protocol was developed for purifying phycocyanin (PC) from Spirulina platensis (CCC540) by using ammonium sulphate precipitation, followed by a single step chromatography by using DEAE-Cellulose-11 and acetate buffer. Precipitation with 65 % ammonium sulphate resulted in 80 % recovery of phycocyanin with purity of 1.5 (A620/A280). Thro1ugh chromatography an 80 % recovery of phycocyanin with a purity of 4.5 (A620/A280) was achieved. In SDS_PAGE analysis, the purified PC showed the presence of two subunit α (16 kD) and β (17 kD).
Electronic supplementary material
The online version of this article (doi:10.1007/s40502-014-0094-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4113674  PMID: 25089058
Spirulina; DEAE-Cellulose-11; Phycocyanin
9.  MRS in Early and Presymptomatic Carriers of a Novel Octapeptide Repeat Insertion in the Prion Protein Gene 
To evaluate the proton MR spectroscopy (1H MRS) changes in carriers of a novel octapeptide repeat insertion in the Prion Protein Gene (PRNP) and family history of frontotemporal dementia with ataxia. Four at-risk mutation carriers and 13 controls were compared using single voxel, short TE, 1H MRS from the posterior cingulate gyrus. The mutation carriers had an increased choline/creatine, p=0.003 and increased myoinositol/creatine ratio, p=0.003. 1H MRS identified differences in markers of glial activity and choline metabolism in pre- and early symptomatic carriers of a novel PRNP gene octapeptide insertion. These findings expand the possible diagnostic utility of 1H MRS in familial prion disorders.
PMCID: PMC3480551  PMID: 22612156
MRS; MRI; familial prion disorders; frontotemporal dementia
10.  Lipotropes promote immunobiochemical plasticity and protect fish against low-dose pesticide-induced oxidative stress 
Cell Stress & Chaperones  2013;19(1):61-81.
An experiment was conducted to evaluate the role of different lipotropes in modulating immunity and biochemical plasticity under conditions of sublethal low-dose pesticide-induced stress in fish. Labeo rohita fish fingerlings were divided in two sets with one set of fish continuously exposed to low-dose endosulfan (1/10th of 96-h LC50) for 21 days, the other was unexposed, and both sets of fish were fed with practical diets supplemented with either 2 % lecithin, 0.5 % betaine, or 0.1 % choline and compared against unsupplemented diet. Low-dose endosulfan exposure had adverse effects (P < 0.05/P < 0.01) on hematological profile (erythrocyte count, hemoglobin, and hematocrit), serum protein (total protein, albumin, and globulin) and lipid profile (cholesterol and triglyceride), anti-oxidative status (ascorbic acid content of muscle, liver, brain, and kidney and activity of anti-oxidative enzymes: catalase and superoxide dismutase), neurotransmission (acetylcholinesterase activity in muscle and brain), immunological attributes (WBC count, albumin to globulin ratio, phagocytic activity, and serum cortisol), and metabolic plasticity as revealed from enzyme activities (muscle lactate dehydrogenase, liver and kidney glucose-6-phosphatase dehydrogenase-G6PDH activity). Dietary lipotropes prevented these effects completely or partially and the effects were lipotrope dependent. Kinetics (maximum velocity value Vmax, catalytic efficiency and Michaelis constant Km) of G6PDH enzyme from crude extracts of liver and kidney indicated inhibition due to endosulfan but lipotropes could protect enzyme and showed a stabilizing effect. The supplements also helped maintain integrity of histoarchitecture of the hepatocytes in endosulfan-exposed fish to a great extent. Feeding lipotropes to fish reared in endosulfan-free water also improved hematological and serum protein and lipid profiles and were immunostimulatory. In conclusion, dietary lipotropes, especially betaine and lecithin at the levels used, improve erythropoiesis, serum protein and lipid profile, anti-oxidant status, immunocompetence, neurotransmission, and protect the livers of L. rohita fingerlings even when continuously exposed to low-dose endosulfan.
PMCID: PMC3857435  PMID: 23666764
Lipotropes; Pesticide stress; Hematological profile; Serum protein and lipid profile; Anti-oxidant status; Immunocompetence; Acetylcholinesterase activity; Biochemical plasticity; G6PDH kinetics; Labeo rohita; Immunostimulants
11.  Lipotropes Protect against Pathogen-Aggravated Stress and Mortality in Low Dose Pesticide-Exposed Fish 
PLoS ONE  2014;9(4):e93499.
The decline of freshwater fish biodiversity corroborates the trends of unsustainable pesticide usage and increase of disease incidence in the last few decades. Little is known about the role of nonlethal exposure to pesticide, which is not uncommon, and concurrent infection of opportunistic pathogens in species decline. Moreover, preventative measures based on current knowledge of stress biology and an emerging role for epigenetic (especially methylation) dysregulation in toxicity in fish are lacking. We herein report the protective role of lipotropes/methyl donors (like choline, betaine and lecithin) in eliciting primary (endocrine), secondary (cellular and hemato-immunological and histoarchitectural changes) and tertiary (whole animal) stress responses including mortality (50%) in pesticide-exposed (nonlethal dose) and pathogen-challenged fish. The relative survival with betaine and lecithin was 10 and 20 percent higher. This proof of cause-and-effect relation and physiological basis under simulated controlled conditions indicate that sustained stress even due to nonlethal exposure to single pollutant enhances pathogenic infectivity in already nutritionally-stressed fish, which may be a driver for freshwater aquatic species decline in nature. Dietary lipotropes can be used as one of the tools in resurrecting the aquatic species decline.
PMCID: PMC3972094  PMID: 24690771
12.  The Effect of N-Alkyl Substituents on the Usability of Imidazolium Cation-Based Ionic Liquids in Microemulsion Systems: A Technical Note 
AAPS PharmSciTech  2013;14(2):551-557.
PMCID: PMC3666005  PMID: 23463260
drug delivery; hemolysis; imidazolium; ionic liquids; microemulsion
13.  Feedback about action performed can alter the sense of self-agency 
Sense of agency refers to the sense of authorship of an action and its outcome. Sense of agency is often explained through computational models of motor control (e.g., the comparator model). Previous studies using the comparator model have manipulated action-outcome contingency to understand its effect on the sense of agency. More recent studies have shown that cues related to outcome, priming outcome and priming action have an effect on agency attribution. However, relatively few studies have focused on the effect of recalibrating internal predictions on the sense of agency. This study aims to investigate how feedback about action can recalibrate prediction and modulates the sense of agency. While participants performed a Flanker task, we manipulated the feedback about the validity of the action performed, independent of their responses. When true feedback is given, the sense of agency would reflect congruency between the sensory outcome and the action performed. The results show an opposite effect on the sense of agency when false feedback was given. We propose that feedback about action performed can recalibrate the prediction of sensory outcome and thus alter the sense of agency.
PMCID: PMC3933776  PMID: 24611059
sense of agency; motor control; forward model; error monitoring mechanisms; Flanker task; error feedback; action intention
14.  Difficult mask ventilation due to a large oral tumour 
Indian Journal of Anaesthesia  2014;58(1):101-102.
PMCID: PMC3968642  PMID: 24700924
15.  Genomic architecture of HIV-1 infection: Current status & challenges 
Studies on host genomics have revealed the existence of identifiable HIV-1 specific protective factors among infected individuals who remain naturally resistant viraemia controllers with little or no evidence of virus replication. These factors are broadly grouped into those that are immune associated (MHC, chemokines, cytokines, CTLs and others), linked to viral entry (chemokine co-receptors and ligands), act as post-entry restriction elements (TRIM5a, APOBEC3) and those associated with viral replication (cytokines and others). These features have been identified through multiple experimental approaches ranging from candidate gene approaches, genome wide association studies (GWAS), expression analysis in conjunction with functional assays in humans to primate based models. Several studies have highlighted the individual and population level gross differences both in the viral clade sequences as well as host determined genetic associations. This review collates current information on studies involving major histocompatibility complex (MHC) as well as non MHC genes in the context of HIV-1 infection and AIDS involving varied ethnic groups. Special focus of the review is on the genetic studies carried out on the Indian population. Further challenges with regard to therapeutic interventions based on current knowledge have been discussed along with discussion on documented cases of stem cell therapy and very early highly active antiretroviral therapy (HAART) interventions.
PMCID: PMC3928698  PMID: 24434320
AIDS; chemokine; elite controllers; genes; HIV-1; HLA; restriction; viraemia
16.  Protocol optimization for enhanced production of pigments in Spirulina 
Spirulina has attracted special attention due to its importance as human foodstuff and natural colours with specific functional properties. These functional properties have been attributed to phycobilins, carotenoids, phenolics and unsaturated fatty acids. Present study was conducted under controlled phytotron conditions to identify the efficient strains of Spirulina in terms of pigment synthesis and to optimize their enhanced production. Methodology for enhanced production was standardized by varying specific environmental parameters (light intensity, temperature, carbon dioxide concentration, pH and NaCl level). Different strains of Spirulina depicted variability and environmental parameters showed distinct influence on pigments. Growth and pigment production was recorded to be most efficient under optimized conditions of light intensity (70 μmol m−2 s−1), temperature (30 °C), CO2 concentration (550 ppm and 750 ppm), pH (10.5) and NaCl level (2 g L−1).
PMCID: PMC3991003  PMID: 24764599
Mass production; Pigments; Spirulina
17.  Genetic Dissection of Yield and Its Component Traits Using High-Density Composite Map of Wheat Chromosome 3A: Bridging Gaps between QTLs and Underlying Genes 
PLoS ONE  2013;8(7):e70526.
Earlier we identified wheat (Triticum aestivum L.) chromosome 3A as a major determinant of grain yield and its component traits. In the present study, a high-density genetic linkage map of 81 chromosome 3A-specific markers was developed to increase the precision of previously identified yield component QTLs, and to map QTLs for biomass-related traits. Many of the previously identified QTLs for yield and its component traits were confirmed and were localized to narrower intervals. Four novel QTLs one each for shoot biomass (Xcfa2262-Xbcd366), total biomass (wPt2740-Xcfa2076), kernels/spike (KPS) (Xwmc664-Xbarc67), and Pseudocercosporella induced lodging (PsIL) were also detected. The major QTLs identified for grain yield (GY), KPS, grain volume weight (GVWT) and spikes per square meter (SPSM) respectively explained 23.2%, 24.2%, 20.5% and 20.2% of the phenotypic variation. Comparison of the genetic map with the integrated physical map allowed estimation of recombination frequency in the regions of interest and suggested that QTLs for grain yield detected in the marker intervals Xcdo549-Xbarc310 and Xpsp3047-Xbarc356 reside in the high-recombination regions, thus should be amenable to map-based cloning. On the other hand, QTLs for KPS and SPSM flanked by markers Xwmc664 and Xwmc489 mapped in the low-recombination region thus are not suitable for map-based cloning. Comparisons with the rice (Oryza sativa L.) genomic DNA sequence identified 11 candidate genes (CGs) for yield and yield related QTLs of which chromosomal location of two (CKX2 and GID2-like) was confirmed using wheat aneuploids. This study provides necessary information to perform high-resolution mapping for map-based cloning and for CG-based cloning of yield QTLs.
PMCID: PMC3722237  PMID: 23894667
18.  Comment: Molar approach with backward, upward, right and posterior manoeuvre 
Indian Journal of Anaesthesia  2013;57(4):431-432.
PMCID: PMC3800354  PMID: 24163476
19.  Onosma L.: A review of phytochemistry and ethnopharmacology 
Pharmacognosy Reviews  2013;7(14):140-151.
The genus Onosma L. (Boraginaceae) includes about 150 species distributed world-wide in which only about 75 plants has been described for its morphology and less than 10 plants for their chemical constituents and clinical potential. The phytochemical reports of this genus revels that it comprise mainly aliphatic ketones, lipids, naphthazarins, alkaloids, phenolic compounds, naphthoquinones, flavones while most important are shikonins and onosmins. The plants are traditionally used as laxative, anthelmintic and for alexipharmic effects. The plants are also equally use in eye, blood diseases, bronchitis, abdominal pain, stangury, thirst, itch, lecoderma, fever, wounds, burns, piles and urinary calculi. The flowers of various plants are prescribed as stimulants, cardiotonic, in body swelling while leaves are used as purgative and in cutaneous eruptions. The roots are used for coloring food stuffs, oils and dying wool and in medicinal preparations. This review emphasizes the distribution, morphology, phytochemical constituents, ethnopharmacology, which may help in future research.
PMCID: PMC3841992  PMID: 24347922
Alkannin; hispidone; naphthoquinones; Ratanjot; shikonin
20.  IgM-monoclonal gammopathy neuropathy and tremor: A first epidemiologic case control study 
Parkinsonism & related disorders  2012;18(6):748-752.
Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled.
Materials and methods
An IgM-MGUS neuropathy case cohort (n=207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n=414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions.
Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p=0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p=0.025) and demyelinating nerve conductions (p=0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p=0.03) but not with NIS severity (p=0.57). Tremor occurrence associated with older age in controls, (p=0.004) but not in IgM-MGUS cases (p=0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p=0.04).
This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor.
PMCID: PMC3372617  PMID: 22475624
Tremor; Peripheral Neuropathy; IgM-MGUS
21.  Regulation of protumorigenic pathways by Insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis 
Molecular Cancer  2013;12:63.
Insulin like growth factor binding proteins modulate the mitogenic and pro survival effects of IGF. Elevated expression of IGFBP2 is associated with progression of tumors that include prostate, ovarian, glioma among others. Though implicated in the progression of breast cancer, the molecular mechanisms involved in IGFBP2 actions are not well defined. This study investigates the molecular targets and biological pathways targeted by IGFBP2 in breast cancer.
Transcriptome analysis of breast tumor cells (BT474) with stable knockdown of IGFBP2 and breast tumors having differential expression of IGFBP2 by immunohistochemistry was performed using microarray. Differential gene expression was established using R-Bioconductor package. For validation, gene expression was determined by qPCR. Inhibitors of IGF1R and integrin pathway were utilized to study the mechanism of regulation of β-catenin. Immunohistochemical and immunocytochemical staining was performed on breast tumors and experimental cells, respectively for β-catenin and IGFBP2 expression.
Knockdown of IGFBP2 resulted in differential expression of 2067 up regulated and 2002 down regulated genes in breast cancer cells. Down regulated genes principally belong to cell cycle, DNA replication, repair, p53 signaling, oxidative phosphorylation, Wnt signaling. Whole genome expression analysis of breast tumors with or without IGFBP2 expression indicated changes in genes belonging to Focal adhesion, Map kinase and Wnt signaling pathways. Interestingly, IGFBP2 knockdown clones showed reduced expression of β- catenin compared to control cells which was restored upon IGFBP2 re-expression. The regulation of β-catenin by IGFBP2 was found to be IGF1R and integrin pathway dependent. Furthermore, IGFBP2 and β-catenin are co-ordinately overexpressed in breast tumors and correlate with lymph node metastasis.
This study highlights regulation of β-catenin by IGFBP2 in breast cancer cells and most importantly, combined expression of IGFBP2 and β-catenin is associated with lymph node metastasis of breast tumors.
PMCID: PMC3698021  PMID: 23767917
IGFBP2; Breast cancer; Wnt signaling; β-catenin; Integrin
22.  Ditosylate Salt of Itraconazole and Dissolution Enhancement Using Cyclodextrins 
AAPS PharmSciTech  2012;13(3):863-874.
Salt formation has been a promising approach for improving the solubility of poorly soluble acidic and basic drugs. The aim of the present study was to prepare the salt form of itraconazole (ITZ), a hydrophobic drug to improve the solubility and hence dissolution performance. Itraconazolium ditolenesulfonate salt (ITZDITOS) was synthesized from ITZ using acid addition reaction with p-toluenesulfonic acid. Salt characterization was performed using 1H NMR, mass spectrometry, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The particle size and morphology was studied using dynamic light scattering technique and scanning electron microscopy, respectively. The solubility of the salt in water and various pharmaceutical solvents was found multifold than ITZ. The dissolution study exhibited 5.5-fold greater percentage release value in 3 h of ITZDITOS (44.53%) as compared with ITZ (8.54%). Results of in vitro antifungal studies using broth microdilution technique indicate that ITZDITOS possessed similar antifungal profile as that of ITZ when tested against four fungal pathogens. Furthermore, the physical mixtures of ITZDITOS with two cyclodextrins, β-cyclodextrin (β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared in different molar ratios and were evaluated for in vitro release. It was observed that in only 30 min of dissolution study, about 74 and 81% of drug was released from 1:3 molar ratios of ITZDITOS with β-CD and ITZDITOS with HP-β-CD, respectively, which was distinctly higher than the drug released from ITZ commercial capsules (70%). The findings warrant further preclinical and clinical studies on ITZDITOS so that it can be established as an alternative to ITZ for developing oral formulations.
PMCID: PMC3429683  PMID: 22669594
antifungal; BCS class II; dissolution rate; insoluble; itraconazole
23.  Rupatadine 
In the title compound (systematic name: 8-chloro-11-{1-[(5-methyl­pyridin-3-yl)meth­yl]piperidin-4-yl­idene}-6,11-di­hydro-5H-benzo[5,6]cyclo­hepta­[1,2-b]pyridine), C26H26ClN3, the dihedral angle between the mean planes of the chloro­phenyl and cyclo­hepta­[1,2-b]pyridinyl rings fused to the cyclo­heptane ring is 56.6 (1)°. The mean planes of the cyclo­hepta­[1,2-b]pyridinyl and 5-methyl­pyridin-3-yl rings are twisted by 64.9 (4)°. The central piperizene group is in a slightly distorted chair configuration. A weak intra­molecular C—H⋯N inter­action is observed between the cyclo­hepta­[1,2-b]pyridinyl and piperidin-4-yl­idene moieties.
PMCID: PMC3685114  PMID: 23795133
24.  Activation of TGF-β Pathway by Areca Nut Constituents: A Possible Cause of Oral Submucous Fibrosis 
PLoS ONE  2012;7(12):e51806.
Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and areca nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-β signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-β in epithelial cells. In an attempt to understand the role of areca nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with areca nut water extract or TGF-β. Interestingly, 64% of the differentially regulated genes by areca nut water extract matches with the TGF-β induced gene expression profile. Out of these, expression of 57% of genes was compromised in the presence of ALK5 (TβRI) inhibitor and 7% were independently induced by areca nut, highlighting the importance of TGF-β in areca nut actions. Areca nut water extract treatment induced p-SMAD2 and TGF-β downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-β in promoting OSF. Water extract of areca nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of areca nut were able to induce TGF-β signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-β2 and THBS1 (activator of latent TGF-β) in HaCaT cells suggesting areca nut mediated activation of p-SMAD2 involves up-regulation and activation of TGF-β. These data suggest a major causative role for TGF-β that is induced by areca nut in OSF progression.
PMCID: PMC3526649  PMID: 23284772
25.  OA01.11. Toxicity study and testicular regeneration property of swarna vanga 
Ancient Science of Life  2012;32(Suppl 1):S11.
Swarna-Vanga (SV) is a famous Kupipakva metallic preparation, which are therapeutically used as rejuvenator, anti-diabetic, and for testicular regeneration (Spermatogenesis) etc since 18th century. It contains Parad (mercury-Hg), Vanga (tin-Sn) and Gandhaka (Sulphur-S) in major amounts and our ancient author use different proportion of mercury in SV with respect to tin. So, in present study an attempt has been made to evaluate testicular regeneration property of SV with its safety and efficacy on albino rats.
1. Pharmaceutical Study: Preparation of SV in different proportion of Sn:Hg as 1:1,1:1/2, 1:1/4, 1:1/6. 2. Experimental Study: a) Toxicity study of SV for short (14 days) and long(40 days) duration in different doses, b) Regeneration property of SV on induced CdCl2 (Cadmium Chloride) testicular germinal epithelium of albinorats.
SV is a metallic preparation which contains mercury, tin and sulphur in major amount and the best product of SV is made by half of the mercury with the tin. SV does not show any toxic effects on therapeutic dose (12.5-25 gm/body weight of albino rats) but show some toxic effects on higher dose in longer duration. The ability of SV in generation of testicular germinal epithelium is seen on partial damaged testis which is produced by inducing CdCl2.
1) The presence of mercury at least in half proportion to tin in is necessary in making the SV of good standards, 2) SV is not toxic in therapeutic dose and is slightly toxic on higher doses in long duration, 3) SV has the property to regenerate partially damaged testicular tissue.
PMCID: PMC3800863

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