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1.  Immobilization with Atrophy Induces Increased Expression of Neuronal Nicotinic α7 Acetylcholine Receptors in Muscle Contributing to Neurotransmission 
Anesthesiology  2014;120(1):76-85.
Mature acetylcholine receptor (AChR) isoform normally mediates muscle contraction. The hypothesis that α7AChRs upregulate during immobilization and contribute to neurotransmission was tested pharmacologically using specific blockers to mature (waglerin-1), immature (αA-OIVA), and α7AChRs methyllycaconitine, and non-specific muscle AChR antagonist, α-bungarotoxin.
Mice were immobilized; contralateral limb was control. Fourteen days later, anesthetized mice were mechanically ventilated. Nerve-stimulated tibialis muscle contractions on both sides were recorded, and blockers enumerated above sequentially administered via jugular vein. Data are mean ± S.E.
Immobilization (N=7) induced tibialis muscle atrophy (40.6 ± 2.8 vs 52.1 ± 2.0 mg, p<0.01) and decrease of twitch tension (34.8 ± 1.1 vs. 42.9 ± 1.5 g, p< 0.01). Waglerin-1 (0.3 ± 0.05 μg/g) significantly (p=0.001, N=9) depressed twitch tension on contralateral (≥ 97%) versus immobilized side (~45%). Additional waglerin-1 (total dose 1.06 ± 0.12 μg/g or ~15.0 X ED50 in normals) could not depress twitch ≥ 80% on immobilized side. Immature AChR blocker, αA-OIVA (17.0 ± 0.25 μg/g) did not change tension bilaterally. Administration of α-bungarotoxin (N=4) or methyllycaconitine (N=3) caused ≥ 96% suppression of the remaining twitch tension on immobilized side. Methyllycaconitine, administered first (N=3), caused equipotent inhibition by waglerin-1 on both sides. Protein expression of α7AChRs was significantly (N=3, p<0.01) increased on the immobilized side.
Ineffectiveness of waglerin-1 suggests the twitch tension during immobilization is maintained by receptors other than mature AChRs. Since αA-OIVA caused no changes, immature AChRs contribute minimally to neurotransmission. During immobilization ~20% of twitch tension is maintained by upregulation of α-bungarotoxin- and methyllycaconitine-sensitive α7AChRs.
PMCID: PMC3910258  PMID: 24126263
2.  Non-surgically-induced disuse muscle atrophy and neuromuscular dysfunction upregulates alpha7 acetylcholine receptors 
Previous models of disuse have invariably used surgical methods require repetitive plaster casts applications. A method of disuse atrophy that does not require repetitive application is described. A modified plastic pipette tubing was applied to one hindlimb from thigh to foot resulting in immobilization of knee in extension and ankle in plantar flexion position. This method resulted in loss of soleus muscle mass to 11, 22, 39, and 45% at 3, 7, 14 and 21 days, respectively, in association with a significant decrease of tibialis twitch (25%) and tetanic tensions (26%) at 21 days, compared to contralateral side and/or sham immobilized controls. Immunohistochemical analysis of soleus using fluorescent α-bungarotoxin revealed a significant increase in the number of synapses per unit area (818+31 vs 433+16/mm2) and increase in muscle fibers per unit area (117 vs 83/mm2) most likely related to atrophy of muscle fibers bringing synapses closer. A three fold increase in alpha7 acetylcholine receptor (α7AChR) protein expression along with increased expression of α1AChR subunit on immobilized vs contralateral side was observed. The physiology and pharmacology of the novel finding of upregulation of α7AChRs with disuse requires further study.
PMCID: PMC4086193  PMID: 24383867
α7acetylcholine receptors; external plastic casting; immobilization; muscle atrophy; neuromuscular dysfunction
3.  Variations in DEPDC5 gene and its association with chronic hepatitis C virus infection in Saudi Arabia 
BMC Infectious Diseases  2014;14(1):632.
Variations at DEPDC5 gene have been recently reported as genetic markers associated with hepatocellular carcinoma (HCC) progression in chronic HCV-infected patients. This study was conducted to assess the association of DEPDC5 variants with advanced liver cirrhosis and HCC development among chronic HCV-infected patients in Saudi Arabian population.
Six-hundred and one HCV-infected patients were genotyped for DEPDC5 polymorphisms (rs1012068 and rs5998152), in comparison with 592 non-infected healthy control subjects. The allelic frequency and genotype distribution of both DEPDC5 polymorphisms were determined followed by haplotype frequency estimation and multiple logistic regression analysis.
The frequency of the risk alleles of both rs1012068 and rs5998152 was shown to be more in healthy control subjects than in patients (p = 0.0001, OR = 0.704, CI = 0.591-0.839; p = 0.002, OR = 0.761, CI = 0. 0.639-0.907, respectively). Also, our results revealed that GT for SNP rs1012068 (OR =1.715; 95% CI 1.132-2.597; p = 0.0104) and CT for SNP rs5998152 (OR = 1.932; 95% CI 1.276-2.925; p = 0.0017) showed significant association with development of cirrhosis compared with the GG and CC genotypes, respectively. The data also revealed that subjects with the T allele of both SNPs appeared to have a lower susceptibility to HCV-related cirrhosis/HCC than those with the G allele of rs1012068 (p = 0.038, OR = 1.353, 95 % CI 1.017-1.800) and C allele of rs5998152 (p = 0.043, OR = 1.342, 95 % CI 1.010-1.784). Haplotype analysis showed that a combination of T-T alleles of rs1012068 and rs5998152 was significantly associated with liver cirrhosis (frequency = 71.3% and p = 0.027) and with cirrhosis/HCC (frequency = 71.4% and P = 0.045). Also, multiple logistic regression analysis showed that rs5998152 (OR = 2.844, 95% CI 1.333-6.069 and p = 0.007), rs1012068 (OR = 2.793, 95% CI 1.316-5.928 and p = 0.010), age (OR = 1.029, 95% CI 1.001-1.057 and p = 0.041) and HCV genotypes (OR = 0.247, 95% CI 0.097-0.630 and p = 0.003) were independently associated with chronicity of HCV infection.
Genetic variations in DEPDC5 gene region may influence HCV-associated liver cirrhosis and/or HCC development.
PMCID: PMC4311515  PMID: 25551790
4.  Genetic relatedness among indigenous rice varieties in the Eastern Himalayan region based on nucleotide sequences of the Waxy gene 
BMC Research Notes  2014;7:953.
Indigenous rice varieties in the Eastern Himalayan region of Northeast India are traditionally classified into sali, boro and jum ecotypes based on geographical locality and the season of cultivation. In this study, we used DNA sequence data from the Waxy (Wx) gene to infer the genetic relatedness among indigenous rice varieties in Northeast India and to assess the genetic distinctiveness of ecotypes.
The results of all three analyses (Bayesian, Maximum Parsimony and Neighbor Joining) were congruent and revealed two genetically distinct clusters of rice varieties in the region. The large group comprised several varieties of sali and boro ecotypes, and all agronomically improved varieties. The small group consisted of only traditionally cultivated indigenous rice varieties, which included one boro, few sali and all jum varieties. The fixation index analysis revealed a very low level of differentiation between sali and boro (FST = 0.005), moderate differentiation between sali and jum (FST = 0.108) and high differentiation between jum and boro (FST = 0.230) ecotypes.
The genetic relatedness analyses revealed that sali, boro and jum ecotypes are genetically heterogeneous, and the current classification based on cultivation type is not congruent with the genetic background of rice varieties. Indigenous rice varieties chosen from genetically distinct clusters could be used in breeding programs to improve genetic gain through heterosis, while maintaining high genetic diversity.
Electronic supplementary material
The online version of this article (doi:10.1186/1756-0500-7-953) contains supplementary material, which is available to authorized users.
PMCID: PMC4320456  PMID: 25547027
Boro; Ecotype; Genetic relatedness; Indigenous rice varieties; Jum; Sali
5.  Diagnostic Utility of Impedance-pH Monitoring in Refractory Non-erosive Reflux Disease 
Approximately one-third of non-erosive reflux disease (NERD) patients are refractory to proton pump inhibitors (PPI) and face a therapeutic challenge. Therefore, it is important to differentiate between pathological and non-pathological reflux utilizing multichannel intraluminal impedance-pH (MII-pH) to analyze symptom-reflux association and diagnose true NERD versus hyper-sensitive esophagus (HE) and functional heartburn (FH). Herein, we evaluated the diagnostic yield of MII-pH in refractory NERD and sub-classified it based on quantity and quality of acid/non-acid reflux and reflux-symptom association.
Sixty symptomatic NERD patients on twice daily PPI for > 2 months were prospectively evaluated by MII-pH. Distal and proximal refluxes, bolus exposure time (BET), esophageal acid exposure time, symptom index (SI) and symptom association probability (SAP) were measured.
Thirty-two (53%) patients had BET > 1.4% (MII-pH positive-true NERD), while 28 (47%) had BET < 1.4% (MII-pH negative NERD) where SI and SAP were negative in 15/60 (25%; categorized as FH) and SI or SAP were positive in 13/60 (22%; identified as HE). Thirty-eight (63%) patients reported significant SI or SAP parameters where > 80% of symptoms were associated with non-acid reflux. The number of distal refluxes in true NERD versus FH or HE were significantly different, but not between FH and HE.
Approximately 60% of refractory PPI NERD patients had positive reflux-symptom association, primarily due to non-acid reflux. Nearly half of NERD patients on PPI had normal MII-pH monitoring, sub-divided further into FH and HE equally.
PMCID: PMC4204403  PMID: 25273120
Impedance-pH monitoring; Non-erosive reflux disease; Refractory NERD
6.  The Association of Toll-Like Receptor 4 Polymorphism with Hepatitis C Virus Infection in Saudi Arabian Patients 
BioMed Research International  2014;2014:357062.
Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects (P < 0.0001; OR = 0.404, 95% CI = 0.281–0.581) and (P < 0.0001; OR = 0.298, 95% CI = 0.201–0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency = 94.7% and P = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population.
PMCID: PMC4142570  PMID: 25177689
7.  Patterns of nucleotide diversity and phenotypes of two domestication related genes (OsC1 and Wx) in indigenous rice varieties in Northeast India 
BMC Genetics  2014;15:71.
During the domestication of crops, individual plants with traits desirable for human needs have been selected from their wild progenitors. Consequently, genetic and nucleotide diversity of genes associated with these selected traits in crop plants are expected to be lower than their wild progenitors. In the present study, we surveyed the pattern of nucleotide diversity of two selected trait specific genes, Wx and OsC1, which regulate amylose content and apiculus coloration respectively in cultivated rice varieties. The analyzed samples were collected from a wide geographic area in Northeast (NE) India, and included contrasting phenotypes considered to be associated with selected genes, namely glutinous and nonglutinous grains and colored and colorless apiculus.
No statistically significant selection signatures were detected in both Wx and OsC1gene sequences. However, low level of selection that varied across the length of each gene was evident. The glutinous type varieties showed higher levels of nucleotide diversity at the Wx locus (πtot = 0.0053) than nonglutinous type varieties (πtot = 0.0043). The OsC1 gene revealed low levels of selection among the colorless apiculus varieties with lower nucleotide diversity (πtot = 0.0010) than in the colored apiculus varieties (πtot = 0.0023).
The results revealed that functional mutations at Wx and OsC1genes considered to be associated with specific phenotypes do not necessarily correspond to the phenotypes in indigenous rice varieties in NE India. This suggests that other than previously reported genomic regions may also be involved in determination of these phenotypes.
PMCID: PMC4070345  PMID: 24935343
Indigenous; Nucleotide diversity; NE India; Rice; Trait specific genes
8.  Gastroprotective Effect of Freeze Dried Stripped Snakehead Fish (Channa striata Bloch.) Aqueous Extract against Aspirin Induced Ulcerogenesis in Pylorus Ligated Rats 
ISRN Pharmacology  2014;2014:327606.
Channa striata (Bloch.) is a fresh water fish belonging to the family Channidae. The stripped snakehead fish possesses wide range of medicinal properties. In view of traditional use of C. striata for wound healing, the present study was undertaken to investigate the beneficial effects of orally administered freeze dried aqueous extract of Channa striata (AECS) in experimentally induced gastric ulcers in Wistar rats. Aspirin induced ulcerogenesis in pyloric ligation model was used for the assessment of antiulcer activity and Ranitidine (50 mg/kg) was employed as the standard drug. The various gastric parameters like volume of gastric juice, pH, free and total acidities, ulcer index, and levels of antioxidant enzymes like catalase, superoxide dismutase, and lipid peroxidation marker malondialdehyde were determined. AECS at concentrations of 40% and 50% w/v significantly decreased the volume of gastric juice and increased the levels of catalase while considerable decrease in free and total acidities and increase in superoxide dismutase were observed with the treatment of standard drug and AECS (50% w/v). All the test doses of AECS markedly decreased ulcer index and malondialdehyde compared to the standard drug whereas AECS 30% w/v did not alter volume of gastric juice, pH, free and total acidities, catalase, and superoxide dismutase. From these findings, it can be concluded that AECS is devoid of acid neutralizing effects at lower doses and possesses antisecretory and antiulcer activities and this could be related to its antioxidant mechanism.
PMCID: PMC4058147  PMID: 24977051
9.  Effects of Calorie Restriction and Diet-Induced Obesity on Murine Colon Carcinogenesis, Growth and Inflammatory Factors, and MicroRNA Expression 
PLoS ONE  2014;9(4):e94765.
Obesity is an established colon cancer risk factor, while preventing or reversing obesity via a calorie restriction (CR) diet regimen decreases colon cancer risk. Unfortunately, the biological mechanisms underlying these associations are poorly understood, hampering development of mechanism-based approaches for preventing obesity-related colon cancer. We tested the hypotheses that diet-induced obesity (DIO) would increase (and CR would decrease) colon tumorigenesis in the mouse azoxymethane (AOM) model. In addition, we established that changes in inflammatory cytokines, growth factors, and microRNAs are associated with these energy balance-colon cancer links, and thus represent mechanism-based targets for colon cancer prevention. Mice were injected with AOM once a week for 5 weeks and randomized to: 1) control diet; 2) 30% CR diet; or 3) DIO diet. Mice were euthanized at week 5 (n = 12/group), 10 (n = 12/group), and 20 (n = 20/group) after the last AOM injection. Colon tumors were counted, and cytokines, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), adipokines, proliferation, apoptosis, and expression of microRNAs (miRs) were measured. The DIO diet regimen induced an obese phenotype (∼36% body fat), while CR induced a lean phenotype (∼14% body fat); controls were intermediate (∼26% body fat). Relative to controls, DIO increased (and CR decreased) the number of colon tumors (p = 0.01), cytokines (p<0.001), IGF-1 (p = 0.01), and proliferation (p<0.001). DIO decreased (and CR increased) IGFBP-3 and apoptosis (p<0.001). miRs including mir-425, mir-196, mir-155, mir-150, mir-351, mir-16, let-7, mir34, and mir-138 were differentially expressed between the dietary groups. We conclude that the enhancing effects of DIO and suppressive effects of CR on colon carcinogenesis are associated with alterations in several biological pathways, including inflammation, IGF-1, and microRNAs.
PMCID: PMC3986228  PMID: 24732966
10.  Functional Androdioecy in Critically Endangered Gymnocladus assamicus (Leguminosae) in the Eastern Himalayan Region of Northeast India 
PLoS ONE  2014;9(2):e87287.
Gymnocladus assamicus is a critically endangered tree species endemic to Northeast India, and shows sexual dimorphism with male and hermaphrodite flowers on separate trees. We studied phenology, reproductive biology and mating system of the species. The flowers are small, tubular, odorless and last for about 96 hours. Pollen grains in both morphs were viable and capable of fertilization leading to fruit and seed set. Scanning electron micrographs revealed morphologically similar pollen in both male and hermaphrodite flowers. The fruit set in open pollinated flowers was 43.61 percent, while controlled autogamous and geitonogamous pollinations yielded 76.81 and 65.58 percent fruit set respectively. Xenogamous pollinations between male and hermaphrodite flowers resulted in 56.85 percent fruit set and pollinations between hermaphrodite flowers yielded 67.90 percent fruit set. This indicates a functionally androdioecious mating system and pollination limited fruit set in G. assamicus. Phylogenetic analyses of Gymnocladus and the sister genus Gleditsia are needed to assess if the androdioecious mating system in G. assamicus evolved from dioecy as a result of selection for hermaphrodites for reproductive assurance during colonization of pollination limited high altitude ecosystems.
PMCID: PMC3938411  PMID: 24586267
11.  Acute pancreatitis induced thrombotic thrombocytopenic purpura 
Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome of unknown cause with an estimated incidence of one case per million. The disease is characterized by a pentad of symptoms: Thrombocytopenia, microangiopathic hemolytic anemia, neurologic changes, renal dysfunction, and fever. It causes thrombosis in the microvasculature of several organs, producing diverse manifestations. Acute pancreatitis (AP) is a well-described consequence of TTP. Acute pancreatitis triggering TTP is uncommon.
PMCID: PMC3943117  PMID: 24678155
Microangiopathic hemolytic anemia; pancreatitis; thrombotic thrombocytopenic purpura
12.  Current Trends in Water-in-Diesel Emulsion as a Fuel 
The Scientific World Journal  2014;2014:527472.
Water-in-diesel emulsion (WiDE) is an alternative fuel for CI engines that can be employed with the existing engine setup with no additional engine retrofitting. It has benefits of simultaneous reduction of both NOx and particulate matters in addition to its impact in the combustion efficiency improvement, although this needs further investigation. This review paper addresses the type of emulsion, the microexplosion phenomenon, emulsion stability and physiochemical improvement, and effect of water content on the combustion and emissions of WiDE fuel. The review also covers the recent experimental methodologies used in the investigation of WiDE for both transport and stationary engine applications. In this review, the fuel injection pump and spray nozzle arrangement has been found to be the most critical components as far as the secondary atomization is concerned and further investigation of the effect of these components in the microexplosion of the emulsion is suggested to be center of focus.
PMCID: PMC3916022  PMID: 24563631
14.  Vitamin D receptor gene polymorphisms in breast and renal cancer: Current state and future approaches 
International Journal of Oncology  2013;44(2):349-363.
Cancer is a major health problem and cause of death worldwide that accounted for 7.6 million deaths in 2008, which is projected to continue rising with an estimated 13.1 million deaths in 2030 according to WHO. Breast cancer is the leading cause of cancer-based death among women around the world and its incidence is increasing annually with a similar tendency. In contrast, renal cell carcinoma accounts for only 3% of total human malignancies but it is still the most common type of urological cancer with a high prevalence in elderly men (>60 years of age). There are several factors linked with the development of renal cell cancer only, while others are connected only with breast cancer. Genetic risk factors and smoking are the factors which contribute to carcinogenesis in general. Some evidence exists indicating that vitamin D receptor (VDR) gene polymorphisms are associated with both breast and renal cancer; therefore, we put forward the hypothesis that polymorphisms in the VDR gene may influence both the occurrence risks of these cancers and their prognosis. However, the relationship between VDR polymorphisms and these two specific cancers remains a controversial hypothesis, and consequently needs further confirmation via clinical research together with genetic investigations. Here, we aimed to assess the correlation between the different alleles of VDR gene polymorphisms and renal cell cancer and breast cancer risks separately through a systematic review of the present literature. In contrast, this analysis has revealed that some VDR gene polymorphisms, such as: Bsm1, poly(A), Taq1, Apa1, are to some extent associated with breast cancer risk. Other polymorphisms were found to be significantly associated with renal cell cancer. Namely, they were Fok1, Bsm1, Taq1 and Apa1, which encode proteins participating mainly in proliferation, apoptosis and cell cycle regulation. However, data concerning renal cancer are not sufficient to firmly establish the VDR gene polymorphism association.
PMCID: PMC3898813  PMID: 24297042
vitamin D; vitamin D receptor gene polymorphisms; breast cancer; renal cancer
15.  Novel Genes Associated with Colorectal Cancer Are Revealed by High Resolution Cytogenetic Analysis in a Patient Specific Manner 
PLoS ONE  2013;8(10):e76251.
Genomic abnormalities leading to colorectal cancer (CRC) include somatic events causing copy number aberrations (CNAs) as well as copy neutral manifestations such as loss of heterozygosity (LOH) and uniparental disomy (UPD). We studied the causal effect of these events by analyzing high resolution cytogenetic microarray data of 15 tumor-normal paired samples. We detected 144 genes affected by CNAs. A subset of 91 genes are known to be CRC related yet high GISTIC scores indicate 24 genes on chromosomes 7, 8, 18 and 20 to be strongly relevant. Combining GISTIC ranking with functional analyses and degree of loss/gain we identify three genes in regions of significant loss (ATP8B1, NARS, and ATP5A1) and eight in regions of gain (CTCFL, SPO11, ZNF217, PLEKHA8, HOXA3, GPNMB, IGF2BP3 and PCAT1) as novel in their association with CRC. Pathway and target prediction analysis of CNA affected genes and microRNAs, respectively indicates TGF-β signaling pathway to be involved in causing CRC. Finally, LOH and UPD collectively affected nine cancer related genes. Transcription factor binding sites on regions of >35% copy number loss/gain influenced 16 CRC genes. Our analysis shows patient specific CRC manifestations at the genomic level and that these different events affect individual CRC patients differently.
PMCID: PMC3813709  PMID: 24204606
16.  Prostaglandin Analogous and Antioxidant Activity Mediated Gastroprotective Action of Tabernaemontana divaricata (L.) R. Br. Flower Methanolic Extract against Chemically Induced Gastric Ulcers in Rats 
BioMed Research International  2013;2013:185476.
The present study was conducted to evaluate the antiulcerogenic effect and recognize the basic mechanism of action of Tabernaemontana divaricata (L.) R. Br. flowers. T. divaricata flower methanolic extract (TDFME) was screened for antiulcer activity versus aspirin and ethanol induced gastric ulcers at three doses—125, 250, and 500 mg/kg—orally using misoprostol as a standard. Besides histopathological examination, seven parameters, that is, ulcer index, total protein, nonprotein sulphhydryls, mucin, catalase, malondialdehyde, and superoxide dismutase levels, were estimated. In addition to HPLC profiling, GC-MS analysis and electrospray ionization—high resolution mass spectral (ESI-HRMS) analysis of crude TDFME were carried out in an attempt to identify known phytochemicals present in the extract on the basis of m/z value. The results revealed a significant increase in the levels of catalase, superoxide dismutase, mucin, and nonprotein sulphhydryls, while they revealed a reduction in ulcer index, the levels of total protein, and malondialdehyde. Histopathological observations also demonstrated the protective effect. Though all the doses of TDFME exhibited gastroprotective function, higher doses were found to be more effective. Mass spectral analysis gave a few characteristic m/z values suggesting the presence of a few known indole alkaloids, while HPLC profiling highlighted the complexity of the extract. TDFME was found to exhibit its gastroprotective effect through antioxidant mechanism and by enhancing the production of gastric mucous.
PMCID: PMC3856123  PMID: 24350249
17.  Generalized Lymphadenopathy as the First Presentation of Granulocytic Sarcoma: A Diagnostic Challenge 
Case Reports in Medicine  2013;2013:483291.
Introduction. Granulocytic sarcoma (GS), also known as chloroma or extramedullary myeloblastoma, is a solid tumor composed of primitive precursors of the granulocytic series that include myeloblasts, promyelocytes, and myelocytes. Granulocytic sarcoma is a rare tumor that may develop during acute myeloid leukemia (AML) but less frequently may precede its presentation. Although generalized lymph node enlargement is a presentation for malignant lymphoma, it can also rarely be the early presenting sign of GS. Methods. We present a case of GS mimicking lymphoma in a 45-year-old male. The patient presented with bilateral neck masses and had widespread, prominent lymphadenopathy secondary to AML as the first presenting manifestation of GS for the last 4 months with concurrent marrow AML. Result. A clinical diagnosis of lymphoma was suspected; fine needle aspiration cytology findings were also suggestive of lymphoma. However, peripheral blood and bone marrow examination reported as acute myeloid leukemia with monocytic differentiation and histopathology of excised lymph node confirmed it to be a GS not lymphoma. Conclusion. GS is often misdiagnosed as malignant lymphoma because of cytomorphologic and histologic similarities of the blasts to large cell lymphoma. A careful search for immature myeloid is a useful clue to the diagnosis accompanied with appropriate immunophenotyping.
PMCID: PMC3824813  PMID: 24282418
18.  Lipopolysaccharide Up-regulates Alpha7 Acetylcholine Receptors: Stimulation with GTS-21 Mitigates Growth Arrest of Macrophages and Improves Survival in Burned Mice 
Shock (Augusta, Ga.)  2012;38(2):213-219.
Nicotinic stimulation of the alpha7 acetylcholine receptors (α7AChRs) mitigates the lipopolysaccharide (LPS)-induced TNF-α and other cytokines release in macrophages. This effect is blocked by α7AChR antagonist, α-bungarotoxin (BTX). We tested and confirmed the hypotheses that LPS up-regulates α7AChRs and the prototypical α7AChR antagonists, vecuronium, and BTX do not block the effects of GTS-21, a specific α7AChR agonist, on TNF-α release. With the knockdown of α7AChR expression by siRNA, GTS-21 effects on inhibition of TNF-α release were not demonstrable. In addition, GTS-21 mitigated the LPS-induced growth arrest of macrophages in vitro in J774A.1 cells and ex vivo in peritoneal macrophages obtained from mice at three days after burn. Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS up-regulates α7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via α7AChRs and are preserved even when co-treated with prototypical antagonist, BTX, or clinically used muscle nicotinic antagonist, vecuronium; (iii) activation of α7AChRs by GTS-21 partially reverses the LPS-induced proliferation arrest and (iv) GTS-21 reduces mortality in mice with burn injury. The in vivo beneficial effects of GTS-21 in burn injury warrant further studies.
PMCID: PMC3399057  PMID: 22683726
alpha7 acetylcholine receptor agonist; alpha7 acetylcholine receptor antagonists; α-bungarotoxin; tumor necrosis factor-α; up-regulation; vecuronium
19.  Lung Transplantation Triggered "Jackhammer Esophagus": A Case Report and Review of Literature 
A 19-years-old girl was referred for lung transplant due to end stage lung disease secondary to idiopathic bilateral bronchiectasis. Her routine pre lung transplant evaluation showed normal esophageal high-resolution manometry (HRM) and 24-hours impedance pH monitoring. Four weeks after the bilateral sequential lung transplantation (LTx), she developed dysphagia, chest pain and regurgitation, complicated by aspiration pneumonia. Repeated HRM showed Jackhammer esophagus, delayed gastric emptying and abnormal 24-hour pH impedance monitoring consistent with the diagnosis of gastroesophageal reflux disease. Twelve weeks after LTx, she was symptom free, HRM and 24-hour impedance pH monitoring returned to normal. To the best of our knowledge, this rare transient esophageal hypercontractility episode occurred after LTx and recovered without any specific treatment was never reported in literature. The etiopathogenesis of Jackhammer esophagus in general and LTx induced dysmotility in particular is discussed and reviewed.
PMCID: PMC3714418  PMID: 23875107
High-resolution manometry; Jackhammer esophagus; Lung transplantation
20.  EGFR Somatic Mutations in Lung Tumors: Radon Exposure and Passive-smoking in Former- and Never-smoking U.S. Women 
Lung cancer patients with mutations in EGFR tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke.
This hypothesis was investigated by analyzing EGFR mutations in seventy lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive-smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic.
Overall, the frequency of EGFR mutation was 41% [95% Confidence Interval (CI): 32-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors.
The results suggest that EGFR mutations are common in female, never-smoking, lung cancer cases from the U.S, and EGFR mutations are unlikely due to exposure to radon or passive-smoking.
PMCID: PMC3372599  PMID: 22523180
EGFR mutations; never-smokers; lung cancer; radon; passive-smoking; second hand smoke; tobacco smoke
21.  The Single IgG IL-1 related receptor (Sigirr) controls Toll-like receptor responses in differentiated human intestinal epithelial cells 
Intestinal epithelial cells (IEC) are constantly exposed to enteric microbes. Although IECs express TLRs that recognize bacterial products, activation of these TLRs is strictly controlled through poorly understood mechanisms, producing a state of hypo-responsiveness and preventing unwanted inflammation. The Single IgG IL-1 related receptor (Sigirr) is a negative regulator of TLRs that is expressed by IEC and recently shown to inhibit experimental colitis. However, the importance of Sigirr in IEC hyporesponsiveness and its distribution within the human colon is unknown. In this study, we investigated the role of Sigirr in regulating epithelial specific TLR responses and characterize its expression in colonic biopsies. Transformed and non-transformed human IEC were cultured as monolayers. Transient gene silencing and stable over-expression of Sigirr was performed to assess innate IEC responses. Sigirr expression in human colonic biopsies was examined by immunohistochemistry. Bacterial infection of IEC and exposure to flagellin transiently decreased Sigirr protein expression, concurrent with secretion of the neutrophil chemokine IL-8. Sigirr gene silencing augmented chemokine responses to bacterial flagellin, Pam3Cys and the cytokine IL-1β. Conversely, stable over-expression of Sigirr diminished NF-κB mediated IL-8 responses to TLR ligands. We also found that Sigirr expression increased as IECs differentiated in culture. This observation was confirmed in biopsy sections, where Sigirr expression within colonic crypts was prominent in IECs at the apex and diminished at the base. Our findings show that Sigirr broadly regulates innate responses in differentiated human IEC, and may therefore modulate epithelial involvement in infectious and inflammatory bowel diseases.
PMCID: PMC3652552  PMID: 20130217
Enterocytes; chemokines; flagellin; bacterial infection; differentiation
22.  Subcellular spatial segregation of integrin subtypes by patterned multicomponent surfaces† 
While it is well known that individual integrins are critical mediators of cell behavior, recent work has shown that when multiple types of integrins simultaneously engage the ECM, cell functions are enhanced. However, it is not known how integrins spatially coordinate to regulate cell adhesion because no reliable method exists to segregate integrins on the cell membrane. Here, we use a microcontact printing-based strategy to pattern multiple ECMs that bind distinct integrins in order to study how integrins might interact. In our technique, proteins are first adsorbed uniformly to a poly(dimethyl siloxane) stamp, and then selectively “de-inked.” Our strategy overcomes several inherent limitations of conventional microcontact printing, including stamp collapse and limited functionality of the surface patterns. We show that integrins spatially segregate on surfaces patterned with multiple ECMs, as expected. Interestingly, despite spatial segregation of distinct integrins, cells could form adhesions and migrate across multicomponent surfaces as well as they do on single component surfaces. Together, our data indicate that although cells can segregate individual integrins on the cell surface to mediate ECM-specific binding, integrins function cooperatively to guide cell adhesion and migration.
PMCID: PMC3586560  PMID: 21298148
23.  Emergence of new lineage of Dengue virus 3 (genotype III) in Lucknow, India 
Background and Objectives
Dengue has re-emerged as an important arboviral disease causing significant morbidity. It has become hyperendemic in the Indian subcontinent with all four known dengue serotypes circulating.
Materials and Methods
Multiple sequence alignments and phylogenetic trees of DENV-3 were constructed to determine the extent of the isolated dengue virus genetic heterogeneity and phylogeny.
Sequencing and phylogenetic analysis of the C-prM gene junction revealed an active circulation of a new lineage of DENV-3 (genotype III) in this region of India.
Continuous epidemiological surveillance to monitor the incursion and spread of dengue virus genotypes in this region of India is needed.
PMCID: PMC3577557  PMID: 23466682
Dengue virus; phylogenetic analysis; genotype III
24.  Hepatitis C Genotype 4: Genotypic Diversity, Epidemiological Profile, and Clinical Relevance of Subtypes in Saudi Arabia 
Hepatitis C virus genotypes 4 (HCV-4) is the most prevalent genotype in Saudi Arabia, although it's various subtypes, mode and route of transmission remains unknown. The aim of this study was to analyze (i) the variability of the HCV-4 subtypes, the route and source of HCV transmission and (ii) the influence of HCV-4 subtypes on their therapeutic response.
Patients and Methods:
Sixty-four HCV-4 patients were analyzed retrospectively for the prevalence of various sub-genotypes and the possible mode of transmission, and it was correlated with their treatment response to pegylated interferon (PEG-IFN) α-2a and ribavirin therapy.
Positive history of blood or blood products transfusion was noted in 22 patients (34%), hemodialysis in 10 patients (15.6%), surgery in 7 patients (11%), and unknown etiology in 25 patients (39%). Prevalence of HCV-4 subtypes was 4a = 48.4% (31/64), 4d = 39% (25/64), 4n = 6.25% (4/64), and remaining combined (4m, 4l, 4r, 4o) 6.25% (4/64). No significant correlation between subtypes and the source of transmission was recognized (P = 0.62). Sustained virological response in all HCV-4 patients was 64% (41/64), while in each subtypes separately it was 4a 77.4% (24/31), 4d 52% (13/25), and combined (4n, 4m, 4l, 4r, 4o) 62.5% (5/8) (P = 0.046).
No obvious cause for the mode of HCV transmission was noted in majority of the patients. No significant correlation was observed between HCV-4 subtypes and the source of HCV infection. 4a and 4d subtypes were the most common in Saudi Arabia, and patients infected with 4a subtype responded significantly better to combination therapy than to 4d subtype.
PMCID: PMC3603486  PMID: 23319035
Hepatitis C virus; HCV genotype 4; subtypes of HCV-4
25.  Tissue Distribution and Gender-Divergent Expression of 78 Cytochrome P450 mRNAs in Mice 
Toxicological Sciences  2011;124(2):261-277.
Cytochrome P450 (Cyp) enzymes from the first four families (Cyp1–4) play a major role in metabolizing xenobiotics, affecting drug pharmacokinetics and chemical-induced toxicity. Due to cloning of the mouse genome, many novel Cyp isoforms have been identified, but their tissue distribution of expression is unknown. This study compared the tissue distribution of all 78 Cyps from the Cyp1–4 families in C57BL/6 mice providing not only an indication of which tissues novel Cyps may have their greatest importance but also a cohesive comparison of the tissue distribution of all Cyp1–4 isoforms. Transcripts of the 78 Cyps were quantified by multiplex suspension arrays and quantitative real-time PCR in 14 tissues. Hierarchical clustering indicated that in male mice, 52% of the Cyp species were expressed highest in liver, 10% in kidney, 10% in duodenum/jejunum, 10% in testes, 5% in lung, and < 4% in colon, brain, heart, and stomach. Female mice had a similar pattern of Cyp messenger RNA expression; however, compared with males, females had 7% more Cyps that were liver predominant, 2% more Cyps that were stomach predominant, but 1% less Cyps that were kidney and lung predominant. Differences in gender expression were observed in 29 of the Cyps, with 24 being higher in females than males. Additionally, the data suggest a correlation between the spatial arrangement of genes within a gene cluster and their organ-predominant expression, indicating a common regulatory mechanism may be present within these clusters. In conclusion, this study provides novel data on the tissue distribution and gender-divergent expression of 78 functional mouse Cyp isoforms.
PMCID: PMC3216415  PMID: 21920951
cytochrome P450; mRNA; mice; tissue distribution

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