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1.  Olmesartan Attenuates Tacrolimus-Induced Biochemical and Ultrastructural Changes in Rat Kidney Tissue 
BioMed Research International  2014;2014:607246.
Tacrolimus, a calcineurin inhibitor, is clinically used as an immunosuppressive agent in organ transplantation, but its use is limited due to its marked nephrotoxicity. The present study investigated the effect of olmesartan (angiotensin receptor blocker) on tacrolimus-induced nephrotoxicity in rats. A total of 24 rats were divided into four groups, which included control, tacrolimus, tacrolimus + olmesartan, and olmesartan groups. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. Tacrolimus significantly increased BUN and creatinine level. Treatment with olmesartan reversed tacrolimus-induced changes in the biochemical markers (BUN and creatinine) of nephrotoxicity. Tacrolimus significantly decreased GSH level and catalase activity while increasing MDA level. Olmesartan also attenuated the effects of tacrolimus on MDA, GSH, and catalase. In tacrolimus group histological examination showed marked changes in renal tubule, mitochondria, and podocyte processes. Histopathological and ultrastructural studies showed that treatment with olmesartan prevented tacrolimus-induced renal damage. These results suggest that olmesartan has protective effects on tacrolimus-induced nephrotoxicity, implying that RAS might be playing role in tacrolimus-induced nephrotoxicity.
doi:10.1155/2014/607246
PMCID: PMC4058524  PMID: 24987695
2.  Irritable Bowel Syndrome in a Bangladeshi Urban Community: Prevalence and Health Care Seeking Pattern 
Background/Aims:
Although irritable bowel syndrome (IBS) is a common gastrointestinal disorder, its prevalence is unknown, especially in the urban population of Bangladesh. This community-based study aimed to find out the prevalence of IBS and healthcare-seeking patterns using the Rome-II definition.
Materials and Methods:
A population-based cross-sectional survey of 1503 persons aged 15 years and above was carried out in an urban community of Bangladesh. The subjects were interviewed using a valid questionnaire based on Rome-II criteria in a home setting. Statistical analysis was performed with Statistical Package for Social Science (SPSS) Programmers and the level of significance was set at P ≤ 0.05.
Results:
A response rate of 97.2% yielded 1503 questionnaires for analysis. The prevalence of IBS was found to be 7.7% (n = 116) with a male to female ratio of 1:1.36 (49 vs. 67). “Diarrhoea-predominant IBS” (50%, n = 58) was the predominant IBS subgroup. Symptoms of abdominal pain associated with a change in stool frequency (100%) and consistency (88.8%) were quite common. All IBS symptoms were more prevalent among women (P < 0.000). In the past one year, 65.5% (n = 76) IBS subjects had consulted a physician with a slightly higher rate of women consulters (68.6 vs. 61.2%). The main predictor for healthcare-seeking was the presence of multiple dyspeptic symptoms.
Conclusions:
The prevalence of IBS in the urban community was found to be similar to that in rural communities. A higher rate of consultation was found among urban IBS subjects than in the rural subjects, with sex not seen to be a discriminator to seek consultation.
doi:10.4103/1319-3767.56099
PMCID: PMC2981840  PMID: 19794269
Healthcare-seeking; irritable bowel syndrome prevalence; Rome-II; urban Bangladesh
3.  Reusable and Mediator-Free Cholesterol Biosensor Based on Cholesterol Oxidase Immobilized onto TGA-SAM Modified Smart Bio-Chips 
PLoS ONE  2014;9(6):e100327.
A reusable and mediator-free cholesterol biosensor based on cholesterol oxidase (ChOx) was fabricated based on self-assembled monolayer (SAM) of thioglycolic acid (TGA) (covalent enzyme immobilization by dropping method) using bio-chips. Cholesterol was detected with modified bio-chip (Gold/Thioglycolic-acid/Cholesterol-oxidase i.e., Au/TGA/ChOx) by reliable cyclic voltammetric (CV) technique at room conditions. The Au/TGA/ChOx modified bio-chip sensor demonstrates good linearity (1.0 nM to 1.0 mM; R = 0.9935), low-detection limit (∼0.42 nM, SNR∼3), and higher sensitivity (∼74.3 µAµM−1cm−2), lowest-small sample volume (50.0 μL), good stability, and reproducibility. To the best of our knowledge, this is the first statement with a very high sensitivity, low-detection limit, and low-sample volumes are required for cholesterol biosensor using Au/TGA/ChOx-chips assembly. The result of this facile approach was investigated for the biomedical applications for real samples at room conditions with significant assembly (Au/TGA/ChOx) towards the development of selected cholesterol biosensors, which can offer analytical access to a large group of enzymes for wide range of biomedical applications in health-care fields.
doi:10.1371/journal.pone.0100327
PMCID: PMC4065056  PMID: 24949733
4.  Analysis of Oxidative Stress Status, Catalase and Catechol-O-Methyltransferase Polymorphisms in Egyptian Vitiligo Patients 
PLoS ONE  2014;9(6):e99286.
Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT) and catechol-O-Methyltransferase (COMT) gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population.
doi:10.1371/journal.pone.0099286
PMCID: PMC4051781  PMID: 24915010
5.  Adapted motivational interviewing to improve the uptake of treatment for glaucoma in Nigeria: study protocol for a randomized controlled trial 
Trials  2014;15:149.
Background
Glaucoma is a chronic eye disease associated with irreversible visual loss. In Africa, glaucoma patients often present late, with very advanced disease. One-off procedures, such as laser or surgery, are recommended in Africa because of lack of or poor adherence to medical treatment. However, acceptance of surgery is usually extremely low. To prevent blindness, adherence to treatment needs to improve, using acceptable, replicable and cost-effective interventions. After reviewing the literature and interviewing patients in Bauchi (Nigeria) motivational interviewing (MI) was selected as the intervention for this trial, with adaptation for glaucoma (MIG). MI is designed to strengthen personal motivation for, and commitment to a specific goal by eliciting and exploring a person’s reasons for change within an atmosphere of acceptance and compassion. The aim of this study is to assess whether MIG increases the uptake of laser or surgery amongst glaucoma patients where this is the recommended treatment. The hypothesis is that MIG increases the uptake of treatment. This will be the first trial of MI in Africa.
Methods
This is a hospital based, single centre, randomized controlled trial of MIG plus an information sheet on glaucoma and its treatment (the latter being “standard care”) compared with standard care alone for glaucoma patients where the treatment recommended is surgery or laser.
Those eligible for the trial are adults aged 17 years and above who live within 200 km of Bauchi with advanced glaucoma where the examining ophthalmologist recommends surgery or laser. After obtaining written informed consent, participants will be randomly allocated to MIG plus standard care, or standard care alone. Motivational interviewing will be delivered in Hausa or English by one of two MIG trained personnel. One hundred and fifty participants will be recruited to each arm. The primary outcome is the proportion of participants undergoing laser or surgery within two months of the date given to re attend for the procedure. MIG quality will be assessed using the validated MI treatment integrity scale.
Discussion
Motivational interviewing may be an important tool to increase the acceptance of treatment for glaucoma. The approach is potentially scalable and may be useful for other chronic conditions in Africa.
Trial registration
ISRCTN79330571 (Controlled-Trials.com).
doi:10.1186/1745-6215-15-149
PMCID: PMC4021714  PMID: 24773760
Glaucoma; Motivational interviewing; Africa; Blindness; Treatment adherence; Randomized clinical trial
7.  A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors 
Purpose
As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer.
Methods
This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2–8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms.
Results
Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90 % confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90 % CI: −2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval.
Conclusions
Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.
doi:10.1007/s00280-012-2030-8
PMCID: PMC3899892  PMID: 23344712
Moxifloxacin; Pazopanib; Pharmacokinetics; QTc; Safety; Tyrosine kinase inhibitor
8.  Pretreatment of Gymnema sylvestre revealed the protection against acetic acid-induced ulcerative colitis in rats 
Background
Overproduction of free radicals and decreased antioxidant capacity are well-known risk factors for inflammatory bowel diseases. Gymnema sylvestre (GS) leaves extract is distinguished for its anti-diabetic, antioxidant and anti-inflammatory properties. Present study is designed to evaluate the preventative activities of GS against acetic acid (AA)-induced ulcerative colitis in Wistar rats.
Methods
Experimentally ulcerative colitis (UC) was induced by AA in animals pretreated with three different doses of GS leaves extract (50, 100, 200 mg/kg/day) and a single dose of mesalazine (MES, 300 mg/kg/day) for seven days. Twenty four hours later, animals were sacrificed and the colonic tissues were collected. Colonic mucus content was determined using Alcian blue dye binding technique. Levels of thiobarbituric acid reactive substances (TBARS), total glutathione sulfhydryl group (T-GSH) and non-protein sulfhydryl group (NPSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were estimated in colon tissues. Colonic nucleic acids (DNA and RNA) and total protein (TP) concentrations were also determined. Levels of pro-inflammatory cytokines including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) as well as prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated in colonic tissues. The histopathological changes of the colonic tissues were also observed.
Results
In AA administered group TBARS levels were increased, while colonic mucus content, T-GSH and NP-SH, SOD and CAT were reduced in colon. Pretreatment with GS inhibited TBARS elevation as well as mucus content, T-GSH and NP-SH reduction. Enzymatic activities of SOD and CAT were brought back to their normal levels in GS pretreated group. A significant reduction in DNA, RNA and TP levels was seen following AA administration and this inhibition was significantly eliminated by GS treatment. GS pretreatment also inhibited AA-induced elevation of pro-inflammatory cytokines, PGE2 and NO levels in colon. The apparent UC protection was further confirmed by the histopathological screening.
Conclusion
The GS leaves extract showed significant amelioration of experimentally induced colitis, which may be attributed to its anti-inflammatory and antioxidant property.
doi:10.1186/1472-6882-14-49
PMCID: PMC3922996  PMID: 24507431
Gymnema sylvestre; Inflammatory bowel diseases; Oxidative stress; Ulcerative colitis
9.  Multiple introductions of highly pathogenic avian influenza H5N1 viruses into Bangladesh 
Highly pathogenic H5N1 and low pathogenic H9N2 influenza viruses are endemic to poultry markets in Bangladesh and have cocirculated since 2008. H9N2 influenza viruses circulated constantly in the poultry markets, whereas highly pathogenic H5N1 viruses occurred sporadically, with peaks of activity in cooler months. Thirty highly pathogenic H5N1 influenza viruses isolated from poultry were characterized by antigenic, molecular, and phylogenetic analyses. Highly pathogenic H5N1 influenza viruses from clades 2.2.2 and 2.3.2.1 were isolated from live bird markets only. Phylogenetic analysis of the 30 H5N1 isolates revealed multiple introductions of H5N1 influenza viruses in Bangladesh. There was no reassortment between the local H9N2 influenza viruses and H5N1 genotype, despite their prolonged cocirculation. However, we detected two reassortant H5N1 viruses, carrying the M gene from the Chinese H9N2 lineage, which briefly circulated in the Bangladesh poultry markets and then disappeared. On the other hand, interclade reassortment occurred within H5N1 lineages and played a role in the genesis of the currently dominant H5N1 viruses in Bangladesh. Few ‘human-like' mutations in H5N1 may account for the limited number of human cases. Antigenically, clade 2.3.2.1 H5N1 viruses in Bangladesh have evolved since their introduction and are currently mainly homogenous, and show evidence of recent antigenic drift. Although reassortants containing H9N2 genes were detected in live poultry markets in Bangladesh, these reassortants failed to supplant the dominant H5N1 lineage.
doi:10.1038/emi.2014.11
PMCID: PMC3944120
Bangladesh; clades; H5N1; H9N2; live bird markets; phylogenetic tree; reassortment
10.  Nitrophenol Chemi-Sensor and Active Solar Photocatalyst Based on Spinel Hetaerolite Nanoparticles 
PLoS ONE  2014;9(1):e85290.
In this contribution, a significant catalyst based on spinel ZnMn2O4 composite nanoparticles has been developed for electro-catalysis of nitrophenol and photo-catalysis of brilliant cresyl blue. ZnMn2O4 composite (hetaerolite) nanoparticles were prepared by easy low temperature hydrothermal procedure and structurally characterized by X-ray powder diffraction (XRD), field emission scanning electron microscopy (FESEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) and UV-visible spectroscopy which illustrate that the prepared material is optical active and composed of well crystalline body-centered tetragonal nanoparticles with average size of ∼38±10 nm. Hetaerolite nanoparticles were applied for the advancement of a nitrophenol sensor which exhibited high sensitivity (1.500 µAcm−2 mM−1), stability, repeatability and lower limit of detection (20.0 µM) in short response time (10 sec). Moreover, hetaerolite nanoparticles executed high solar photo-catalytic degradation when applied to brilliant cresyl blue under visible light.
doi:10.1371/journal.pone.0085290
PMCID: PMC3897427  PMID: 24465525
11.  Oral Rehabilitation of Parkinson's Disease Patient: A Review and Case Report 
Case Reports in Dentistry  2014;2014:432475.
Parkinson's disease is usually seen in adults in their middle and late ages. Most people with this disease are less likely to opt for dental treatments unless it is an acute condition. Tremors caused by Parkinson's disease can make dental appointments, especially prolonged treatments, a challenge. The case presented here was successfully treated with an immediate denture for the partially edentulous maxillary and mandibular arches. Early morning brief appointments were given for the procedure. Patient was instructed to take the prescribed parkinsonism medications 60 to 90 minutes before the appointment to utilize the advantage of its peak response. Sympathetic and caring approach towards the patient was employed to reduce his anxiety during the procedures. Some modification of technics and materials was adopted to suit the special situation.
doi:10.1155/2014/432475
PMCID: PMC3914341  PMID: 24551462
12.  OncomiRdbB: a comprehensive database of microRNAs and their targets in breast cancer 
BMC Bioinformatics  2014;15:15.
Background
Given the estimate that 30% of our genes are controlled by microRNAs, it is essential that we understand the precise relationship between microRNAs and their targets. OncomiRs are microRNAs (miRNAs) that have been frequently shown to be deregulated in cancer. However, although several oncomiRs have been identified and characterized, there is as yet no comprehensive compilation of this data which has rendered it underutilized by cancer biologists. There is therefore an unmet need in generating bioinformatic platforms to speed the identification of novel therapeutic targets.
Description
We describe here OncomiRdbB, a comprehensive database of oncomiRs mined from different existing databases for mouse and humans along with novel oncomiRs that we have validated in human breast cancer samples. The database also lists their respective predicted targets, identified using miRanda, along with their IDs, sequences, chromosome location and detailed description. This database facilitates querying by search strings including microRNA name, sequence, accession number, target genes and organisms. The microRNA networks and their hubs with respective targets at 3'UTR, 5'UTR and exons of different pathway genes were also deciphered using the 'R' algorithm.
Conclusion
OncomiRdbB is a comprehensive and integrated database of oncomiRs and their targets in breast cancer with multiple query options which will help enhance both understanding of the biology of breast cancer and the development of new and innovative microRNA based diagnostic tools and targets of therapeutic significance. OncomiRdbB is freely available for download through the URL link http://tdb.ccmb.res.in/OncomiRdbB/index.htm.
doi:10.1186/1471-2105-15-15
PMCID: PMC3926854  PMID: 24428888
MicroRNAs; Breast cancer; Targets; 3'UTR; miRanda; TLDA
13.  Fabrication of Smart Chemical Sensors Based on Transition-Doped-Semiconductor Nanostructure Materials with µ-Chips 
PLoS ONE  2014;9(1):e85036.
Transition metal doped semiconductor nanostructure materials (Sb2O3 doped ZnO microflowers, MFs) are deposited onto tiny µ-chip (surface area, ∼0.02217 cm2) to fabricate a smart chemical sensor for toxic ethanol in phosphate buffer solution (0.1 M PBS). The fabricated chemi-sensor is also exhibited higher sensitivity, large-dynamic concentration ranges, long-term stability, and improved electrochemical performances towards ethanol. The calibration plot is linear (r2 = 0.9989) over the large ethanol concentration ranges (0.17 mM to 0.85 M). The sensitivity and detection limit is ∼5.845 µAcm−2mM−1 and ∼0.11±0.02 mM (signal-to-noise ratio, at a SNR of 3) respectively. Here, doped MFs are prepared by a wet-chemical process using reducing agents in alkaline medium, which characterized by UV/vis., FT-IR, Raman, X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (XRD), and field-emission scanning electron microscopy (FE-SEM) etc. The fabricated ethanol chemical sensor using Sb2O3-ZnO MFs is simple, reliable, low-sample volume (<70.0 µL), easy of integration, high sensitivity, and excellent stability for the fabrication of efficient I–V sensors on μ-chips.
doi:10.1371/journal.pone.0085036
PMCID: PMC3890290  PMID: 24454785
14.  ALTERED BLOOD SPHINGOLIPIDOMICS AND ELEVATED PLASMA INFLAMMATORY CYTOKINES IN COMBAT VETERANS WITH POST-TRAUMATIC STRESS DISORDER 
Patients with post-traumatic stress disorder (PTSD) have greater risk of developing cardiovascular disease (CVD). While chronically elevated plasma cholesterol and pro-inflammatory cytokines levels increase CVD risk, several studies have shown that cholesterol reduction does not reduce CVD risk. Acid sphingomyelinase (ASMase) activation has been implicated in both CVD and major depressive disorder. We investigated plasma pro-inflammatory cytokine levels, ASMase activity, and changes in sphingolipids in PTSD patients compared to healthy controls. Levels of interleukin 6, interleukin 10, interferon-γ and tumor necrosis factor-α were higher in PTSD patients than controls. Plasma ASMase activity and sphingosine 1-phosphate were higher in the PTSD group (1.6-fold and 2-fold, respectively; p<0.05). The results suggest that CVD risk factors in PTSD patients remain high despite cholesterol reduction.
PMCID: PMC3882130  PMID: 24403911
15.  Aberrant p16INK4A methylation: Relation to viral related chronic liver disease and hepatocellular carcinoma 
Background:
Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer related deaths. Several studies have shown that the tumor suppressor gene p16INK4A is frequently downregulated by aberrant methylation of the 5’-cytosine-phosphoguanine island within the promoter region.
Aim:
To find out the frequency of methylated p16INK4A in the peripheral blood of HCC and cirrhotic patients and to evaluate its role in hepatocarcinogenesis.
Patients and Methods:
This study was performed on 58 subjects: 30 HCC patients, 20 cirrhotic patients, and eight healthy volunteers. Methylation of p16INK4A was examined using methylation specific polymerase chain reaction (PCR) (MSP). Comparison of quantitative variables between the study groups was done using Mann-Whitney U test for independent samples when not normally distributed. For comparing categorical data, Chi-square (χ2) test was performed. Exact test was used instead when the expected frequency was less than 5.
Results:
Methylation of p16INK4A was found in 6.7% of HCC patients, 5% of liver cirrhosis (LC) patients, and none of the healthy volunteers; 66.67% of the p16INK4A-methylated cases (2/3) were positive for anti-hepatitis C virus (HCV) antibodies (one of them had HCC). All HCC cases with aberrant p16INK4A methylation show very high serum alpha fetoprotein (AFP) level (9,080; 30,000 μg/mL). There were no significant associations between the status of p16INK4A methylation and tumor size.
Conclusion:
Hypermethylation of p16INK4A was found to be infrequent among Egyptian patients with HCC.
doi:10.4103/2278-330X.126498
PMCID: PMC3961859  PMID: 24665436
Hepatocellular carcinoma; methylation; p16INK4A
16.  Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway 
Introduction
The existence of breast cancer stem-like cells (BCSCs) has profound implications for cancer prevention. Genistein, a predominant isoflavone found in soy products, has multiple robust anti-tumor effects in various cancers, especially in the breast and prostate cancer. In this study, we aimed to evaluate genistein inhibition of BCSCs and its potential mechanism by culturing MCF-7 breast cancer cells and implanting these cells into nude mice.
Methods
Cell counting, colony formation and cell apoptosis analysis were used to evaluate the effect of genistein on breast cancer cells’ growth, proliferation and apoptosis. We then used mammosphere formation assay and CD44CD24 staining to evaluate the effect of genistein on BCSCs in vitro. A nude mice xenograft model was employed to determine whether genistein could target BCSCs in vivo, as assessed by real-time polymerase chain reaction (PCR) and immunohistochemical staining. The potential mechanism was investigated utilizing real-time PCR, western blotting analysis and immunohistochemical staining.
Results
Genistein inhibited the MCF-7 breast cancer cells’ growth and proliferation and promoted apoptosis. Both in vitro and in vivo genistein decreased breast cancer stem cells, and inhibited breast cancer stem-like cells through down-regulation of the Hedgehog-Gli1 Signaling Pathway.
Conclusions
We demonstrated for the first time that genistein inhibits BCSCs by down-regulating Hedgehog-Gli1 signaling pathway. These findings provide support and rationale for investigating the clinical application of genistein in treating breast cancer, and specifically by targeting breast cancer stem cells.
doi:10.1186/scrt357
PMCID: PMC4054948  PMID: 24331293
17.  Former Mucinous Bronchioloalveolar Carcinoma Revisited 
Case Reports in Medicine  2013;2013:284323.
This is a brief case report of invasive multicentric mucinous adenocarcinoma presented at a rather young age with bronchorrhea and persistent consolidation that ended up with the patient demise; nevertheless, we demonstrate relevant radiological and pathological features with emphasis on the new classification of bronchioloalveolar carcinoma, a term that should no longer be in use.
doi:10.1155/2013/284323
PMCID: PMC3863513  PMID: 24369471
18.  Epidemiology of Antituberculosis Drug Resistance in Saudi Arabia: Findings of the First National Survey 
The real magnitude of antituberculosis (anti-TB) drug resistance in Saudi Arabia is still unknown because the available data are based on retrospective laboratory studies that were limited to hospitals or cities. A representative national survey was therefore conducted to investigate the levels and patterns of anti-TB drug resistance and explore risk factors. Between August 2009 and July 2010, all culture-positive TB patients diagnosed in any of the tuberculosis reference laboratories of the country were enrolled. Isolates obtained from each patient were tested for susceptibility to first-line anti-TB drugs by the automated Bactec MGIT 960 method. Of the 2,235 patients enrolled, 75 cases (3.4%) were lost due to culture contamination and 256 (11.5%) yielded nontuberculous mycobacteria (NTM). Finally, 1,904 patients (85.2% of those enrolled) had available drug susceptibility testing results. Monoresistance to streptomycin (8.1%; 95% confidence interval [CI], 7.2 to 9.1), isoniazid (5.4%; 95% CI, 4.7 to 6.2), rifampin (1%; 95% CI, 0.7 to 1.3) and ethambutol (0.8%; 95% CI, 0.5 to 1.2) were observed. Multidrug-resistant TB (MDR-TB) was found in 1.8% (95% CI, 1.4 to 2.4) and 15.9% (95% CI, 15.4 to 16.5) of new and previously treated TB cases, respectively. A treatment history of active TB, being foreign-born, having pulmonary TB, and living in the Western part of the country were the strongest independent predictors of MDR-TB. Results from the first representative national anti-TB drug resistance survey in Saudi Arabia suggest that the proportion of MDR-TB is relatively low, though there is a higher primary drug resistance. A strengthened continuous surveillance system to monitor trends over time and second-line anti-TB drug resistance as well as implementation of innovative control measures, particularly among immigrants, is warranted.
doi:10.1128/AAC.02403-12
PMCID: PMC3632946  PMID: 23459478
19.  Interaction of HIF-1α and Notch3 Is Required for the Expression of Carbonic Anhydrase 9 in Breast Carcinoma Cells 
Genes & Cancer  2013;4(11-12):513-523.
Expression of carbonic anhydrase 9 (CA9) is associated with poor prognosis and increased tumor aggressiveness and does not always correlate with HIF-1α expression. Presently, we analyzed the regulation of CA9 expression during hypoxia by HIF-1α, Notch3, and the von Hippel-Lindau (VHL) in breast carcinoma cells. Both HIF-1α and Notch3 were absolutely required for the expression of CA9 mRNA, protein, and reporter. Reciprocal co-immunoprecipitation of HIF-1α, Notch3 intracellular domain (NICD3), and pVHL demonstrated their association. The presence of common consensus prolyl hydroxylation and pVHL binding motifs (L(XY)LAP);LLPLAP2191 suggested an oxygen-dependent regulation for NICD3. However, unlike the HIF-1α protein, NICD3 protein levels were not modulated with hypoxia or hypoxia-mimetic agents. Surprisingly, mutations of the common prolyl hydroxylation and pVHL binding domain lead to the loss of CA9 mRNA, protein, and reporter activity. Chromatin immunoprecipitation assay demonstrated the association of NICD3, HIF-1α, and pVHL at the CA9 promoter. Further, the NICD3 mutant defective in prolyl hydroxylation and subsequent pVHL binding caused a reduction in cell proliferation of breast carcinoma cells. We show here for the first time that the interaction of HIF-1α with NICD3 is important for the regulation of CA9 expression. These findings suggest that although CA9 is a hypoxia-responsive gene, its expression is modulated by the interaction of HIF-1α, Notch3, and VHL proteins. Targeting the expression of CA9 by targeting upstream regulators could be useful in cancer/stem cell therapy.
doi:10.1177/1947601913481670
PMCID: PMC3877659  PMID: 24386511
hypoxia; Notch3; CA9; PBX1; VHL
20.  Microstructural Evolution during DPRM Process of Semisolid Ledeburitic D2 Tool Steel 
The Scientific World Journal  2013;2013:828926.
Semisolid metal processing is a relatively new technology that offers several advantages over liquid processing and solid processing because of the unique behaviour and characteristic microstructure of metals in this state. With the aim of finding a minimum process chain for the manufacture of high-quality production at minimal cost for forming, the microstructural evolution of the ledeburitic AISI D2 tool steel in the semisolid state was studied experimentally. The potential of the direct partial remelting (DPRM) process for the production of AISI D2 with a uniform globular microstructure was revealed. The liquid fraction was determined using differential scanning calorimetry. The microstructures of the samples were investigated using an optical microscope and a scanning electron microscope equipped with an energy dispersive spectroscopy analyser, while X-ray phase analysis was performed to identify the phase evolution and the type of carbides. Mechanical characterisation was completed by hardness measurements. The typical microstructure after DPRM consists of metastable austenite which was located particularly in the globular grains (average grain size about 50 μm), while the remaining interspaces were filled by precipitated eutectic carbides on the grain boundaries and lamellar network.
doi:10.1155/2013/828926
PMCID: PMC3808712  PMID: 24223510
21.  A PEPTIDE ANTAGONIST DISRUPTS NATURAL KILLER CELL INHIBITORY SYNAPSE FORMATION1 
Productive engagement of MHC Class I by inhibitory NK cell receptors depends on the peptide bound by the MHC class I molecule. Peptide:MHC complexes that bind weakly to killer cell immunoglobulin-like receptors (KIR) can antagonize the inhibition mediated by high affinity peptide:MHC complexes and cause NK cell activation. We show that low affinity peptide:MHC complexes stall inhibitory signalling at the step of SHP-1 recruitment and do not go on to form the KIR microclusters induced by high affinity peptide:MHC, which are associated with Vav dephosphorylation and downstream signalling. Furthermore the low affinity peptide:MHC complexes prevented the formation of KIR microclusters by high affinity peptide:MHC. Thus peptide antagonism of NK cells is an active phenomenon of inhibitory synapse disruption.
doi:10.4049/jimmunol.1201032
PMCID: PMC3672982  PMID: 23382564
22.  Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats 
AIM: To evaluate the ameliorative effect of naringenin (NG) during ulcerative colitis (UC) in rats.
METHODS: Rats were treated with three different doses (25, 50 and 100 mg/kg per day) of NG and a single dose of mesalazine (MES, 300 mg/kg per day) for seven days prior to ulcerative colitis induction by 4% acetic acid (AA). Twenty four hours after AA rectal administration, animals were scarified and the colonic tissues were dissected. Colonic mucus content was estimated using Alcian blue dye binding technique. In colon tissues, levels of total glutathione sulphadryls (T-GSH), non-protein sulphadryls (NP-SH) and thiobarbituric acid reactive substances (TBARS) were evaluated. The activities of the antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD) were measured. Concentrations of nucleic acids (DNA and RNA) and total protein were also estimated in colon tissues. Colonic levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated. In cross section of colitis tissue the histopathological changes were observed.
RESULTS: Colonic mucus content was decreased in AA compared to controls (587.09 ± 65.59 mg/kg vs 941.78 ± 68.41 mg/kg, P < 0.001). AA administration markedly reduced T-GSH (5.25 ± 0.37 nmol/L vs 3.04 ± 0.24 nmol/L, P < 0.01), NP-SH (3.16 ± 0.04 nmol/L vs 2.16 ± 0.30 nmol/L, P < 0.01), CAT (6.77 ± 0.40 U/mg vs 3.04 ± 0.2 U/mg, P < 0.01) and SOD (3.10 ± 0.11 U/mg vs 1.77 ± 0.18 U/mg, P < 0.01) while TBARS, TNF-α, IL-1β, IL-6, PGE2 and NO levels (15.09 ± 3.84 nmol/L vs 59.90 ± 16.34 nmol/L, P < 0.01; 113.56 ± 1.91 pg/mg vs 134.24 ± 4.77 pg/mg, P < 0.01; 209.20 ± 36.38 pg/mg vs 422.19 ± 31.47 pg/mg, P < 0.01; 250.83 ± 25.09 pg/mg vs 638.58 ± 115.9 pg/mg, P < 0.01; 248.19 ± 36.98 pg/mg vs 541.74 ± 58.34 pg/mg, P < 0.01 and 81.26 ± 2.98 mmol/g vs 101.90 ± 10.73 mmol/g, P < 0.001) were increased in colon of rats with UC compared controls respectively.Naringenin supplementation, significantly and dose dependently increased the colonic mucus content. The elevated TBARS levels were significantly decreased (39.35 ± 5.86 nmol/L, P < 0.05; 26.74 ± 3.17 nmol/L, P < 0.01 nmol/L and 17.74 ± 2.69 nmol/L, P < 0.01) compared to AA (59.90 ± 16.34 nmol/L) group while the decreased levels of T-GSH and NP-SH and activities of CAT and SOD found increased by NG treatments in dose dependent manner. The decreased values of nucleic acids and total protein in AA group were also significantly (P < 0.01) increased in all three NG supplemented groups respectively. NG pretreatment inhibited the TNF-α levels (123.76 ± 3.76 pg/mg, 122.62 ± 3.41 pg/mg and 121.51 ± 2.61 pg/mg vs 134.24 ± 4.78 pg/mg, P < 0.05) compared to AA group, respectively. Interleukins, IL-1β and IL-6 levels were also decreased in NG50 + AA (314.37 ± 16.31 pg/mg and 292.58 ± 23.68 pg/mg, P < 0.05) and NG100 + AA (416.72 ± 49.62 pg/mg and 407.96 ± 43.87 pg/mg, P < 0.05) when compared to AA (352.46 ± 8.58 pg/mg and 638.58 ± 115.98 pg/mg) group. Similar decrease (P < 0.05) was seen in PGE2 and NO values when compared to AA group. The group pretreated with MES, as a reference drug, showed significant (P < 0.01) protection against the changes induced in colon tissue by AA administration respectively.
CONCLUSION: In present study, NG produced antioxidant and anti-inflammatory effects demonstrating protective effect in inflammatory bowel disease.
doi:10.3748/wjg.v19.i34.5633
PMCID: PMC3769899  PMID: 24039355
Naringenin; Ulcerative colitis; Inflammatory bowel disease; Oxidative stress
23.  Semisolid Metal Processing Techniques for Nondendritic Feedstock Production 
The Scientific World Journal  2013;2013:752175.
Semisolid metal (SSM) processing or thixoforming is widely known as a technology that involves the formation of metal alloys between solidus and liquidus temperatures. For the procedure to operate successfully, the microstructure of the starting material must consist of solid near-globular grains surrounded by a liquid matrix and a wide solidus-to-liquidus transition area. Currently, this process is industrially successful, generating a variety of products with high quality parts in various industrial sectors. Throughout the years since its inception, a number of technologies to produce the appropriate globular microstructure have been developed and applied worldwide. The main aim of this paper is to classify the presently available SSM technologies and present a comprehensive review of the potential mechanisms that lead to microstructural alterations during the preparation of feedstock materials for SSM processing.
doi:10.1155/2013/752175
PMCID: PMC3782119  PMID: 24194689
24.  Green material: ecological importance of imperative and sensitive chemi-sensor based on Ag/Ag2O3/ZnO composite nanorods 
Nanoscale Research Letters  2013;8(1):380.
In this report, we illustrate a simple, easy, and low-temperature growth of Ag/Ag2O3/ZnO composite nanorods with high purity and crystallinity. The composite nanorods were structurally characterized by field emission scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy which confirmed that synthesized product have rod-like morphology having an average cross section of approximately 300 nm. Nanorods are made of silver, silver oxide, and zinc oxide and are optically active having absorption band at 375 nm. The composite nanorods exhibited high sensitivity (1.5823 μA.cm−2.mM−1) and lower limit of detection (0.5 μM) when applied for the recognition of phenyl hydrazine utilizing I-V technique. Thus, Ag/Ag2O3/ZnO composite nanorods can be utilized as a redox mediator for the development of highly proficient phenyl hydrazine sensor.
doi:10.1186/1556-276X-8-380
PMCID: PMC3846800  PMID: 24011288
Composite nanorods; Structural properties; Optical properties; Phenyl hydrazine sensing
25.  Meis1 regulates Foxn4 expression during retinal progenitor cell differentiation 
Biology Open  2013;2(11):1125-1136.
Summary
The transcription factor forkhead box N4 (Foxn4) is a key regulator in a variety of biological processes during development. In particular, Foxn4 plays an essential role in the genesis of horizontal and amacrine neurons from neural progenitors in the vertebrate retina. Although the functions of Foxn4 have been well established, the transcriptional regulation of Foxn4 expression during progenitor cell differentiation remains unclear. Here, we report that an evolutionarily conserved 129 bp noncoding DNA fragment (Foxn4CR4.2 or CR4.2), located ∼26 kb upstream of Foxn4 transcription start site, functions as a cis-element for Foxn4 regulation. CR4.2 directs gene expression in Foxn4-positive cells, primarily in progenitors, differentiating horizontal and amacrine cells. We further determined that the gene regulatory activity of CR4.2 is modulated by Meis1 binding motif, which is bound and activated by Meis1 transcription factor. Deletion of the Meis1 binding motif or knockdown of Meis1 expression abolishes the gene regulatory activity of CR4.2. In addition, knockdown of Meis1 expression diminishes the endogenous Foxn4 expression and affects cell lineage development. Together, we demonstrate that CR4.2 and its interacting Meis1 transcription factor play important roles in regulating Foxn4 expression during early retinogenesis. These findings provide new insights into molecular mechanisms that govern gene regulation in retinal progenitors and specific cell lineage development.
doi:10.1242/bio.20132279
PMCID: PMC3828759  PMID: 24244849
Enhancer; Foxn4; Meis1; Retinal progenitor; Horizontal cell; Amacrine cell

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