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1.  Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women 
Human Reproduction (Oxford, England)  2013;28(4):1135-1143.
Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry?
Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner.
Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women.
We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche.
For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10−6, binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile.
Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results.
This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare.
PMCID: PMC3600840  PMID: 23406970
menarche; genome-wide association study; genetics; reproductive endocrinology
2.  Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies 
Annals of Oncology  2012;24(4):1079-1087.
Epidemiological studies have reported inconsistent associations between cruciferous vegetable (CV) intake and colorectal cancer (CRC) risk. To our knowledge, a comprehensive and quantitative assessment of the association between CV intake and CRC has not been reported.
Relevant articles were identified by searching MEDLINE. We pooled the relative risks (RR) from individual studies using a random-effect model and carried out heterogeneity and publication bias analyses.
Twenty-four case–control and 11 prospective studies were included in our analysis. When all studies were pooled, we yielded a significantly inverse association between CV (RR: 0.82; 95% confidence interval 0.75–0.90) intake and CRC risk. Specific analysis for cabbage and broccoli yielded similar result. When separately analyzed, case–control studies of CV intake yield similar results, and the results from the prospective studies showed borderline statistical significance. Moreover, significant inverse associations were also observed in colon cancer and its distal subsite both among prospective and case–control studies.
Findings from this meta-analysis provide evidence that high intake of CV was inversely associated with the risk of CRC and colon cancer in humans. Further analysis on other specific CV, food preparation methods, stratified results by anatomic cancer site, and subsite of colon cancer should be extended in future study.
PMCID: PMC3603442  PMID: 23211939
colorectal cancer; cruciferous vegetables; dietary; epidemiology; meta-analysis
3.  Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells 
Disease Models & Mechanisms  2014;7(3):351-362.
Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.
PMCID: PMC3944495  PMID: 24487409
NCU-G1; Lysosome; Fibrosis
4.  The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium 
British Journal of Cancer  2013;108(3):727-734.
Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes.
We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28 829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma.
Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)⩾30 vs BMI<25 kg m−2 (OR: 1.73, 95% CI: 1.22–2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41–3.83). Older age at menarche was inversely associated with uterine sarcoma risk (⩾15 years vs <11 years (OR: 0.70, 95% CI: 0.34–1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82–3.26) or MMMTs (OR: 2.25, 95% CI: 1.60–3.15, P-heterogeneity=0.01).
In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.
PMCID: PMC3593566  PMID: 23348519
risk factors; uterine sarcoma; pooled analysis; obesity; diabetes
5.  On the Age of Leprosy 
Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae and the newly discovered Mycobacterium lepromatosis. Human leprosy has been documented for millennia in ancient cultures. Recent genomic studies of worldwide M. leprae strains have further traced it along global human dispersals during the past ∼100,000 years. Because leprosy bacilli are strictly intracellular, we wonder how long humans have been affected by this disease-causing parasite. Based on recently published data on M. leprae genomes, M. lepromatosis discovery, leprosy bacilli evolution, and human evolution, it is most likely that the leprosy bacilli started parasitic evolution in humans or early hominids millions of years ago. This makes leprosy the oldest human-specific infection. The unique adaptive evolution has likely molded the indolent growth and evasion from human immune defense that may explain leprosy pathogenesis. Accordingly, leprosy can be viewed as a natural consequence of a long parasitism. The burden of leprosy may have affected minor selection on human genetic polymorphisms.
PMCID: PMC3923669  PMID: 24551248
6.  Dietary glycemic load, glycemic index, and carbohydrates on the risk of primary liver cancer among Chinese women and men 
Annals of Oncology  2012;24(1):238-244.
Dietary glycemic index (GI) and glycemic load (GL) typically have a positive relationship with obesity and diabetes, which are risk factors for liver cancer. However, studies on their association with liver cancer have yielded inconsistent results. Therefore, we assessed the association of GI, GL, and carbohydrates with liver cancer risk.
Patients and methods
A total of 72 966 women and 60 207 men from the Shanghai Women's Health Study (SWHS) and the Shanghai Men's Health Study (SMHS) were included for analysis. Food frequency questionnaire (FFQ) data were used to calculate daily dietary GI, GL, and carbohydrate intake. These values were energy adjusted and categorized into quintiles. The hazard ratios (HRs) and 95% confidence intervals (CI) were calculated with adjustment for potential confounders.
After a median follow-up time of 11.2 years for the SWHS and 5.3 years for the SMHS, 139 and 208 incident liver cancer cases were identified in the SWHS and SMHS, respectively. In multivariable Cox regression models, no statistically significant trends by quintile of GI, GL, or carbohydrate intake were observed. Stratification by chronic liver disease/hepatitis, diabetes, or body mass index (BMI) did not alter the findings.
There is little evidence that dietary GI, GL, or carbohydrates affect the incidence of liver cancer in this Asian population.
PMCID: PMC3525137  PMID: 22898034
Chinese men and women; cohort study; diet; glycemic index; glycemic load; primary liver cancer
7.  Severe Leprosy Reactions Due to Mycobacterium lepromatosis 
Leprosy is caused by the well known Mycobacterium leprae and the newly discovered Mycobacterium lepromatosis. We describe here 2 cases of leprosy with unusual clinical presentation caused by M. lepromatosis. The patients, a 32-year-old man and a 50-year-old woman, both of Mexican origin, manifested high fever, lymphadenopathy, and florid skin lesions in the form of erythema nodosum and Lucio’s phenomenon as the first clinical presentation. Heavy infiltration of acid-fast bacilli was identified in the tissues that led to the diagnosis of lepromatous leprosy or diffuse leprosy. The patients were treated with multi-drug regimen and responded appropriately. From the lymph node tissue, we showed the bacillus to be M. lepromatosis, not M. leprae as presumed previously, by using differential polymerase chain reactions and analysis of gene sequences. These cases add to the growing studies on this organism, expand its endemic regions in Mexico, and provide more clinical insight.
PMCID: PMC3529828  PMID: 23111393
Leprosy; diffuse lepromatosis leprosy; Lucio’s phenomenon; erythema nodosum; Mycobacterium lepromatosis
8.  Meat consumption and risk of lung cancer: evidence from observational studies 
Annals of Oncology  2012;23(12):3163-3170.
A number of epidemiological studies have reported inconsistent findings on the association between meat consumption and lung cancer.
We therefore conducted a systematic review and meta-analysis to investigate the relationship between meat consumption and lung cancer risk in epidemiological studies.
Twenty-three case–control and 11 cohort studies were included. All studies adjusted for smoking or conducted in never smokers. The summary relative risks (RRs) of lung cancer for the highest versus lowest intake categories were 1.35 (95% confidence interval (CI) 1.08–1.69) for total meat, 1.34 (95% CI 1.18–1.52) for red meat, and 1.06 (95% CI 0.90–1.25) for processed meat. An inverse association was found between poultry intake and lung cancer (RR = 0.91, 95% CI 0.85–0.97), but not for total white meat (RR = 1.06, 95% CI 0.82–1.37) or fish (RR = 1.01, 95% CI 0.96–1.07).
The relationship between meat intake and lung cancer risk appears to depend on the types of meat consumed. A high intake of red meat may increase the risk of lung cancer by about 35%, while a high intake of poultry decreases the risk by about 10%. More well-designed cohort studies on meat mutagens or heme iron, meat cooking preferences, and doneness level are needed to fully characterize this meat–lung cancer association.
PMCID: PMC3501234  PMID: 22855553
case–control study; cohort study; lung cancer; meat consumption; meta-analysis
9.  Superficial parotid lobe–sparing delineation approach: a better method of dose optimization to protect the parotid gland in intensity-modulated radiotherapy for nasopharyngeal carcinoma 
Current Oncology  2013;20(6):e577-e584.
We used a superficial parotid lobe–sparing delineation approach for dose optimization with better protection for the parotid glands in intensity-modulated radiotherapy (imrt) for nasopharyngeal carcinoma (npc) patients.
Compared with traditional contouring of the entire parotid glands as organs at risk (oars) in imrt for npc, we used a superficial parotid lobe–sparing delineation approach of contouring the superficial parotid lobes as oars. Changes in dose to the parotid glands, the targets, and other oars were evaluated.
The mean dose to the parotid glands overall decreased by more than 4 Gy in the test plans. Impressively, the mean dose to the superficial parotid lobes in the test plans was not more than 30 Gy, regardless of clinical stage. In T1–3 npc patients, the dose distributions for targets were not significantly different in the control plans and the test plans. However, for some T4 patients, the dose distributions for targets and brainstem in the test plans could not meet clinical requirements.
The superficial parotid lobe–sparing delineation approach can significantly lower the mean dose to the entire parotid and to the superficial parotid lobe in T1–3 npc patients, which would be expected to result in less xerostomia and better quality of life for those patients.
PMCID: PMC3851355  PMID: 24311959
Intensity-modulated radiotherapy; nasopharyngeal carcinoma; superficial parotid lobes
10.  Dissection of the TssB-TssC Interface during Type VI Secretion Sheath Complex Formation 
PLoS ONE  2013;8(11):e81074.
The Type VI secretion system (T6SS) is a versatile machine that delivers toxins into either eukaryotic or bacterial cells. At a molecular level, the T6SS is composed of a membrane complex that anchors a long cytoplasmic tubular structure to the cell envelope. This structure is thought to resemble the tail of contractile bacteriophages. It is composed of the Hcp protein that assembles into hexameric rings stacked onto each other to form a tube similar to the phage tail tube. This tube is proposed to be wrapped by a structure called the sheath, composed of two proteins, TssB and TssC. It has been shown using fluorescence microscopy that the TssB and TssC proteins assemble into a tubular structure that cycles between long and short conformations suggesting that, similarly to the bacteriophage sheath, the T6SS sheath undergoes elongation and contraction events. The TssB and TssC proteins have been shown to interact and a specific α-helix of TssB is required for this interaction. Here, we confirm that the TssB and TssC proteins interact in enteroaggregative E. coli. We further show that this interaction requires the N-terminal region of TssC and the conserved α-helix of TssB. Using site-directed mutagenesis coupled to phenotypic analyses, we demonstrate that an hydrophobic motif located in the N-terminal region of this helix is required for interaction with TssC, sheath assembly and T6SS function.
PMCID: PMC3840085  PMID: 24282569
11.  The Leprosy Agents Mycobacterium lepromatosis and Mycobacterium leprae in Mexico 
Mycobacterium leprae was the only known cause of leprosy until 2008, when a new species, named Mycobacterium lepromatosis, was found to cause diffuse lepromatous leprosy (DLL), a unique form of leprosy endemic in Mexico.
We sought to differentiate the leprosy agents among 120 Mexican patients with various clinical forms of leprosy and to compare their relative prevalence and disease features. Archived skin biopsy specimens from these patients were tested for both M. leprae and M. lepromatosis using polymerase chain reaction-based species-specific assays.
Eighty-seven (72.5%) patients were confirmed for etiologic species, including 55 with M. lepromatosis, 18 with M. leprae, and 14 with both organisms. The endemic regions of each agent differed but overlapped. Patients with M. lepromatosis were younger and from more states, and their clinical diagnoses included 13 DLL, 34 lepromatous leprosy (LL), and eight other forms of leprosy. By contrast, the diagnoses of patients with M. leprae included none DLL, 15 LL and three other forms. Thus, M. lepromatosis caused DLL specifically (p=0.023). Patients with M. lepromatosis also showed more variable skin lesions and the extremities were the commonest biopsy sites. Finally, patients with dual infections manifested all clinical forms and accounted for 16.1% of all species-confirmed cases.
M. lepromatosis is another cause of leprosy and is probably more prevalent than M. leprae in Mexico. It mainly causes LL and also specifically DLL. Dual infections caused by both species may occur in endemic area.
PMCID: PMC3397401  PMID: 22788812
leprosy; diffuse lepromatous leprosy; Lucio’s phenomenon; Mycobacterium lepromatosis; Mycobacterium leprae
12.  Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine—a pooled analysis of over 500 000 subjects in the Asia Cohort Consortium 
Annals of Oncology  2011;23(7):1894-1898.
The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case–control studies from Europe and United States.
Subjects and methods
We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500 000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking.
A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI >27.5 kg/m2, compared with 22.6–25.0, 1.50; 95% confidence interval (CI) 0.76–2.96]. No association was suggested for tobacco smoking; men drinking >400 g of ethanol per week had an HR of 1.57 (95% CI 0.66–3.70), compared with abstainers.
Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.
PMCID: PMC3493138  PMID: 22147734
alcohol drinking; body mass index; prospective studies; small intestine cancer; tobacco smoking
13.  Expression of a Yersinia pseudotuberculosis Type VI Secretion System Is Responsive to Envelope Stresses through the OmpR Transcriptional Activator 
PLoS ONE  2013;8(6):e66615.
The Type VI secretion system (T6SS) is a macromolecular complex widespread in Gram-negative bacteria. Although several T6SS are required for virulence towards host models, most are necessary to eliminate competitor bacteria. Other functions, such as resistance to amoeba predation, biofilm formation or adaptation to environmental conditions have also been reported. This multitude of functions is reflected by the large repertoire of regulatory mechanisms shown to control T6SS expression, production or activation. Here, we demonstrate that one T6SS gene cluster encoded within the Yersinia pseudotuberculosis genome, T6SS-4, is regulated by OmpR, the response regulator of the two-component system EnvZ-OmpR. We first identified OmpR in a transposon mutagenesis screen. OmpR does not control the expression of the four other Y. pseudotuberculosis T6SS gene clusters and of an isolated vgrG gene, and responds to osmotic stresses to bind to and activate the T6SS-4 promoter. Finally, we show that T6SS-4 promotes Y. pseudotuberculosis survival in high osmolarity conditions and resistance to deoxycholate.
PMCID: PMC3686713  PMID: 23840509
15.  Evaluation of the IMMULITE® 2000 CMV IgM assay 
Herpesviridae  2012;3:2.
Diagnosis of cytomegalovirus (CMV) infection is challenging because of the high rate of asymptomatic infection and the low specificity of associated symptoms and signs. As a result, laboratory testing is an essential aid in making an accurate diagnosis. The presence of CMV IgM is indicative of primary CMV infection. In pregnancy, diagnosis of primary infection is important because primary maternal infection increases fetal infection risk substantially. Fetal infection can result in serious sequelae ranging from neurological deficits to death. Diagnosis among the immunocompromised is also critical for the timely initiation of therapy that can reduce morbidity and mortality risk.
The IMMULITE® 2000 CMV IgM assay qualitatively detects CMV IgM antibodies in human serum or plasma to aid in the diagnosis of current or recent CMV infection. To determine expected values in apparently healthy subjects, 136 samples were tested. Reproducibility, normal range, and method comparison studies were also performed to evaluate the assay's performance. The assay's reproducibility was evaluated across three sites. Seven hundred and eighteen (n = 718) individual patient serum samples, which included samples from CMV IgM-positive (n = 109, determined by the Abbott IMx CMV or the Diamedix CMV IgM assays), pregnant (n = 210), HIV-positive (n = 30), immunosuppressed (n = 102), and transplant patients (n = 17) and from patients with potentially cross-reacting conditions (n = 136) were evaluated in the method comparison study. The positive, negative, and overall agreement between the IMMULITE 2000 CMV IgM assay and the VIDAS CMV IgM assay (predicate assay) were determined.
The assay demonstrated excellent reproducibility with a total CV of less than 10%. The positive, negative, and overall agreement between the IMMULITE 2000 assay and the VIDAS assay were > 95% for the method comparison samples. Among potentially cross-reactive samples, the overall agreement between the two assays was 96%. Similarly, among the immunocompromised and pregnant subjects, the overall agreement was ~96% and ~97%, respectively.
The IMMULITE 2000 CMV IgM assay demonstrated excellent reproducibility, minimal cross-reactivity, and performance comparable to that of the VIDAS CMV IgM assay. It can aid in the diagnosis of acute CMV or recent CMV infection by qualitatively detecting the CMV IgM antibodies in human serum or plasma.
PMCID: PMC3317848  PMID: 22377002
16.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
17.  Isolation and Characterization of “Pseudomonas andersonii” from Four Cases of Pulmonary Granulomas and Emended Species Description▿ 
Journal of Clinical Microbiology  2011;49(4):1518-1523.
“Pseudomonas andersonii” is a Gram-negative bacillus initially isolated from a granulomatous lung lesion. Novel species status has not been validated for this single strain. We report four additional cases of pulmonary granuloma involving P. andersonii and further characterize the organism. These patients had pulmonary nodules that were surgically resected and which grew P. andersonii on routine culture. Mycobacterium avium complex was concomitantly isolated in two cases, and fungal structures were identified histopathologically in two other cases. The five P. andersonii strains described to date were similar in growth characteristics, biochemical reactions, matrix-assisted laser desorption ionization–time of flight mass spectrometry protein profiles, and susceptibility to antimicrobial agents. Their 16S rRNA genes were 99.9 to 100% identical but less than 95.0% similar to those of all other known bacteria. The gyrA genes of these strains were 99.5 to 100% identical. These shared features illustrate P. andersonii as a unique and distinct bacterium and support the novel species status of the organism.
PMCID: PMC3122798  PMID: 21270229
18.  Letter to the Editor 
PMCID: PMC3954013  PMID: 24648589
19.  Helicobacter pylori Bacteremia with Sepsis Syndrome ▿  
Journal of Clinical Microbiology  2010;48(12):4661-4663.
A 65-year-old woman with a history of gastric bleeding, breast cancer, antineoplastic chemotherapy, and prednisone use presented with a fever, chest pain, a dry cough, hypotension, and prominent pulmonary bronchovascular markings. She was treated with piperacillin-tazobactam and azithromycin and rapidly improved. Six days later, the blood culture grew a pleomorphic Gram-negative bacillus. Initial subculture failed, but the organism was identified as Helicobacter pylori by sequencing the 16S rRNA gene. The bacterium eventually grew on brucella agar upon extended incubation.
PMCID: PMC3008481  PMID: 20861342
20.  Aortic Valve Endocarditis Possibly Caused by a Haematobacter-Like Species ▿  
Journal of Clinical Microbiology  2010;48(10):3791-3793.
Haematobacter is a newly proposed genus for a group of fastidious Gram-negative aerobic bacilli isolated mostly from blood samples from patients with septicemia. The Haematobacter genus currently includes two species, H. massiliensis and H. missouriensis. We report isolation of a novel Haematobacter-like species from the blood of a 65-year-old man who suffered from probable aortic valve endocarditis. The possible causative role was suggested by the monomicrobial culture and the absence of another causative agent in a patient with probable endocarditis by Duke criteria. This fastidious organism could not be identified by routine biochemical tests. Sequencing analysis of the 16S rRNA gene (1,425 bp) best matched the known Haematobacter species yet was substantially different with a nucleotide similarity of 96.7%. This strain also reduced nitrate to nitrite, unlike known species. This case is likely the first reported case of endocarditis possibly caused by a Haematobacter-like organism.
PMCID: PMC2953082  PMID: 20610676
21.  PPARδ regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury 
Cerebral endothelial cell (CEC) degeneration significantly contributes to blood-brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor δ (PPARδ) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARδ is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARδ overexpression can suppress OGD-induced caspase-3 activity, Golgi fragmentation, and CEC death through an increase of bcl-2 protein levels without change of bcl-2 mRNA levels. To explore the molecular mechanisms, we have identified that upregulation of PPARδ can alleviate ODG-activated microRNA-15a (miR-15a) expression in CECs. Moreover, we have demonstrated that bcl-2 is a translationally-repressed target of miR-15a. Intriguingly, gain- or loss-of-miR-15a function can significantly reduce or increase OGD-induced CEC death, respectively. Furthermore, we have identified that miR-15a is a transcriptional target of PPARδ. Consistent with the in vitro findings, we found that intracerebroventricular infusion of a specific PPARδ agonist, GW 501516, significantly reduced ischemia-induced miR-15a expression, increased bcl-2 protein levels, and attenuated caspase-3 activity and subsequent DNA fragmentation in isolated cerebral microvessels, leading to decreased BBB disruption and reduced cerebral infarction in mice after transient focal cerebral ischemia. Taken together, these results suggest that PPARδ plays a vascular-protective role in ischemia-like insults via transcriptional repression of miR-15a, resulting in subsequent release of its posttranscriptional inhibition of bcl-2. Thus, regulation of PPARδ-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction.
PMCID: PMC2874744  PMID: 20445066
PPARδ; microRNAs; cell death; cerebral vascular endothelial cell; cerebral ischemia
22.  The Granular Chloride Channel ClC-3 Is Permissive For Insulin Secretion 
Cell metabolism  2009;10(4):316-323.
Insulin secretion from pancreatic β–cells is dependent on maturation and acidification of the secretory granule necessary for prohormone convertase cleavage of proinsulin. Previous studies in isolated β–cells revealed that acidification may be dependent on the granule membrane chloride channel ClC-3, in a step permissive for a regulated secretory response. In this study, immuno-electron microscopy of β–cells revealed colocalization of ClC-3 and insulin on secretory granules. Clc-3−/− mice as well as isolated islets demonstrate impaired insulin secretion; clc3−/− β–cells are defective in regulated insulin exocytosis and granular acidification. Increased amounts of proinsulin were found in the majority of secretory granules in the clc-3−/− mice while in clc3+/+ cells, proinsulin was confined to the immature secretory granules. These results demonstrate that in pancreatic β–cells chloride channels, specifically ClC-3, are localized on insulin granules and play a role in insulin processing as well as insulin secretion through regulation of granular acidification.
PMCID: PMC2778193  PMID: 19808024
23.  Comparative Sequence Analysis of Mycobacterium leprae and the New Leprosy-Causing Mycobacterium lepromatosis▿  
Journal of Bacteriology  2009;191(19):6067-6074.
Mycobacterium lepromatosis is a newly discovered leprosy-causing organism. Preliminary phylogenetic analysis of its 16S rRNA gene and a few other gene segments revealed significant divergence from Mycobacterium leprae, a well-known cause of leprosy, that justifies the status of M. lepromatosis as a new species. In this study we analyzed the sequences of 20 genes and pseudogenes (22,814 nucleotides). Overall, the level of matching of these sequences with M. leprae sequences was 90.9%, which substantiated the species-level difference; the levels of matching for the 16S rRNA genes and 14 protein-encoding genes were 98.0% and 93.1%, respectively, but the level of matching for five pseudogenes was only 79.1%. Five conserved protein-encoding genes were selected to construct phylogenetic trees and to calculate the numbers of synonymous substitutions (dS values) and nonsynonymous substitutions (dN values) in the two species. Robust phylogenetic trees constructed using concatenated alignment of these genes placed M. lepromatosis and M. leprae in a tight cluster with long terminal branches, implying that the divergence occurred long ago. The dS and dN values were also much higher than those for other closest pairs of mycobacteria. The dS values were 14 to 28% of the dS values for M. leprae and Mycobacterium tuberculosis, a more divergent pair of species. These results thus indicate that M. lepromatosis and M. leprae diverged ∼10 million years ago. The M. lepromatosis pseudogenes analyzed that were also pseudogenes in M. leprae showed nearly neutral evolution, and their relative ages were similar to those of M. leprae pseudogenes, suggesting that they were pseudogenes before divergence. Taken together, the results described above indicate that M. lepromatosis and M. leprae diverged from a common ancestor after the massive gene inactivation event described previously for M. leprae.
PMCID: PMC2747882  PMID: 19633074
24.  Animal food intake and cooking methods in relation to endometrial cancer risk in Shanghai 
British Journal of Cancer  2006;95(11):1586-1592.
We evaluated animal food intake and cooking methods in relation to endometrial cancer risk in a population-based case–control study in Shanghai, China. A validated food frequency questionnaire was used to collect the usual dietary habits of 1204 cases and 1212 controls aged 30–69 years between 1997 and 2003. Statistical analyses were based on an unconditional logistic regression model adjusting for potential confounders. High intake of meat and fish was associated with an increased risk of endometrial cancer, with adjusted odds ratios for the highest vs the lowest quartile groups being 1.7 (95% confidence interval: 1.3–2.2) and 2.4 (1.8–3.1), respectively. The elevated risk was observed for all types of meat and fish intake. Intake of eggs and milk was not related to risk. Cooking methods and doneness levels for meat and fish were not associated with risk, nor did they modify the association with meat and fish consumption. Our study suggests that animal food consumption may play an important role in the aetiology of endometrial cancer, but cooking methods have minimal influence on risk among Chinese women.
PMCID: PMC2360744  PMID: 17060930
endometrial cancer; dietary factor; case–control study
25.  Epidemiologic Analysis of Reactivated Cytomegalovirus Antigenemia in Patients with Cancer▿  
Journal of Clinical Microbiology  2007;45(4):1126-1132.
The epidemiologic features of reactivated cytomegalovirus (CMV) antigenemia were studied among 4,382 cancer patients who were cared for and tested at the University of Texas M. D. Anderson Cancer Center from 2001 to 2004. The effects of stem cell transplant (SCT) status, underlying disease, age, sex, ethnicity, and antibody status (prior to CMV exposure) on the incidence of CMV antigenemia were determined; and the CMV burdens were quantified. Antigenemia occurred in 9.3% of patients with non-SCT (n = 2511), 12.0% with autologous SCT (n = 582), and 39.1% with allogeneic SCT (n = 1289). Non-SCT patients with lymphoid tumors had a significantly higher rate of antigenemia than those with myeloid tumors (13.6% versus 3.9%) (P < 0.001); however, after allogeneic SCT, the underlying diseases had little effect, except for multiple myeloma (56.8%) (P = 0.014). Among the allogeneic SCT recipients, higher CMV antigenemia rates were also associated with female sex, older age, and positivity for pre-SCT CMV antibody. Depending on the underlying disease and its associated initial CMV risk, allogeneic SCT increased the risk by 2.6- to 29.6-fold (overall, 4.0-fold). With or without SCT, Asians had the highest CMV antigenemia rates and burdens, followed by blacks, Hispanics, and whites, and these partially correlated with antibody prevalence. Among the 808 patients with antigenemia, the circulating peak CMV burden was significantly higher among non-SCT patients (geometric mean, 18.7 positive cells per 106 leukocytes) than among allogeneic SCT patients (geometric mean, 7.7 positive cells per 106 leukocytes) or autologous SCT patients (geometric mean, 7.0 positive cells per 106 leukocytes) who underwent monitoring for CMV. Together, these results allow stratification of CMV risks and suggest a substantial CMV reactivation among non-SCT cancer patients and, thus, the need for better diagnosis and control.
PMCID: PMC1865821  PMID: 17287334

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