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1.  Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing 
Virology  2012;436(2):295-303.
The family Polyomaviridae is comprised of circular double-stranded DNA viruses, several of which are associated with diseases, including cancer, in immunocompromised patients. Here we describe a novel polyomavirus recovered from the fecal microbiota of a child in Malawi, provisionally named STL polyomavirus (STLPyV). We detected STLPyV in clinical stool specimens from USA and The Gambia at up to 1% frequency. Complete genome comparisons of two STLPyV strains demonstrated 5.2% nucleotide divergence. Alternative splicing of the STLPyV early region yielded a unique form of T antigen, which we named 229T, in addition to the expected large and small T antigens. STLPyV has a mosaic genome and shares an ancestral recombinant origin with MWPyV. The discovery of STLPyV highlights a novel alternative splicing strategy and advances our understanding of the complex evolutionary history of polyomaviruses.
PMCID: PMC3693558  PMID: 23276405
Polyomavirus; Virus discovery; Tumor antigen; Alternative splicing; Recombination
2.  Genetic Variation of Vibrio cholerae during Outbreaks, Bangladesh, 2010–2011 
Emerging Infectious Diseases  2014;20(1):54-60.
Most isolates are closely related, but genetic variation implies accelerated transmission of some lineages.
Cholera remains a major public health problem. To compare the relative contribution of strains from the environment with strains isolated from patients during outbreaks, we performed multilocus variable tandem repeat analyses on samples collected during the 2010 and 2011 outbreak seasons in 2 geographically distinct areas of Bangladesh. A total of 222 environmental and clinical isolates of V. cholerae O1 were systematically collected from Chhatak and Mathbaria. In Chhatak, 75 of 79 isolates were from the same clonal complex, in which extensive differentiation was found in a temporally consistent pattern of successive mutations at single loci. A total of 59 isolates were collected from 6 persons; most isolates from 1 person differed by sequential single-locus mutations. In Mathbaria, 60 of 84 isolates represented 2 separate clonal complexes. The small number of genetic lineages in isolates from patients, compared with those from the environment, is consistent with accelerated transmission of some strains among humans during an outbreak.
PMCID: PMC3884724  PMID: 24377372
multilocus sequence analysis; infectious disease outbreaks; Vibrio cholerae; bacteria; Bangladesh; cholera; outbreak
3.  Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes 
Archives of general psychiatry  2011;68(7):10.1001/archgenpsychiatry.2011.71.
Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway.
To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes.
Case-control postmortem and clinical study.
Maryland Brain Collection, outpatient clinics.
Postmortem specimens from schizophrenia patients (n=32) and control donors (n=32) and a clinical sample of schizophrenia patients (n=248) and healthy controls (n=228).
Main Outcome Measures
Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response).
In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes.
Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.
PMCID: PMC3855543  PMID: 21727251
4.  Diarrheagenic Pathogens in Polymicrobial Infections 
Emerging Infectious Diseases  2011;17(4):606-611.
During systematic active surveillance of the causes of diarrhea in patients admitted to the Infectious Diseases and Beliaghata General Hospital in Kolkata, India, we looked for 26 known gastrointestinal pathogens in fecal samples from 2,748 patients. Samples from about one-third (29%) of the patients contained multiple pathogens. Polymicrobial infections frequently contained Vibrio cholerae O1 and rotavirus. When these agents were present, some co-infecting agents were found significantly less often (p = 10–5 to 10–33), some were detected significantly more often (p = 10–5 to 10–26), and others were detected equally as often as when V. cholerae O1 or rotavirus was absent. When data were stratified by patient age and season, many nonrandom associations remained statistically significant. The causes and effects of these nonrandom associations remain unknown.
PMCID: PMC3377398  PMID: 21470448
Diarrhea; Vibrio infections; rotavirus; Vibrio cholerae; coinfection; bacteria; viruses; parasites; research
5.  Vibrio cholerae O1 El Tor and O139 Bengal Strains Carrying ctxBET, Bangladesh 
Emerging Infectious Diseases  2013;19(10):1713-1715.
PMCID: PMC3810759  PMID: 24050113
Vibrio cholerae; ctxBET; ctxBCL; altered El Tor; prototype El Tor; antibiotic resistance; PFGE; pulsed-field gel electrophoresis; bacteria
6.  Molecular Epidemiology of O139 Vibrio cholerae: Mutation, Lateral Gene Transfer, and Founder Flush 
Emerging Infectious Diseases  2003;9(7):810-814.
Vibrio cholerae in O-group 139 was first isolated in 1992 and by 1993 had been found throughout the Indian subcontinent. This epidemic expansion probably resulted from a single source after a lateral gene transfer (LGT) event that changed the serotype of an epidemic V. cholerae O1 El Tor strain to O139. However, some studies found substantial genetic diversity, perhaps caused by multiple origins. To further explore the relatedness of O139 strains, we analyzed nine sequenced loci from 96 isolates from patients at the Infectious Diseases Hospital, Calcutta, from 1992 to 2000. We found 64 novel alleles distributed among 51 sequence types. LGT events produced three times the number of nucleotide changes compared to mutation. In contrast to the traditional concept of epidemic spread of a homogeneous clone, the establishment of variant alleles generated by LGT during the rapid expansion of a clonal bacterial population may be a paradigm in infections and epidemics.
PMCID: PMC3023423  PMID: 12890320
cholera; evolution; base sequence; DNA; bacterial; evolution; molecular sequence data; research
7.  A small core predatory genome in the divergent marine Bacteriovorax marinus SJ and the terrestrial Bdellovibrio bacteriovorus 
The ISME journal  2012;7(1):148-160.
Bacteriovorax marinus SJ is a predatory delta-proteobacterium isolated from a marine environment. The genome sequence of this strain provides an interesting contrast to that of the terrestrial predatory bacterium B. bacteriovorus HD100. Based on their predatory lifestyle, Bacteriovorax were originally designated members of the genus Bdellovibrio but subsequently were re-assigned to a new genus and family based on genetic and phenotypic differences. B. marinus attaches to Gram negative bacteria, attaches, penetrates through the cell wall to form a bdelloplast, in which it replicates, as shown using microscopy.
Bacteriovorax is distinct, since it shares only 30% of its gene products with its closest sequenced relatives. Remarkably, 34% of predicted genes over 500 nt in length were completely unique with no significant matches in the databases. As expected Bacteriovorax shares several characteristic loci with the other delta-proteobacteria.
A shared geneset Bacteriovorax and Bdellovibrio that is not conserved amongst other delta-proteobacteria such as Myxobacteria (which destroy prey bacteria externally via lysis), or the non-predatory Desulfo-bacteria and Geobacter species was identified. These 291 gene orthologues common to both Bacteriovorax and Bdellovibrio may be key indicators of predatory-specific processes required for prey entry. The hit locus from Bd. bacteriovorus is implicated in the switch from predatory to prey/host-independent (HI) growth. Although the locus is conserved in B. marinus, the sequence has only limited similarity. The results of this study advance understanding of both the similarities and differences between Bdellovibrio and Bacteriovorax and confirm the distant relationship between the two and their separation into different genera.
PMCID: PMC3526173  PMID: 22955231
8.  Prolonged Colonization with the Methicillin-Resistant Staphylococcus aureus Strain USA300 among Residents of Extended Care Facilities 
We performed a retrospective cohort study (n = 129) to assess whether residents of extended care facilities who were initially colonized or infected with the methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 were less likely to have prolonged colonization than were residents colonized or infected with other MRSA strains. We found no difference in prolonged colonization (adjusted odds ratio, 1.1 [95% confidence interval, 0.5–2.4]).
PMCID: PMC3677585  PMID: 20569116
9.  Evidence of Missense Mutations on the Neuregulin 1 Gene Affecting Function of Prepulse Inhibition 
Biological psychiatry  2007;63(1):17-23.
Neuregulin 1 (NRG1) is one of the leading candidate genes in schizophrenia. Rodents with NRG1 knock-out showed significantly impaired prepulse inhibition (PPI) in the original report linking NRG1 to schizophrenia (Stefansson et al 2002). PPI is a widely used surrogate measure of psychosis in animal models and is considered a schizophrenia endophenotype. We hypothesized that if NRG1 influences PPI in rodents, then it should have a similar effect on PPI in humans.
We examined the potential neurophysiological effects of two nonsynonymous single nucleotide polymorphisms (SNPs) located on NRG1 (rs3924999 and rs10503929) on PPI. Genotyping were completed in 430 unrelated individuals, including 244 schizophrenia cases and 186 controls. PPI was available in a subgroup of 113 cases and 63 controls.
Rs3924999 genotype was significantly associated with PPI (p=0.003): PPI was lowest in the subjects who were homozygous for the minor allele A/A carriers, intermediate in A/G carriers, and highest in homozygous major alleles G/G carriers. The associations persisted within cases (p=0.02) and controls (p=0.02) analyzed separately. An additive model suggested that rs3924999 alone contributes to 7.9% of the PPI variance. In contrast, rs10503929 genotype was not associated with PPI (p=0.85). Schizophrenia patients had reduced PPI compared to control subjects (p=0.04). Neither SNP was associated with schizophrenia (all p>0.37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p=0.05).
A missense mutation on rs3924999 of the neuregulin 1 gene may have a functional effect on prepulse inhibition in both schizophrenia and healthy control populations.
PMCID: PMC3569848  PMID: 17631867
schizophrenia; glutamatergic; psychosis; endophenotype; nonsynonymous; polymorphism; PPI; NRG; NMDA; SNP
10.  Polymorphisms in migraine-associated gene, atp1a2, and ischemic stroke risk in a biracial population: the genetics of early onset stroke study 
SpringerPlus  2013;2:46.
In a recent meta-analysis migraine was associated with a two-fold increase in stroke risk. While the mechanism driving this association is unknown, one intriguing hypothesis is that migraineurs are genetically predisposed to developing ischemic stroke. Mutations in the ATP1A2 gene are implicated in familial hemiplegic migraine type II and increase the severity of ischemic brain injury in animal models. To further explore these observations, we assessed the association between ATP1A2 polymorphisms, migraine, and the risk of ischemic stroke in participants of the Genetics of Early-Onset Stroke Study, a population-based case–control study of ischemic stroke among men and women aged 15–49. Using responses to a headache symptoms questionnaire, subjects were classified as having no migraine, or migraine with or without visual aura. Evaluating a total of 134 ATP1A2 polymorphisms genotyped using a combination of Illumina platforms (Cardiovascular Gene-centric 50 K SNP Array and HumanOmni1-Quad_v1-0_B Bead Chip), only one polymorphism (rs2070704) demonstrated a nominally significant association with stroke in an age-, gender-, ethnicity-adjusted model (OR = 0.83, 95% CI = 0.71-0.98, p = 0.025) and in a vascular risk factor model adjusting for age, gender, ethnicity, hypertension, diabetes, smoking, and myocardial infarction (OR = 0.74, 95% CI = 0.63-0.89, p = 0.001). Ethnicity-stratified analyses demonstrated a significant association for rs2070704 among African-Americans (OR = 0.68, 95% CI = 0.53-0.90, p = 0.005) but not Caucasians (OR = 0.82, 95% CI = 0.64-1.04, p = 0.107). These associations were unchanged when migraine subtypes were included as co-variates. We did not observe an association between ATP1A2 polymorphisms and migraine. While our results do not demonstrate a strong relationship between ATP1A2 polymorphisms and migraine associated stroke risk, the results are hypothesis generating and indicate that an association between ATP1A2 polymorphisms and stroke risk may exist. Additional studies are required.
PMCID: PMC3582818  PMID: 23459313
Headache; Migraine; Stroke; Genetics; ATP1A2; Young
11.  Identification of Coli Surface Antigen 23, a Novel Adhesin of Enterotoxigenic Escherichia coli 
Infection and Immunity  2012;80(8):2791-2801.
Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea, mainly in developing countries. Although there are 25 different ETEC adhesins described in strains affecting humans, between 15% and 50% of the clinical isolates from different geographical regions are negative for these adhesins, suggesting that additional unidentified adhesion determinants might be present. Here, we report the discovery of Coli Surface Antigen 23 (CS23), a novel adhesin expressed by an ETEC serogroup O4 strain (ETEC 1766a), which was negative for the previously known ETEC adhesins, albeit it has the ability to adhere to Caco-2 cells. CS23 is encoded by an 8.8-kb locus which contains 9 open reading frames (ORFs), 7 of them sharing significant identity with genes required for assembly of K88-related fimbriae. This gene locus, named aal (adhesion-associated locus), is required for the adhesion ability of ETEC 1766a and was able to confer this adhesive phenotype to a nonadherent E. coli HB101 strain. The CS23 major structural subunit, AalE, shares limited identity with known pilin proteins, and it is more closely related to the CS13 pilin protein CshE, carried by human ETEC strains. Our data indicate that CS23 is a new member of the diverse adhesin repertoire used by ETEC strains.
PMCID: PMC3434557  PMID: 22645287
12.  A small predatory core genome in the divergent marine Bacteriovorax marinus SJ and the terrestrial Bdellovibrio bacteriovorus 
The ISME Journal  2012;7(1):148-160.
Bacteriovorax marinus SJ is a predatory delta-proteobacterium isolated from a marine environment. The genome sequence of this strain provides an interesting contrast to that of the terrestrial predatory bacterium Bdellovibrio bacteriovorus HD100. Based on their predatory lifestyle, Bacteriovorax were originally designated as members of the genus Bdellovibrio but subsequently were re-assigned to a new genus and family based on genetic and phenotypic differences. B. marinus attaches to Gram-negative bacteria, penetrates through the cell wall to form a bdelloplast, in which it replicates, as shown using microscopy. Bacteriovorax is distinct, as it shares only 30% of its gene products with its closest sequenced relatives. Remarkably, 34% of predicted genes over 500 nt in length were completely unique with no significant matches in the databases. As expected, Bacteriovorax shares several characteristic loci with the other delta-proteobacteria. A geneset shared between Bacteriovorax and Bdellovibrio that is not conserved among other delta-proteobacteria such as Myxobacteria (which destroy prey bacteria externally via lysis), or the non-predatory Desulfo-bacteria and Geobacter species was identified. These 291 gene orthologues common to both Bacteriovorax and Bdellovibrio may be the key indicators of host-interaction predatory-specific processes required for prey entry. The locus from Bdellovibrio bacteriovorus is implicated in the switch from predatory to prey/host-independent growth. Although the locus is conserved in B. marinus, the sequence has only limited similarity. The results of this study advance understanding of both the similarities and differences between Bdellovibrio and Bacteriovorax and confirm the distant relationship between the two and their separation into different families.
PMCID: PMC3526173  PMID: 22955231
Bacteriovorax; Bdellovibrio; genome sequence; BALO; subtractive hybridization; host-interaction locus
13.  USA300 Methicillin-Resistant Staphylococcus aureus Bacteremia and the Risk of Severe Sepsis: Is USA300 MRSA Associated with More Severe Infections? 
USA300 methicillin-resistant Staphylococcus aureus (MRSA) is increasing as a cause of severe community-associated bacteremic infections. We assessed severe sepsis in response to infection in patients with USA300 MRSA compared to non-USA300 MRSA bacteremia.
A cohort study was conducted from 1997–2008 comparing sepsis in response to infection in 271 patients with MRSA bacteremia from four VA hospitals.
Sixty-seven (25%) patients with MRSA bacteremia were USA300 MRSA; 204 (75%) were non-USA300 MRSA. The proportion of MRSA bacteremia caused by USA300 MRSA increased over time (χ2 p<0.0001). Adjusting for age and nosocomial infection, patients with USA300 MRSA bacteremia were more likely to have severe sepsis or septic shock in response to infection than patients with non-USA300 MRSA bacteremia (adjusted Relative Risk=1.82; 95% CI: 1.16–2.87; p=0.01).
This suggests that patients with USA300 MRSA are more likely to develop severe sepsis in response to their infection, which could be due to host or bacterial differences.
PMCID: PMC3118841  PMID: 21558047
14.  A CHRNA5 Allele Related to Nicotine Addiction and Schizophrenia 
Genes, brain, and behavior  2011;10(5):530-535.
Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, one could hypothesize that genes associated with smoking might be over-represented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia and thus difficult to explain the increased smoking in schizophrenia. A functional smoking-related nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) nonsynonymous SNP rs16969968 (Asp398Asn) has recently been discovered and replicated. As such, we tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in schizophrenia patient smokers (p=0.001) and in control smokers (p=0.029). Furthermore, the same risk allele is significantly associated with schizophrenia in both Caucasian (p=0.022) and African American (p=0.006) nonsmoker schizophrenia patients compared to control nonsmokers. Intriguing, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, but whether and how this SNP contributes to the increased smoking prevalence in schizophrenia patients requires additional studies.
PMCID: PMC3126887  PMID: 21418140
smoking; nicotine addiction; schizophrenia; nAChR; alpha5; comorbidity
15.  Return of Chloroquine-Susceptible Falciparum Malaria in Malawi Was a Reexpansion of Diverse Susceptible Parasites 
The Journal of infectious diseases  2010;202(5):801-808.
The spread of drug-resistant Plasmodium falciparum malaria has been a major impediment to malaria control and threatens prospects for elimination. We recently demonstrated the return of chloroquine-susceptible malaria in Malawi after chloroquine use was abandoned. In this study, we trace the origins of chloroquine-resistant and chloroquine-susceptible parasites in Malawi by sequencing the P. falciparum chloroquine resistance transporter gene (pfcrt) and by genotyping microsatellites flanking this gene in isolates from infections that occurred in Malawi from 1992 through 2005. Malaria parasites from 2005 harbored the expected wild-type pfcrt haplotype associated with chloroquine susceptibility and have maintained high levels of diversity without linkage disequilibrium, which suggests that the return of chloroquine susceptibility is not the result of a back mutation in a formerly resistant parasite or a new selective sweep. Chloroquine-susceptible parasites that predominate in Malawi likely represent a reexpansion of the susceptible parasites that survived in the population despite widespread drug pressure in the region.
PMCID: PMC3380613  PMID: 20662717
16.  Molecular Epidemiology of Geographically Dispersed Vibrio cholerae, Kenya, January 2009–May 2010 
Emerging Infectious Diseases  2012;18(6):925-931.
Isolates represent multiple genetic lineages, a finding consistent with multiple emergences from endemic reservoirs.
Numerous outbreaks of cholera have occurred in Kenya since 1971. To more fully understand the epidemiology of cholera in Kenya, we analyzed the genetic relationships among 170 Vibrio cholerae O1 isolates at 5 loci containing variable tandem repeats. The isolates were collected during January 2009–May 2010 from various geographic areas throughout the country. The isolates grouped genetically into 5 clonal complexes, each comprising a series of genotypes that differed by an allelic change at a single locus. No obvious correlation between the geographic locations of the isolates and their genotypes was observed. Nevertheless, geographic differentiation of the clonal complexes occurred. Our analyses showed that multiple genetic lineages of V. cholerae were simultaneously infecting persons in Kenya. This finding is consistent with the simultaneous emergence of multiple distinct genetic lineages of V. cholerae from endemic environmental reservoirs rather than recent introduction and spread by travelers.
PMCID: PMC3358164  PMID: 22607971
phenotypes; genotypes; Vibrio cholerae; cholera; characterization; molecular epidemiology; outbreaks; bacteria; Kenya
17.  Rare Variants in Ischemic Stroke: An Exome Pilot Study 
PLoS ONE  2012;7(4):e35591.
The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined.
PMCID: PMC3334983  PMID: 22536414
18.  The Role of Patient-to-Patient Transmission in the Acquisition of Imipenem-Resistant Pseudomonas aeruginosa Colonization in the Intensive Care Unit 
The Journal of Infectious Diseases  2009;200(6):900-905.
Imipenem-resistant Pseudomonas aeruginosa (IRPA) is an emerging problem. The causal role of antibiotic selective pressure versus patient-to-patient transmission has not been assessed using a large cohort.
Patients who were admitted to the medical and surgical intensive care units (ICUs) at the University of Maryland Medical Center from 2001 through 2006 had multiple perianal culture samples collected. Using pulsed-field gel electrophoresis (PFGE), the number of patients who acquired IRPA as a result of patient-to-patient transmission was determined. We also analyzed a subset of patients who had a previous surveillance culture that grew an imipenem-susceptible P. aeruginosa (ISPA) and a subsequent culture that grew IRPA.
Our cohort consisted of 7071 patients. Three hundred patients were colonized with IRPA. 151 patients had positive culture findings at ICU admission, and 149 patients acquired an IRPA. Among the patients who acquired IRPA, 46 (31%) had a PFGE pattern similar to that for another isolate, and 38 (26%) were found to be colonized with an ISPA on the basis of earlier culture results. Of the 38-patient subset, 28 (74%) had identical PFGE patterns.
Our data showed that, of those cases of IRPA acquisition, 46 (31%) were defined as cases of patient-to-patient transmission, and 28 (19%) were cases of acquisition by the patients’ endogenous flora.
PMCID: PMC3312466  PMID: 19673646
19.  Prospective Cohort Study of Mother-to-Infant Infection and Clearance of Hepatitis C in Rural Egyptian Villages 
Journal of medical virology  2009;81(6):1024-1031.
Although persistent transmission of hepatitis C virus (HCV) from infected mothers to their infants is reported in 4–8%, transient HCV perinatal infection also occurs. This prospective cohort study determined perinatal HCV infection- and early and late clearance-rates in 1,863 mother-infant pairs in rural Egyptian villages. This study found 15.7% and 10.9% of pregnant women had HCV antibodies (anti-HCV) and HCV-RNA, respectively. Among 329 infants born of these mothers, 33 (10.0%) tested positive for both anti-HCV and HCV-RNA 2 months following birth—29 (12.5%) having HCV-RNA positive mothers and 4 (with transient infections) having mothers with only anti-HCV. Fifteen remained HCV-RNA positive at one and/or 2 years (persistent infections), while 18 cleared both virus and antibody by 1 year (transient infections). Among the 15 persistent cases, 7 cleared their infections by 2 or 3 years. At 2- to 6- and at 10- to 12-month maternally acquired anti-HCV was observed in 80% and 5% of infants, respectively. Four perinatally infected and one transiently infected infant were confirmed to be infected by their mothers by the sequence similarity of their viruses. Viremia was 155-fold greater in mothers of infants with persistent than mothers of infants with transient infections. Maternal-infant transmission of HCV is more frequent than generally reported. However, both early and late clearance of infection frequently occurs and only 15 (4.6%) and 8 (2.4%) infants born of HCV-RNA positive mothers had detectable HCV-RNA at one and 2–3 years of age. Investigating how infants clear infection may provide important information about protective immunity to HCV.
PMCID: PMC3235472  PMID: 19382251
perinatal transmission; hepatitis C virus; risk factors; viral clearance; transient infection
20.  Genome-Wide Association Analysis of Ischemic Stroke in Young Adults 
G3: Genes|Genomes|Genetics  2011;1(6):505-514.
Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15–49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 × 10−8), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10−7) and rs1986743 (in ARL6IP6; P = 2.7 × 10−7), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.
PMCID: PMC3276159  PMID: 22384361
epidemiology; genetics; brain infarction; FMNL2
21.  Genetic Diversity of O-Antigen Biosynthesis Regions in Vibrio cholerae▿  
O-antigen biosynthetic (wbf) regions for Vibrio cholerae serogroups O5, O8, and O108 were isolated and sequenced. Sequences were compared to those of other published V. cholerae O-antigen regions. These wbf regions showed a high degree of heterogeneity both in gene content and in gene order. Genes identified frequently showed greater similarities to polysaccharide biosynthesis genes from species other than V. cholerae. Our results demonstrate the plasticity of O-antigen genes in V. cholerae, the diversity of the genetic pool from which they are drawn, and the likelihood that new pandemic serogroups will emerge.
PMCID: PMC3067440  PMID: 21317260
22.  Comparative genomic analysis of Vibrio parahaemolyticus: serotype conversion and virulence 
BMC Genomics  2011;12:294.
Vibrio parahaemolyticus is a common cause of foodborne disease. Beginning in 1996, a more virulent strain having serotype O3:K6 caused major outbreaks in India and other parts of the world, resulting in the emergence of a pandemic. Other serovariants of this strain emerged during its dissemination and together with the original O3:K6 were termed strains of the pandemic clone. Two genomes, one of this virulent strain and one pre-pandemic strain have been sequenced. We sequenced four additional genomes of V. parahaemolyticus in this study that were isolated from different geographical regions and time points. Comparative genomic analyses of six strains of V. parahaemolyticus isolated from Asia and Peru were performed in order to advance knowledge concerning the evolution of V. parahaemolyticus; specifically, the genetic changes contributing to serotype conversion and virulence. Two pre-pandemic strains and three pandemic strains, isolated from different geographical regions, were serotype O3:K6 and either toxin profiles (tdh+, trh-) or (tdh-, trh+). The sixth pandemic strain sequenced in this study was serotype O4:K68.
Genomic analyses revealed that the trh+ and tdh+ strains had different types of pathogenicity islands and mobile elements as well as major structural differences between the tdh pathogenicity islands of the pre-pandemic and pandemic strains. In addition, the results of single nucleotide polymorphism (SNP) analysis showed that 94% of the SNPs between O3:K6 and O4:K68 pandemic isolates were within a 141 kb region surrounding the O- and K-antigen-encoding gene clusters. The "core" genes of V. parahaemolyticus were also compared to those of V. cholerae and V. vulnificus, in order to delineate differences between these three pathogenic species. Approximately one-half (49-59%) of each species' core genes were conserved in all three species, and 14-24% of the core genes were species-specific and in different functional categories.
Our data support the idea that the pandemic strains are closely related and that recent South American outbreaks of foodborne disease caused by V. parahaemolyticus are closely linked to outbreaks in India. Serotype conversion from O3:K6 to O4:K68 was likely due to a recombination event involving a region much larger than the O-antigen- and K-antigen-encoding gene clusters. Major differences between pathogenicity islands and mobile elements are also likely driving the evolution of V. parahaemolyticus. In addition, our analyses categorized genes that may be useful in differentiating pathogenic Vibrios at the species level.
PMCID: PMC3130711  PMID: 21645368
23.  Recent Clonal Origin of Cholera in Haiti 
Emerging Infectious Diseases  2011;17(4):699-701.
Altered El Tor Vibrio cholerae O1, with classical cholera toxin B gene, was isolated from 16 patients with severe diarrhea at St. Mark’s Hospital, Arbonite, Haiti, <3 weeks after onset of the current cholera epidemic. Variable-number tandem-repeat typing of 187 isolates showed minimal diversity, consistent with a point source for the epidemic.
PMCID: PMC3377427  PMID: 21470464
Cholera; Haiti; Vibrio cholerae; bacteria; variable-number tandem-repeat; molecular epidemiology; clonal origin; expedited; dispatch
24.  Relatedness of Vibrio cholerae O1/O139 Isolates from Patients and Their Household Contacts, Determined by Multilocus Variable-Number Tandem-Repeat Analysis▿ ‡ 
Journal of Bacteriology  2010;192(17):4367-4376.
The genetic relatedness of Vibrio cholerae O1/O139 isolates obtained from 100 patients and 146 of their household contacts in Dhaka, Bangladesh, between 2002 and 2005 was assessed by multilocus variable-number tandem-repeat analysis. Isolate genotypes were analyzed at five loci containing tandem repeats. Across the population, as well as within households, isolates with identical genotypes were clustered in time. Isolates from individuals within the same household were more likely to have similar or identical genotypes than were isolates from different households, but even within a household, isolates from different individuals often had different genotypes. When household contacts were sampled regularly for 3 weeks after the illness of the household index patient, isolates with genotypes related to the index patient appeared in contacts, on average, ∼3 days after the index patient, while isolates with unrelated genotypes appeared in contacts ∼6 days after. Limited data revealed that multiple isolates from the same individual collected within days of each other or even from a single stool sample may have identical, similar, or unrelated genotypes as well. Our results demonstrate that genetically related V. cholerae strains cluster in local outbreaks but also suggest that multiple distinct strains of V. cholerae O1 may circulate simultaneously within a household.
PMCID: PMC2937383  PMID: 20585059
25.  Persistent Staphylococcus aureus Colonization Is Not a Strongly Heritable Trait in Amish Families 
PLoS ONE  2011;6(2):e17368.
About 20% of adults are persistently colonized with S. aureus in the anterior nares. Host genetic factors could contribute susceptibility to this phenotype. The objective of this study was to determine whether the phenotype of persistent S. aureus colonization aggregates in family members who live in different households. Healthy adults and their eligible same sex siblings who lived in different households were recruited from the Old Order Amish of Lancaster, Pennsylvania. All participants had two cultures of the anterior nares to determine if they were persistently colonized with S. aureus. Three hundred and ninety eight participants finished the study, of whom 166 were index cases and 232 were siblings of index cases. Eighteen per cent (71/398) of all participants and 17% (29/166) of index cases were persistently colonized with S. aureus. Twenty two per cent (8/36) of siblings of persistently colonized index cases were persistently colonized with S. aureus compared to 17% (34/196) of siblings of non-persistently colonized index cases, yielding a prevalence rate ratio of 1.28 (95% CI: 0.65–2.54, p = 0.64) and sibling relative risk of 1.25 (95% CI: 0.65–2.38, p = 0.51). The heritability of persistent colonization was 0.19±0.21 (p = 0.31). Persistent S. aureus colonization does not strongly aggregate in Amish family members in different households and heritability is low, suggesting that environmental factors or acquired host factors are more important than host genetic factors in determining persistent S. aureus colonization in this community.
PMCID: PMC3046241  PMID: 21386985

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