Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study.

Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia (r = 0.509, P = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder.

MULTIPLE POSTTRANSCRIPTIONAL REGULATORY FEATURES CONTROL EXPRESSION OF ETHANOLAMINE UTILIZATION GENES IN ENTEROCOCCUS FAECALIS

Enterococcus faecalis is a Gram-positive bacterium that lives as a commensal organism in the mammalian gastrointestinal tract, but can behave as an opportunistic pathogen. Our lab discovered that mutation of the eutK gene attenuates virulence of E. faecalis in the C. elegans model host. eutK is part of the ethanolamine metabolic pathway which was previously unknown in E. faecalis. I discovered the presence of two unique posttranscriptional regulatory features that control expression of eut locus genes. The first feature I found is an AdoCBL riboswitch, a cis-acting RNA regulatory element that acts as a positive regulator of gene expression. The second feature I discovered is a unique two-component system, EutVW. The EutV response regulator contains an ANTAR family domain, which binds RNA to trigger transcriptional antitermination. I determined that induction of expression of several genes in the eut locus is dependent on ethanolamine, AdoCBL and the two-component system. AdoCBL and ethanolamine are both required for induction of eut locus gene expression. Additionally, I discovered eutG is regulated by a unique mechanism of antitermination. Both the AdoCBL riboswitch and EutV response regulator control the expression of the downstream gene eutG. EutV potentially acts through a novel antitermination mechanism in which a dimer of EutV binds to a pair of mRNA stem loops forming an antitermination complex. My data show a unique mechanism by which two environmental signals are integrated by two different posttranscriptional regulators to regulate a single locus.

Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF.

BACKGROUND: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies. RESULTS: The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections. CONCLUSION: E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.

EbpR is important for biofilm formation by activating expression of the endocarditis and biofilm-associated pilus operon (ebpABC) of Enterococcus faecalis OG1RF.

We identify ef1090 (renamed ebpR) and show its importance for the transcriptional regulation of expression of the Enterococcus faecalis pilus operon, ebpABC. An ebpR deletion (DeltaebpR) mutant was found to have reduced ebpABC expression with loss of pilus production and a defect in primary adherence with, as a consequence, reduced biofilm formation.

The association of sexual behavior with oropharyngeal cancer and correlations with HPV-16 serologic status

Objectives. This hospital-based case-case study compared the characteristics of sexual behavior in patients with cancer of the oropharynx to patients with cancers of other head and neck sites. Additionally, the prevalence of certain sexual behaviors of HPV-16 seropositive head and neck cancer patients was compared to that of seronegative patients. ^ Methods. One hundred sixty five oropharyngeal cancer patients and 86 patients with cancers of other head and neck sites completed a sexual history questionnaire. ^ Results. Oropharyngeal cancer patients were significantly more likely to have had a greater number of lifetime sex partners, to have engaged in oral-genital sex, and to have had a greater number of oral-genital sex partners than non-oropharyngeal cancer patients. Oral-genital sex was significantly more common in the HPV-16 seropositive group. ^ Conclusion. These findings add to the evidence that HPV-16 is sexually transmitted to the upper aerodigestive tract and that certain sexual behaviors increase the risk for HPV-associated oropharyngeal cancer. ^

Hazardous air pollutants and childhood lymphohematopoietic cancer in Southeast Texas, 1995--2004

Southeast Texas, including Houston, has a large presence of industrial facilities and has been documented to have poorer air quality and significantly higher cancer rates than the remainder of Texas. Given citizens’ concerns in this 4th largest city in the U.S., Mayor Bill White recently partnered with the UT School of Public Health to determine methods to evaluate the health risks of hazardous air pollutants (HAPs). Sexton et al. (2007) published a report that strongly encouraged analytic studies linking these pollutants with health outcomes. In response, we set out to complete the following aims: 1. determine the optimal exposure assessment strategy to assess the association between childhood cancer rates and increased ambient levels of benzene and 1,3-butadiene (in an ecologic setting) and 2. evaluate whether census tracts with the highest levels of benzene or 1,3-butadiene have higher incidence of childhood lymphohematopoietic cancer compared with census tracts with the lowest levels of benzene or 1,3-butadiene, using Poisson regression. The first aim was achieved by evaluating the usefulness of four data sources: geographic information systems (GIS) to identify proximity to point sources of industrial air pollution, industrial emission data from the U.S. EPA’s Toxic Release Inventory (TRI), routine monitoring data from the U.S. EPA Air Quality System (AQS) from 1999-2000 and modeled ambient air levels from the U.S. EPA’s 1999 National Air Toxic Assessment Project (NATA) ASPEN model. Further, once these four data sources were evaluated, we narrowed them down to two: the routine monitoring data from the AQS for the years 1998-2000 and the 1999 U.S. EPA NATA ASPEN modeled data. We applied kriging (spatial interpolation) methodology to the monitoring data and compared the kriged values to the ASPEN modeled data. Our results indicated poor agreement between the two methods. Relative to the U.S. EPA ASPEN modeled estimates, relying on kriging to classify census tracts into exposure groups would have caused a great deal of misclassification. To address the second aim, we additionally obtained childhood lymphohematopoietic cancer data for 1995-2004 from the Texas Cancer Registry. The U.S. EPA ASPEN modeled data were used to estimate ambient levels of benzene and 1,3-butadiene in separate Poisson regression analyses. All data were analyzed at the census tract level. We found that census tracts with the highest benzene levels had elevated rates of all leukemia (rate ratio (RR) = 1.37; 95% confidence interval (CI), 1.05-1.78). Among census tracts with the highest 1,3-butadiene levels, we observed RRs of 1.40 (95% CI, 1.07-1.81) for all leukemia. We detected no associations between benzene or 1,3-butadiene levels and childhood lymphoma incidence. This study is the first to examine this association in Harris and surrounding counties in Texas and is among the first to correlate monitored levels of HAPs with childhood lymphohematopoietic cancer incidence, evaluating several analytic methods in an effort to determine the most appropriate approach to test this association. Despite recognized weakness of ecologic analyses, our analysis suggests an association between childhood leukemia and hazardous air pollution.^

Factors associated with HPV16 status and survival among patients with squamous cell carcinoma of the oropharynx

Background: Squamous cell carcinoma of the oropharynx (SCCOP) is characterized by local tumor aggressiveness, high recurrence rates, a high incidence of second primary tumors, and medical comorbidities. Significant trends in demographic and clinical characteristics as well as survival among SCCOP patients have been observed over time, likely owing to the changing etiology of the disease. Human papillomavirus type 16 (HPV16) infection is associated with a significant proportion of these cancers. Biomarkers that may aid in identifying patients that are at higher risk of recurrence and death are important so that these patients may be followed more closely to improve their quality of life. ^ Study population and methods: The retrospective review (Specific Aim 2) included 3891 newly diagnosed, previously untreated patients presenting to our institution between 1955 and 2004. A total of 2299 patients treated at our institution were included in survival and recursive partitioning analysis. The prospective cohort study (Specific Aim 3) included 266 patients presenting to our institution between January 2006 and September 2009. ^ Results: The results from the retrospective review showed that over time, patients presented at younger ages and were more likely to have base of tongue/tonsil tumors and to be never/former smokers and moreover survival improved significantly over time. In survival and recursive partitioning analyses, the TNM staging system was efficient in prognosticating patients prior to 1995. However, in the recent decade, the TNM staging system was completely inadequate. The factors having the greatest positive effect on overall survival since 1995 were those common to HPV-associated SCCOP. The results from the prospective cohort study indicate that patients with high nodal stage and those with late stage disease have increased levels of pretreatment serum HPV DNA. ^ Conclusions: We saw a distinct improvement in survival among SCCOP patients over the past 50 years at our institution. The main factors contributing to this were changes in clinical characteristics, in particular surrogates for HPV status. The current TNM staging system for SCCOP is inadequate and incorporation of HPV status (and perhaps smoking status) is encouraged. Furthermore, although pretreatment circulating levels of HPV DNA was associated with higher N category and overall disease stage, it has limited utility as a marker for recurrence among SCCOP patients.^