Citations

ABSTRACT Members of the Streptococcus bovis group are important causes of endocarditis. However, factors associated with their pathogenicity, such as adhesins, remain uncharacterized. We recently demonstrated that endocarditis-derived Streptococcus gallolyticus subsp. gallolyticus isolates frequently adhere to extracellular matrix (ECM) proteins. Here, we generated a draft genome sequence of an ECM protein-adherent S. gallolyticus subsp. gallolyticus strain and found, by genome-wide analyses, 11 predicted LPXTG-type cell wall-anchored proteins with characteristics of MSCRAMMs, including a modular architecture of domains predicted to adopt immunoglobulin (Ig)-like folding. A recombinant segment of one of these, Acb, showed high-affinity binding to immobilized collagen, and cell surface expression of Acb correlated with the presence of acb and collagen adherence of isolates. Three of the 11 proteins have similarities to major pilus subunits and are organized in separate clusters, each including a second Ig-fold-containing MSCRAMM and a class C sortase, suggesting that the sequenced strain encodes three distinct types of pili. Reverse transcription-PCR demonstrated that all three genes of one cluster, acb - sbs7 - srtC1 , are cotranscribed, consistent with pilus operons of other gram-positive bacteria. Further analysis detected expression of all 11 genes in cells grown to mid to late exponential growth phases. Wide distribution of 9 of the 11 genes was observed among S. gallolyticus subsp. gallolyticus isolates with fewer genes present in other S. bovis group species/subspecies. The high prevalence of genes encoding putative MSCRAMMs and pili, including a collagen-binding MSCRAMM, among S. gallolyticus subsp. gallolyticus isolates may play an important role in the predominance of this subspecies in S. bovis endocarditis.

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.

Purpose In this study, the authors examined whether rhythm metrics capable of distinguishing languages with high and low temporal stress contrast also can distinguish among control and dysarthric speakers of American English with perceptually distinct rhythm patterns. Methods Acoustic measures of vocalic and consonantal segment durations were obtained for speech samples from 55 speakers across 5 groups (hypokinetic, hyperkinetic, flaccid-spastic, ataxic dysarthrias, and controls). Segment durations were used to calculate standard and new rhythm metrics. Discriminant function analyses (DFAs) were used to determine which sets of predictor variables (rhythm metrics) best discriminated between groups (control vs. dysarthrias; and among the 4 dysarthrias). A cross-validation method was used to test the robustness of each original DFA. Results The majority of classification functions were more than 80% successful in classifying speakers into their appropriate group. New metrics that combined successive vocalic and consonantal segments emerged as important predictor variables. DFAs pitting each dysarthria group against the combined others resulted in unique constellations of predictor variables that yielded high levels of classification accuracy. Conclusions This study confirms the ability of rhythm metrics to distinguish control speech from dysarthrias and to discriminate dysarthria subtypes. Rhythm metrics show promise for use as a rational and objective clinical tool.

Since the first successful application of extracorporeal membrane oxygenation (ECMO) in 1972, ECMO’s role in the management of respiratory and circulatory collapse continues to be refined and debated. Randomized clinical trials aimed at establishing efficacy and patient selection criteria have been fraught with ethical challenges. Growing concerns over rising health care costs require that careful evaluations of cost, utilization, and ethical issues surrounding heroic life-saving interventions such as ECMO are undertaken. Continued analyses of ECMO’s place in the medical management of respiratory and circulatory failure will help ensure that ECMO is used for not only prolonging life but also for providing a chance for “quality of life” following recovery from near-fatal illnesses.

Object The purpose of this study was to evaluate the incidence of seizures or epileptiform abnormalities on electroencephalography (EEG) studies in patients undergoing surgical treatment for acute subdural hematoma (SDH). Methods This was a retrospective study of 134 consecutive patients with acute or acute-on-chronic SDH who underwent surgical treatment at the authors' institution between January 2004 and July 2008. Detailed information was collected regarding baseline clinical data (including preexistent functional impairment); Glasgow Coma Scale (GCS) sum scores before and 24 hours after surgery; presence of clinical seizures; EEG findings; and functional outcome on discharge and up to the 6-month follow-up. All brain CT scans were reviewed to calculate SDH volume and midline shift. The Glasgow Outcome Scale (GOS) score was used for functional assessment, and GOS scores of 1–3 were considered indicative of poor outcome. Univariate and multivariate logistic regression analyses were performed to identify statistical associations. Results Clinical seizures or epileptiform changes on EEG were observed during the acute postoperative period in 33 patients (25%). Preexistent functional impairment and seizures/epileptiform EEG findings after surgery were independently associated with poor functional outcome upon hospital discharge (p < 0.001 for both). Preexistent functional impairment (p < 0.001), lower GCS score before surgery (p = 0.04), and lower GCS score 24 hours after surgery (p = 0.007), but not seizures/epileptiform EEG findings, were independently associated with poor functional recovery at 1- to 6-month follow-up evaluations. Seizures/epileptiform EEG findings had a strong association with lower GCS scores after surgery (p = 0.01), and they were more common in patients who underwent evacuation by craniotomy (p = 0.02). Conclusions Epileptic complications are common after acute SDH evacuation, and should be suspected in patients with an unanticipated depressed level of consciousness after surgery. Seizures worsen early functional outcome, but delayed favorable recovery is possible. Therefore, one should be cautious when discussing prognosis in the early postoperative period of patients with epileptic complications.

Background— There have been significant bidirectional changes in the prevalence of cardiovascular (CV) risk factors over time in the United States, making the net trend in risk for incident CV disease unknown. We assessed these trends by applying the Framingham Heart Study prediction model to national data. Methods and Results— The National Health and Nutrition Examination Survey (NHANES) II (1976–1980), NHANES III (1988–1994), and NHANES 1999–2004 are cross-sectional representative samples of the noninstitutionalized population of the United States. We excluded people with a history of CV disease, pregnant women, participants with missing CV risk factors data, and individuals outside the Framingham age range of 30 to 74 years. The Framingham risk function was used to estimate the 10-year risk for incident symptomatic CV disease. We calculated the slope of change or rate of change per year between NHANES II and III, and between NHANES III and 1999–2004. The difference between slopes was calculated and compared to zero. The average age-adjusted 10-year CV risk between NHANES II and III decreased from 10.0% to 7.9% between NHANES II and III, with a statistically significant slope ( P <0.001). However, the average age-adjusted CV risk decreased at a lesser magnitude between NHANES III and NHANES 1999–2004 from 7.9% to 7.4% ( P <0.001). These slopes were significantly different ( P <0.0001). In women and middle-aged participants, CV risk did not change between NHANES III and NHANES 1999–2004 ( P =0.40). Conclusions— The estimated net risk for CV disease in the US population decreased from 1976–1980 to 1988–1994 but has changed minimally from 1988–1994 to 1999–2004, particularly in women and middle-aged people.

Abstract Background: The next-generation, high-sensitivity cardiac troponin assays can measure quantifiable concentrations of cTn in a majority of individuals, but there are few studies assessing these assays for risk stratification. The present study was undertaken to determine if a research hs-cTnI assay can be useful for predicting death/myocardial infarction (MI), both short- and long-term, in an emergency department acute coronary syndrome (ACS) population. Methods: In a cohort of 383 subjects, originally recruited in 1996, presenting to the emergency department with symptoms suggestive of ACS, the heparin plasma obtained at initial presentation was thawed and measured in 2007 with a research hs-cTnI assay. AccuTnI (Beckman Coulter) measurements were made on these same samples in 2003. The population was divided into 4 groups by hs-cTnI: &lt;5.00, 5.00–9.99, 10.00–40.00, and &gt;40.00 ng/L. Kaplan–Meier, Cox proportional hazards, ROC curves, and logistic regression analyses were used to identify which hs-cTnI concentrations were predictive of death/MI within 10 years after presentation. Results: There were significant differences between the hs-cTnI groups for the probability of death/MI up to 10 years after presentation (P &lt; 0.05). At 6 months, patients with hs-cTnI ≥10.00 ng/L were at higher risk for death/MI (hazard ratio &gt;3.7; P &lt; 0.05) compared with those having hs-cTnI &lt;5.00 ng/L. ROC curve analysis for death/MI at 30 days with the hs-cTnI assay had an area under the curve of 0.74 (95% CI 0.65–0.82), with logistic models yielding an optimal assay threshold of 12.68 ng/L. Conclusions: This research hs-cTnI assay appears useful for risk stratification for death/MI in an ACS population.

AbstractMicrotubules are important cellular targets for anticancer therapy because of their key role in mitosis. Microtubule inhibitors (MTI) such as taxanes, vinca alkaloids, and epothilones stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis. In spite of their antitumor activity, innate or acquired drug resistance to MTIs such as the taxanes is common, limiting their overall clinical efficacy. Further insight into the mechanisms of action of microtubule-targeting drugs has lead to the discovery of novel agents that may provide higher efficacy with limited toxicity and help overcome resistance to conventional MTIs. This review will focus on the different mechanisms of action of MTIs, potential factors related to resistance and tolerability, and will discuss the recent approval as well as the development of new antineoplastic agents. [Mol Cancer Ther 2009;8(8):2086–95]