Aneuploidy: a common and early evidence-based biomarker for carcinogens and reproductive toxicants.

Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity

Distinct Roles of the Adaptor Protein Shc and Focal Adhesion Kinase in Integrin Signaling to ERK

It has been proposed that integrins activate ERK through the adaptor protein Shc independently of focal adhesion kinase (FAK) or through FAK acting on multiple target effectors, including Shc. We show that disruption of the actin cytoskeleton by cytochalasin D causes a complete inhibition of FAK but does not inhibit Shc signaling and activation of ERK. We have then generated primary fibroblasts carrying a targeted deletion of the segment of beta(1) subunit cytoplasmic domain required for activation of FAK. Analysis of these cells indicates that FAK is not necessary for efficient tyrosine phosphorylation of Shc, association of Shc with Grb2, and activation of ERK in response to matrix adhesion. In addition, integrin-mediated activation of FAK does not appear to be required for signaling to ERK following growth factor stimulation. To examine if FAK could contribute to the activation of ERK in a cell type-specific manner through the Rap1/B-Raf pathway, we have used Swiss-3T3 cells, which in contrast to primary fibroblasts express B-Raf. Dominant negative studies indicate that Shc mediates the early phase and peak, whereas FAK, p130(CAS), Crk, and Rap1 contribute to the late phase of integrin-dependent activation of ERK in these cells. In addition, introduction of B-Raf enhances and sustains integrin-mediated activation of ERK in wild-type primary fibroblasts but not in those carrying the targeted deletion of the beta(1) cytoplasmic domain. Thus, the Shc and FAK pathways are activated independently and function in a parallel fashion. Although not necessary for signaling to ERK in primary fibroblasts, FAK may enhance and prolong integrin-mediated activation of ERK through p130(CAS), Crk, and Rap1 in cells expressing B-Raf

High Prevalence of Primary Multidrug Resistant Tuberculosis in Persons with No Known Risk Factors

INTRODUCTION: In high multidrug resistant (MDR) tuberculosis (TB) prevalence areas, drug susceptibility testing (DST) at diagnosis is recommended for patients with risk factors for MDR. However, this approach might miss a substantial proportion of MDR-TB in the general population. We studied primary MDR in patients considered to be at low risk of MDR-TB in Lima, Peru. METHODS: We enrolled new sputum smear-positive TB patients who did not report any MDR-TB risk factor: known exposure to a TB patient whose treatment failed or who died or who was known to have MDR-TB; immunosuppressive co-morbidities, ex prison inmates; prison and health care workers; and alcohol or drug abuse. A structured questionnaire was applied to all enrolled participants to confirm the absence of these factors and thus minimize underreporting. Sputum from all participants was cultured on Lowenstein-Jensen media and DST for first line drugs was performed using the 7H10 agar method. RESULTS: Of 875 participants with complete data, 23.2% (203) had risk factors for MDR-TB elicited after enrolment. Among the group with no reported risk factors who had a positive culture, we found a 6.3% (95%CI 4.4-8.3) (37/584) rate of MDR-TB. In this group no epidemiological characteristics were associated with MDR-TB. Thus, in this group, multidrug resistance occurred in patients with no identifiable risk factors. CONCLUSIONS: We found a high rate of primary MDR-TB in a general population with no identifiable risk factors for MDR-TB. This suggests that in a high endemic area targeting patients for MDR-TB based on the presence of risk factors is an insufficient intervention

The sensitivity of ECG contamination to surgical implantation site in brain computer interfaces.

BACKGROUND Brain sensing devices are approved today for Parkinson's, essential tremor, and epilepsy therapies. Clinical decisions for implants are often influenced by the premise that patients will benefit from using sensing technology. However, artifacts, such as ECG contamination, can render such treatments unreliable. Therefore, clinicians need to understand how surgical decisions may affect artifact probability. OBJECTIVES Investigate neural signal contamination with ECG activity in sensing enabled neurostimulation systems, and in particular clinical choices such as implant location that impact signal fidelity. METHODS Electric field modeling and empirical signals from 85 patients were used to investigate the relationship between implant location and ECG contamination. RESULTS The impact on neural recordings depends on the difference between ECG signal and noise floor of the electrophysiological recording. Empirically, we demonstrate that severe ECG contamination was more than 3.2x higher in left-sided subclavicular implants (48.3%), when compared to right-sided implants (15.3%). Cranial implants did not show ECG contamination. CONCLUSIONS Given the relative frequency of corrupted neural signals, we conclude that implant location will impact the ability of brain sensing devices to be used for "closed-loop" algorithms. Clinical adjustments such as implant location can significantly affect signal integrity and need consideration

Automated versus manual post-processing of perfusion-CT data in patients with acute cerebral ischemia: influence on interobserver variability

The purpose of this study is to compare the variability of PCT results obtained by automatic selection of the arterial input function (AIF), venous output function (VOF) and symmetry axis versus manual selection. Imaging data from 30 PCT studies obtained as part of standard clinical stroke care at our institution in patients with suspected acute hemispheric ischemic stroke were retrospectively reviewed. Two observers performed the post-processing of 30 CTP datasets. Each observer processed the data twice, the first time employing manual selection of AIF, VOF and symmetry axis, and a second time using automated selection of these same parameters, with the user being allowed to adjust them whenever deemed appropriate. The volumes of infarct core and of total perfusion defect were recorded. The cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and blood-brain barrier permeability (BBBP) values in standardized regions of interest were recorded. Interobserver variability was quantified using the Bland and Altman's approach. Automated post-processing yielded lower coefficients of variation for the volume of the infarct core and the volume of the total perfusion defect (15.7% and 5.8%, respectively) compared to manual post-processing (31.0% and 12.2%, respectively). Automated post-processing yielded lower coefficients of variation for PCT values (11.3% for CBV, 9.7% for CBF, and 9.5% for MTT) compared to manual post-processing (23.7% for CBV, 32.8% for CBF, and 16.7% for MTT). Automated post-processing of PCT data improves interobserver agreement in measurements of CBV, CBF and MTT, as well as volume of infarct core and penumbra

The association between food environment, diet quality and malnutrition in low‐ and middle‐income adult populations across the rural—Urban gradient in Vietnam

Background: Economic reforms and trade liberalisation in Vaietnm have transformed the food environment, influencing dietary patterns and malnutrition status. The present study focuses on the relationship between food environments (proximity and density of food outlets) and malnutrition (underweight, overweight, obesity) through diet quality in adult populations across urban, periurban and rural areas of Vietnam. Methods: We evaluated food environment by geospatial mapping of food outlets through a transect walk across the “food ecosystem” from rural to urban areas. Diet quality was assessed using the Diet Quality Index – Vietnamese (DQI‐V) comprising Variety, Adequacy, Moderation and Balance components. Malnutrition status was determined using body mass index. We performed a mediation analysis utilising mixed effect models to control for neighbourhood clustering effects. Confounders included age, education, income and nutrition knowledge score. Results: Analysis of data from 595 adult participants (mean ± SD age: 31.2 ± 6.4 years; 50% female) found that longer distance to the nearest food outlet was associated with higher overall DQI‐V (β = 2.0; 95% confidence interval = 0.2–3.8; p = 0.036) and the Moderation component (β = 2.6; 95% confidence interval = 1.2–4.0; p = 0.001). Outlet density shows a negative association with the odds of underweight among women (odds ratio = 0.62; 95% confidence interval = 0.37–0.96). However, we did not observe statistically significant relationships between diet quality and malnutrition. Education and nutrition knowledge scores were positively associated with diet diversity, while income was negatively associated with diet moderation. Conclusions: The findings of the present study have important implications for nutrition and dietetics practice in Vietnam and globally. It emphasises the need to consider various dimensions of sustainable diets, including economic, health and socio‐cultural/political factors. Longer distances to food outlets are associated with higher diet quality, whereas lower food outlet density increases the odds of underweight among women. This poses challenges in balancing modernisation and its adverse effects on sustainable food systems. Socio‐economic status consistently correlated with diet quality and malnutrition, necessitating further research to promote healthy diets across socio‐economic strata