Stress Induced Remodeling in the Nematode C. elegans

Caenorhabditis elegans is a model organism for studying genetics and neuroscience C. elegans is frequently studied to understand how genes and the environment interact to produce new phenotypes. We take advantage of an organism-wide stress response and genetic tools that provide an excellent model for studying how phenotypes are impacted by stress

HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS.

Kaposi's sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n = 12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression

Triangulating Abuse Liability Assessment for Flavoured Cigar Products Using Physiological, Behavioural Economic and Subjective Assessments: A Within-subjects Clinical Laboratory Protocol

Introduction In the USA, Food and Drug Administration regulations prohibit the sale of flavoured cigarettes, with menthol being the exception. However, the manufacture, advertisement and sale of flavoured cigar products are permitted. Such flavourings influence positive perceptions of tobacco products and are linked to increased use. Flavourings may mask the taste of tobacco and enhance smoke inhalation, influencing toxicant exposure and abuse liability among novice tobacco users. Using clinical laboratory methods, this study investigates how flavour availability affects measures of abuse liability in young adult cigarette smokers. The specific aims are to evaluate the effect of cigar flavours on nicotine exposure, and behavioural and subjective measures of abuse liability. Methods and analyses Participants (projected n=25) are healthy smokers of five or more cigarettes per day over the past 3 months, 18–25 years old, naive to cigar use (lifetime use of 50 or fewer cigar products and no more than 10 cigars smoked in the past 30 days) and without a desire to quit cigarette smoking in the next 30 days. Participants complete five laboratory sessions in a Latin square design with either their own brand cigarette or a session-specific Black & Mild cigar differing in flavour (apple, cream, original and wine). Participants are single-blinded to cigar flavours. Each session consists of two 10-puff smoking bouts (30 s interpuff interval) separated by 1 hour. Primary outcomes include saliva nicotine concentration, behavioural economic task performance and response to various questionnaire items assessing subjective effects predictive of abuse liability. Differences in outcomes across own brand cigarette and flavoured cigar conditions will be tested using linear mixed models

HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi’s Sarcoma during AIDS

Kaposi’s sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n=12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression

High-speed camera characterization of voluntary eye blinking kinematics

This is the final version of the article originally published in the Journal of the Royal Society Interface here: http://rsif.royalsocietypublishing.org/content/10/85/20130227.full.pdf+html?sid=65b57db1-37cf-492f-bf3c-b08f2a8c818d.Blinking is vital to maintain the integrity of the ocular surface and its characteristics such as blink duration and speed can vary significantly, depending on the health of the eyes. The blink is so rapid that special techniques are required to characterize it. In this study, a high-speed camera was used to record and characterize voluntary blinking. The blinking motion of 25 healthy volunteers was recorded at 600 frames per second. Master curves for the palpebral aperture and blinking speed were constructed using palpebral aperture versus time data taken from the high-speed camera recordings, which show that one blink can be divided into four phases; closing, closed, early opening and late opening. Analysis of data from the high-speed camera images was used to calculate the palpebral aperture, peak blinking speed, average blinking speed and duration of voluntary blinking and compare it with data generated by other methods previously used to evaluate voluntary blinking. The advantages of the high-speed camera method over the others are discussed, thereby supporting the high potential usefulness of the method in clinical research

Assessment of carnitine excretion and its ratio to plasma free carnitine as a biomarker for primary carnitine deficiency in newborns

In the Netherlands, newborns are referred by the newborn screening (NBS) Program when a low free carnitine (C0) concentration (&lt;5 μmol/l) is detected in their NBS dried blood spot. This leads to ~85% false positive referrals who all need an invasive, expensive and lengthy evaluation. We investigated whether a ratio of urine C0 / plasma C0 (RatioU:P) can improve the follow-up protocol for primary carnitine deficiency (PCD). A retrospective study was performed in all Dutch metabolic centres, using samples from newborns and mothers referred by NBS due to low C0 concentration. Samples were included when C0 excretion and plasma C0 concentration were sampled on the same day. RatioU:P was calculated as (urine C0 [μmol/mmol creatinine])/(plasma C0 [μmol/l]). Data were available for 59 patients with genetically confirmed PCD and 68 individuals without PCD. The RatioU:P in PCD patients was significantly higher (p value &lt; 0.001) than in those without PCD, median [IQR], respectively: 3.4 [1.2–9.5], 0.4 [0.3–0.8], area under the curve (AUC) 0.837. Classified for age (up to 1 month) and without carnitine suppletion (PCD; N = 12, Non-PCD; N = 40), medians were 6.20 [4.4–8.8] and 0.37 [0.24–0.56], respectively. The AUC for RatioU:P was 0.996 with a cut-off required for 100% sensitivity at 1.7 (yielding one false positive case). RatioU:P accurately discriminates between positive and false positive newborn referrals for PCD by NBS. RatioU:P is less effective as a discriminative tool for PCD in adults and for individuals that receive carnitine suppletion.</p

Stress-relaxation and fatigue behaviour of synthetic brow-suspension materials.

Ptosis describes a low position of the upper eyelid. When this condition is due to poor function of the levator palpebrae superioris muscle, responsible for raising the lid, "brow-suspension" ptosis correction is usually performed, which involves internally attaching the malpositioned eyelid to the forehead musculature using brow-suspension materials. In service, such materials are exposed to both rapid tensile loading and unloading sequences during blinking, and a more sustained tensile strain during extended periods of closure. In this study, various mechanical tests were conducted to characterise and compare some of commonly-used synthetic brow-suspension materials (Prolene(®), Supramid Extra(®) II, Silicone rods (Visitec(®) Seiff frontalis suspension set) and Mersilene(®) mesh) for their time-dependent response. At a given constant tensile strain or load, all of the brow-suspension materials exhibited stress-relaxation or creep, with Prolene(®) having a statistically different relaxation or creep ratio as compared with those of others. Uniaxial tensile cyclic tests through preconditioning and fatigue tests demonstrated drastically different time-dependent response amongst the various materials. Although the tests generated hysteresis force-strain loops for all materials, the mechanical properties such as the number of cycles required to reach the steady-state, the reduction in the peak force, and the cyclic energy dissipation varied considerably. To reach the steady-state, Prolene(®) and the silicone rod required the greatest and the least number of cycles, respectively. Furthermore, the fatigue tests at physiologically relevant conditions (15% strain controlled at 6.5 Hz) demonstrated that the reduction in the peak force during 100,000 cycles ranged from 15% to 58%, with Prolene(®) and the silicone rod exhibiting the greatest and the least value, respectively. Many factors need to be considered to select the most suitable brow-suspension material for ptosis correction. These novel data on the mechanical time-dependent performance could therefore help to guide clinicians in their decision-making process for optimal surgical outcome.This study was supported by a knowledge exchange and enterprise funding (“Discovery to use”) to the authors at University College London (UCL). Authors Ezra and Rose acknowledge funding by the Department of Health through the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology Biomedical Research Centre. All the mechanical testing was performed at Cambridge University and we are very grateful for the facilities provided.This is the accepted manuscript. The final version is available from Elsevier at http://www.sciencedirect.com/science/article/pii/S1751616114003452#

Development of a patient rated scale for mental health global state for use during humanitarian interventions

Funding: Médecins Sans FrontièresWe present the results of a cross-cultural validation of the Mental Health Global State (MHGS) scale for adults and adolescents (<14 years old). We performed two independent studies using mixed methods among 103 patients in Hebron, Occupied Palestinian Territories and 106 in Cauca, Colombia. The MHGS was analyzed psychometrically, sensitivity and specificity, ability to detect clinically meaningful change, compared to the Clinical Global Impression-Severity scale (CGI-S). Principal component analysis was used to reduce the number of questions after data collection. The scale demonstrated good internal consistency, with a Cronbach alpha score of 0.80 in both settings. Test retest reliability was high, ICC 0.70 (95% CI [0.41-0.85]) in Hebron and 0.87 (95% CI [0.76-0.93]) in Cauca; inter-rater reliability was 0.70 (95% CI [0.42-0.85]) in Hebron and 0.76 (95% CI [0.57-0.88]) in Cauca. Psychometric properties were also good, and the tool demonstrated a sensitivity of 85% in Hebron and 100% in Cauca, with corresponding specificity of 80% and 79%, when compared to CGI-S. The MHGS showed promising results to assess global mental health thereby providing an additional easy to use tool in humanitarian interventions. Additional work should focus on validation in at least one more context, to adhere to best practices in transcultural validation