Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study

In myelodysplastic syndromes (MDS), health-related quality of life (HRQoL) represents a relevant patient-reported outcome, which is essential in individualized therapy planning. Prospective data on HRQoL in lower-risk MDS remain rare. We assessed HRQOL by EQ-5D questionnaire at initial diagnosis in 1690 consecutive IPSS-Low/Int-1 MDS patients from the European LeukemiaNet Registry. Impairments were compared with age- and sex-matched EuroQol Group norms. A significant proportion of MDS patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort, and EQ-VAS were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin levels, or red blood cells transfusion need (

Carriage and acquisition of extended-spectrum β-Lactamase–producing enterobacterales among neonates admitted to hospital in Kilifi, Kenya

Background Infections caused by extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) among hospitalized neonates in sub-Saharan Africa pose significant clinical challenges. Data on prevalence and acquisition of ESBL-E carriage among hospitalized neonates in the region are few, and risk factors for transmission are not clearly defined. Methods In a cohort study of consecutive neonatal admissions to Kilifi County Hospital from July 2013 through August 2014, we estimated ESBL-E carriage prevalence on admission using rectal swab cultures and identified risk factors using logistic regression. Using twice-weekly follow-up swabs, we estimated the incidence and identified risk factors for ESBL-E acquisition in hospital using Poisson regression. Results The prevalence of ESBL-E carriage at admission was 10% (59/569). Cesarean delivery, older neonatal age, and smaller household size were significant risk factors. Of the 510 infants admitted without ESBL-E carriage, 238 (55%) acquired carriage during their hospital stay. The incidence of acquisition was 21.4% (95% confidence interval, 19.0%–24.0%) per day. The rate was positively associated with the number of known neonatal ESBL-E carriers and with the total number of neonates on the same ward. Conclusions Carriage of ESBL-E was common among neonates on admission, and in-hospital acquisition was rapid. The dissemination and selection of ESBL-E appears to be driven by hospital exposures, operative delivery, and neonatal ward patient density. Further attention to infection control, patient crowding, and carriage surveillance is warranted

Patient-reported outcome measures of the impact of cancer on patient’s everyday lives: a systematic review

Purpose: Patients with advanced disease are living longer and commonly used patient-reported outcome measures (PROMs) may miss relevant elements of the quality of extended survival. This systematic review examines the measures used to capture aspects of the quality of survival including impact on patients’ everyday lives such as finances, work and family roles. Methods: Searches were conducted in MEDLINE, EMBASE, CINAHL and PsycINFO restricted to English language articles. Information on study characteristics, instruments and outcomes was systematically extracted and synthesised. A predefined set of criteria was used to rate the quality of studies. Results: From 2761 potentially relevant articles, 22 met all inclusion criteria, including 10 concerning financial distress, 3 on roles and responsibilities and 9 on multiple aspects of social well-being. Generally, studies were not of high quality; many lacked bias free participant selection, had confounding factors and had not accounted for all participants. High levels of financial distress were reported and were associated with multiple demographic factors such as age and income. There were few reports concerned with impacts on patients’ roles/responsibilities in everyday life although practical and emotional struggles with parenting were identified. Social difficulties were common and associated with multiple factors including being a caregiver. Many studies were single time-point surveys and used non-validated measures. Exceptions were employment of the COST and Social Difficulties Inventory (SDI), validated measures of financial and social distress respectively. Conclusions: Impact on some important parts of patients’ everyday lives is insufficiently and inconsistently captured. Further PROM development focussing on roles and responsibilities, including work and caring for dependents, is warranted. Implications for Cancer Survivors: Factors such as finances, employment and responsibility for caring for dependents (e.g. children and elderly relatives) can affect the well-being of cancer survivors. There is a need to ensure that any instruments used to assess patients’ social well-being are broad enough to include these areas so that any difficulties arising can be better understood and appropriately supported

Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus

Onchocerciasis, commonly known as river blindness, is caused by the filarial nematode Onchocerca volvulus and is transmitted by a blackfly vector. Over 37 million people are thought to be infected, with over 90 million at risk. Infection predominantly occurs in sub-Saharan Africa. Foci also exist in the Arabian Peninsula and Central and South America. Ivermectin, the sole pharmaceutical available for mass chemotherapy, has been used on a community basis for annual or semi-annual treatment since 1987. Multiple treatments with ivermectin kill the microfilariae that are responsible for the pathology of onchocerciasis. More importantly, ivermectin suppresses the reproductive activity of the adult female worms, thus delaying or preventing the repopulation of the skin with new microfilariae and thereby reducing transmission. This study extends earlier reports of sub-optimal responses to ivermectin by examining repopulation levels of microfilaria one year after treatment, worm burdens per nodule, the age structure of adult female worms recovered from nodules, and the reproductive status of adult female worms 90 days after ivermectin treatment. In some communities which have shown a pattern of sub-optimal response to treatment, the data is consistent with an emergence of ivermectin non response or resistance manifested by a loss of the effect of ivermectin on the suppression of parasite reproduction

Quantifying coronary sinus flow and global LV perfusion at 3T

<p>Abstract</p> <p>Background</p> <p>Despite the large availability of 3T MR scanners and the potential of high field imaging, this technical platform has yet to prove its usefulness in the cardiac MR setting, where 1.5T remains the established standard. Global perfusion of the left ventricle, as well as the coronary flow reserve (CFR), can provide relevant diagnostic information, and MR measurements of these parameters may benefit from increased field strength. Quantitative flow measurements in the coronary sinus (CS) provide one method to investigate these parameters. However, the ability of newly developed faster MR sequences to measure coronary flow during a breath-hold at 3T has not been evaluated.</p> <p>Methods</p> <p>The aim of this work was to measure CS flow using segmented phase contrast MR (PC MR) on a clinical 3T MR scanner. Parallel imaging was employed to reduce the total acquisition time. Global LV perfusion was calculated by dividing CS flow with left ventricular (LV) mass. The repeatability of the method was investigated by measuring the flow three times in each of the twelve volunteers. Phantom experiments were performed to investigate potential error sources.</p> <p>Results</p> <p>The average CS flow was determined to 88 ± 33 ml/min and the deduced LV perfusion was 0.60 ± 0.22 ml/min·g, in agreement with published values. The repeatability (1-error) of the three repeated measurements in each subject was on average 84%.</p> <p>Conclusion</p> <p>This work demonstrates that the combination of high field strength (3T), parallel imaging and segmented gradient echo sequences allow for quantification of the CS flow and global perfusion within a breath-hold.</p

Scientific imperatives, clinical implications, and theoretical underpinnings for the investigation of the relationship between genetic variables and patient-reported quality-of-life outcomes

Objectives There is emerging evidence for a genetic basis of patient-reported quality-of-life (QOL) outcomes that can ultimately be incorporated into clinical research and practice. Objectives are (1) to provide arguments for the timeliness of investigating the genetic basis of QOL given the scientific advances in genetics and patient-reported QOL research; (2) to describe the clinical implications of such investigations; (3) to present a theoretical foundation for investigating the genetic underpinnings of QOL; and (4) to describe a series of papers resulting from the GENEQOL Consortium that was established to move this work forward. Methods Discussion of scientific advances based on relevant literature. Results In genetics, technological advances allow for increases in speed and efficiency and decreases in costs in exploring the genetic underpinnings of disease processes, drug metabolism, treatment response, and survival. In patient-based research, advances yield empirically based and stringent approaches to measurement that are scientifically robust. Insights into the genetic basis of QOL will ultimately allow early identification of patients susceptible to QOL deficits and to target care. The Wilson and Cleary model for patient-reported outcomes was refined by incorporating the genetic underpinnings of QOL. Conclusions This series of papers provides a path for QOL and genetics researchers to work together to move this field forward and to unravel the intricate interplay of the genetic underpinnings of patient-reported QOL outcomes. The ultimate result will be a greater understanding of the process relating disease, patient, and doctor that will have the potential to lead to improved survival, QOL, and health services deliver

Mixed Infection with cagA Positive and cagA Negative Strains of Helicobacter pylori Lowers Disease Burden in The Gambia

BACKGROUND: The prevalence of Helicobacter pylori including strains with putatively virulent genotypes is high, whereas the H. pylori-associated disease burden is low, in Africa compared to developed countries. In this study, we investigated the prevalence of virulence-related H. pylori genotypes and their association with gastroduodenal diseases in The Gambia. METHODS AND FINDINGS: DNA extracted from biopsies and H. pylori cultures from 169 subjects with abdominal pain, dyspepsia or other gastroduodenal diseases were tested by PCR for H. pylori. The H. pylori positive samples were further tested for the cagA oncogene and vacA toxin gene. One hundred and twenty one subjects (71.6%) were H. pylori positive. The cagA gene and more toxigenic s1 and m1 alleles of the vacA gene were found in 61.2%, 76.9% and 45.5% respectively of Gambian patients harbouring H. pylori. There was a high prevalence of cagA positive strains in patients with overt gastric diseases than those with non-ulcerative dyspepsia (NUD) (p = 0.05); however, mixed infection by cagA positive and cagA negative strains was more common in patients with NUD compared to patients with gastric disease (24.5% versus 0%; p = 0.002). CONCLUSION: This study shows that the prevalence of H. pylori is high in dyspeptic patients in The Gambia and that many strains are of the putatively more virulent cagA+, vacAs1 and vacAm1 genotypes. This study has also shown significantly lower disease burden in Gambians infected with a mixture of cag-positive and cag-negative strains, relative to those containing only cag-positive or only cag-negative strains, which suggests that harbouring both cag-positive and cag-negative strains is protective