The Structure of the NPC1L1 N-Terminal Domain in a Closed Conformation

NPC1L1 is the molecular target of the cholesterol lowering drug Ezetimibe and mediates the intestinal absorption of cholesterol. Inhibition or deletion of NPC1L1 reduces intestinal cholesterol absorption, resulting in reduction of plasma cholesterol levels.Here we present the 2.8 Å crystal structure of the N-terminal domain (NTD) of NPC1L1 in the absence of cholesterol. The structure, combined with biochemical data, reveals the mechanism of cholesterol selectivity of NPC1L1. Comparison to the cholesterol free and bound structures of NPC1(NTD) reveals that NPC1L1(NTD) is in a closed conformation and the sterol binding pocket is occluded from solvent.The structure of NPC1L1(NTD) reveals a degree of flexibility surrounding the entrance to the sterol binding pocket, suggesting a gating mechanism that relies on multiple movements around the entrance to the sterol binding pocket

The International Deep Brain Stimulation Registry and Database for Gilles de la Tourette Syndrome: How Does It Work?

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson's disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with DBS worldwide, have delayed regulatory agency approval (e.g., FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry

Saccadic latency in hepatic encephalopathy: a pilot study

Hepatic encephalopathy is a common complication of cirrhosis. The degree of neuro-psychiatric impairment is highly variable and its clinical staging subjective. We investigated whether eye movement response times—saccadic latencies—could serve as an indicator of encephalopathy. We studied the association between saccadic latency, liver function and paper- and pencil tests in 70 patients with cirrhosis and 31 patients after liver transplantation. The tests included the porto-systemic encephalopathy (PSE-) test, critical flicker frequency, MELD score and ammonia concentration. A normal range for saccades was established in 31 control subjects. Clinical and biochemical parameters of liver, blood, and kidney function were also determined. Median saccadic latencies were significantly longer in patients with liver cirrhosis when compared to patients after liver transplantation (244 ms vs. 278 ms p < 0.001). Both patient groups had prolonged saccadic latency when compared to an age matched control group (175 ms). The reciprocal of median saccadic latency (μ) correlated with PSE tests, MELD score and critical flicker frequency. A significant correlation between the saccadic latency parameter early slope (σE) that represents the prevalence of early saccades and partial pressure of ammonia was also noted. Psychometric test performance, but not saccadic latency, correlated with blood urea and sodium concentrations. Saccadic latency represents an objective and quantitative parameter of hepatic encephalopathy. Unlike psychometric test performance, these ocular responses were unaffected by renal function and can be obtained clinically within a matter of minutes by non-trained personnel

Evidence for transient morning water frost deposits on the Tharsis volcanoes of Mars

The present-day water cycle on Mars has implications for habitability and future human exploration. Water ice clouds and water vapour have been detected above the Tharsis volcanic province, suggesting the active exchange of water between regolith and atmosphere. Here we report observational evidence for extensive transient morning frost deposits on the calderas of the Tharsis volcanoes (Olympus, Arsia and Ascraeus Montes, and Ceraunius Tholus) using high-resolution colour images from the Colour and Stereo Surface Imaging System on board the European Space Agency’s Trace Gas Orbiter. The transient bluish deposits appear on the caldera floor and rim in the morning during the colder Martian seasons but are not present by afternoon. The presence of water frost is supported by spectral observations, as well as independent imagery from the European Space Agency’s Mars Express orbiter. Climate model simulations further suggest that early-morning surface temperatures at the high altitudes of the volcano calderas are sufficiently low to support the daily condensation of water—but not CO2 —frost. Given the unlikely seasonal nature of volcanic outgassing, we suggest the observed frost is atmospheric in origin, implying the role of microclimate in local frost formation and a contribution to the broader Mars water cycle

Are women with history of pre-eclampsia starting a new pregnancy in good nutritional status in South Africa and Zimbabwe?

Background Maternal nutritional status before and during pregnancy is an important contributor to pregnancy outcomes and early child health. The aim of this study was to describe the preconceptional nutritional status and dietary intake during pregnancy in high-risk women from South Africa and Zimbabwe. Methods This is a prospective observational study, nested to the CAP trial. Anthropometric measurements before and during pregnancy and dietary intake using 24-h recall during pregnancy were assessed. The Intake Distribution Estimation software (PC-SIDE) was used to evaluate nutrient intake adequacy taking the Estimated Average Requirement (EAR) as a cut-off point. Results Three hundred twelve women who had pre-eclampsia in their last pregnancy and delivered in hospitals from South Africa and Zimbabwe were assessed. 73.7 and 60.2% women in South Africa and Zimbabwe, respectively started their pregnancy with BMI above normal (BMI ≥ 25) whereas the prevalence of underweight was virtually non-existent. The majority of women had inadequate intakes of micronutrients. Considering food and beverage intake only, none of the micronutrients measured achieved the estimated average requirement. Around 60% of pregnant women reported taking folic acid or iron supplements in South Africa, but almost none did so in Zimbabwe. Conclusion We found a high prevalence of overweight and obesity and high micronutrient intake inadequacy in pregnant women who had the previous pregnancy complicated with pre-eclampsia. The obesity figures and micronutrient inadequacy are issues of concern that need to be addressed. Pregnant women have regular contacts with the health system; these opportunities could be used to improve diet and nutrition. Trial registration PACTR201105000267371 . Registered 06 December 2010

The Heidelberg Milestones Communication Approach (MCA) for patients with prognosis &lt;12 months: protocol for a mixed-methods study including a randomized controlled trial

Background: The care needs of patients with a limited prognosis (&lt;12 months median) are complex and dynamic. Patients and caregivers must cope with many challenges, including physical symptoms and disabilities, uncertainty. and compromised self-efficacy. Healthcare is often characterized by disruptions in the transition between healthcare providers. The Milestones Communication Approach (MCA) is a structured, proactive, interprofessional concept that involves physicians and nurses and is aimed at providing coherent care across the disease trajectory. This study aims to evaluate these aspects of MCA: (1) the training of healthcare professionals, (2) implementation context and outcomes, (3) patient outcomes, and (4) effects on interprofessional collaboration. Methods/design: A multiphase mixed-methods design will be used for the study. A total of 100 patients and 120 healthcare professionals in a specialized oncology hospital will be involved. The training outcomes will be documented using a questionnaire. Implementation context and outcomes will be explored through semi-structured interviews and written questionnaires with healthcare professionals and with the training participants and through a content analysis of patient files. Patient outcomes will be assessed in a pragmatic non-blinded randomized controlled trial and in qualitative interviews with patients and caregivers. Trial outcomes are supportive care needs (SCNS-SF34-G), quality of life (SeiQol and Fact-L), depression and anxiety symptoms (PHQ-4), and distress (Distress Thermometer). Qualitative semi-structured interviews on patients’ views will focus on shared decision-making, communication needs, feeling empathy, and further utilization of healthcare services. Interprofessional collaboration will be explored using the UWE-IP-D before the implementation of MCA (t0) and after 3 (t1), 9 (t2), and 12 (t3) months. Discussion: Using guideline-concordant early palliative care, MCA aims to foster patient-centered communication with shared decision-making and facilitation of advance care planning including end-of-life decisions, thus increasing patient quality of life and decreasing aggressive medical care at the end of life. It is assumed that the communication skills training and interprofessional coaching will improve the communication behavior of healthcare providers and influence team communications and team processes. Trial registration German Clinical Trials Register, DRKS00013649 and DRKS00013469. Registered on 22 December 2017