Cholesterol uptake in the intestine is regulated by the LASP1-AKT-NPC1L1 signaling pathway.

Cholesterol is essential for the stability and architecture of the plasma membrane and a precursor of bile acids and steroid hormones in mammals. Excess dietary cholesterol uptake leads to hypercholesterolemia and atherosclerosis and plays a role in cancer development. The role of actin-binding scaffolding protein LIM and SH3 protein 1 (LASP1) in cholesterol trafficking has not been investigated previously. Cholesterol levels, its uptake, and excretion were studied in mice deficient for low-density lipoprotein receptor and Lasp1 (Ldlr-/-Lasp1-/- mice) upon feeding a high-fat diet, and in LASP1-knockdown, differentiated human intestinal epithelial CaCo-2 cells. When compared with diet-fed Ldlr-/- control mice, Ldlr-/-Lasp1-/- mice displayed a reduction in serum cholesterol levels. Mechanistically, we identified a new role of LASP1 in controlling the translocation of the intestinal cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) to the apical cell surface, which was limited in LASP1-knockdown human CaCo-2 enterocytes and in the intestine of Ldlr-/- Lasp1-/- compared with Ldlr-/- mice, linked to LASP1-pAKT signaling but not CDC42 activation. In line, a reduction in cholesterol reabsorption was noted in LASP1-knockdown CaCo-2 cells in vitro, and an enhanced cholesterol excretion via the feces was observed in Ldlr-/- Lasp1-/- mice. These data uncover a novel function of Lasp1 in cholesterol trafficking, promoting cholesterol reabsorption in the intestine. Targeting LASP1 locally could thus represent a novel targeting strategy to ameliorate hypercholesterolemia and associated diseases.NEW & NOTEWORTHY We here uncovered LASP1 as a novel regulator of the shuttling of the sterol transporter NPC1L1 to the cell surface in enterocytes to control cholesterol absorption. Accordingly, LASP1-deficient mice displayed lowered serum cholesterol levels under dietary cholesterol supplementation.

Sex differences in facial expressions of pain: results from a combined sample.

ABSTRACT: Facial expressions of pain play an important role in pain diagnostics and social interactions. Given the prominent impact of sex on various aspects of pain, it is not surprising that sex differences have also been explored regarding facial expressions of pain; however, with inconclusive findings. We aim to further investigate sex differences in facial expressions of pain by using a large, combined sample to maximize statistical power. Data from 7 previous studies of our group were merged, combining in total the data of 392 participants (male: 192, female: 200). All participants received phasic heat pain, with intensities being tailored to the individual pain threshold. Pain intensity ratings were assessed, and facial responses were manually analyzed using the Facial Action Coding. To compare facial and subjective responses between sexes, linear mixed-effects models were used, with study ID as a random effect. We found significant sex differences in facial responses, with females showing elevated facial responses to pain, although they received lower physical heat intensities (women had lower pain thresholds). In contrast, pain intensity ratings did not differ between sexes. Additionally, facial and subjective responses to pain were significantly associated across sexes, with females showing slightly stronger associations. Although variations in facial expressions of pain are very large even within each sex, our findings demonstrate that women facially communicate pain more intensively and with a better match to their subjective experience compared with men. This indicates that women might be better in using facial communication of pain in an intensity-discriminative manner.

Automatic three-dimensional reconstruction of the oesophagus in achalasia patients undergoing POEM: an innovative approach for evaluating treatment outcomes.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) is a standard treatment option for achalasia patients. Treatment response varies due to factors such as achalasia type, degree of dilatation, pressure and distensibility indices. We present an innovative approach for treatment response prediction based on an automatic three-dimensional (3-D) reconstruction of the tubular oesophagus (TE) and the lower oesophageal sphincter (LES) in patients undergoing POEM for achalasia. METHODS: A software was developed, integrating data from high-resolution manometry, timed barium oesophagogram and endoscopic images to automatically generate 3-D reconstructions of the TE and LES. Novel normative indices for TE (volume×pressure) and LES (volume/pressure) were automatically integrated, facilitating pre-POEM and post-POEM comparisons. Treatment response was evaluated by changes in volumetric and pressure indices for the TE and the LES before as well as 3 and 12 months after POEM. In addition, these values were compared with normal value indices of non-achalasia patients. RESULTS: 50 treatment-naive achalasia patients were enrolled prospectively. The mean TE index decreased significantly (p<0.0001) and the mean LES index increased significantly 3 months post-POEM (p<0.0001). In the 12-month follow-up, no further significant change of value indices between 3 and 12 months post-POEM was seen. 3 months post-POEM mean LES index approached the mean LES of the healthy control group (p=0.077). CONCLUSION: 3-D reconstruction provides an interactive, dynamic visualisation of the oesophagus, serving as a comprehensive tool for evaluating treatment response. It may contribute to refining our approach to achalasia treatment and optimising treatment outcomes. TRIAL REGISTRATION NUMBER: 22-0149.

Communication skills of medical students: Evaluation of a new communication curriculum at the University of Augsburg.

Objectives: Teaching communication skills plays a pivotal role in medical curricula. The aim of this article is to describe and evaluate a new communication curriculum developed at the Faculty of Medicine, University of Augsburg (KomCuA), which was conceptualized by an interdisciplinary team based on recommended quality standards (i.e., helical, integrated, longitudinal). Methods: A total of 150 medical students enrolled in the 1st, 3rd, and ≥5th semester participated in the study. They completed an online survey (numerical rating scales and validated questionnaires) evaluating their current communication skills, how these developed across the curriculum in terms of quality and self-confidence, and how helpful they considered practicing in small group tutorials with simulated patients. The students' attitudes towards communication and empathy in the context of medical care were additionally assessed. The students' responses were compared across semesters using one-way univariate analysis of variance (ANOVA). Results: Overall, students reported improved communications skills due to attending the KomCuA and further considered practicing with simulated patients as being very helpful (large effect sizes). Compared to 1st semester students, 3rd and ≥5th semester students reported better communication skills (medium to large effect sizes). Additionally, ≥5th semester students showed stronger agreement towards the relevance of empathy in the context of medical care (medium effect size) compared to both 1st and 3rd semester students. Conclusion: The KomCuA has shown to be an effective communication curriculum to support medical students in the development of their communication skills and positive attitudes towards empathy. Additional studies assessing students' communication skills and empathic attitudes longitudinally are warranted to confirm the present results and to gain further knowledge on how these essential skills and attitudes develop across medical curricula.

Stress-induced hyperalgesia instead of analgesia in patients with chronic musculoskeletal pain.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

Endocannabinoids increase human adipose stem cell differentiation and growth factor secretion in vitro.

Adipose stem cells (ASCs) possess the capacity to proliferate, to differentiate into various cells types, and they are able to secrete growth factors. These characteristics are supposed to contribute to their potential for regenerative medicine approaches. In order to advance the therapeutic effects of ASCs, different modulatory procedures have been examined. In this context, the endocannabinoid system (ECS) represents an interesting possibility, since the increased availability of cannabinoids and the underlying molecular pathways of the ECS are of relevance for the development of new regenerative strategies. The effects of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were investigated on ASC metabolic activity, quantified by PrestoBlue conversion, and cell numbers, evaluated by crystal violet staining. enzyme-linked immunosorbent assay (ELISA) measures were performed to determine cytokine release, and differentiation was assessed by specific labeling techniques. AEA increased the metabolic activity, while 2-AG decreased it in a concentration dependent manner. AEA significantly enhanced OilRed O staining after adipogenic differentiation by over 100%, and both compounds significantly increased cresolphthalein staining after osteogenic differentiation. By contrast, they did not affect sphere diameter or safranin O staining after chondrogenic differentiation. Both substances significantly increased the release of insulin-like growth factor-1 and hepatocyte growth factor, while only AEA enhanced transforming growth factor-ß secretion. The results demonstrated that stimulating the ECS exerted significant effects on the biology of ASCs. Exposure to endocannabinoids modulated viability, induced release of regenerative growth factors, and promoted adipogenic and osteogenic differentiation. Our findings could be of specific relevance in ASC based therapies for regenerative medicine.

From Stumbling Block to Enabler: The Role of Public Financial Management in Health Service Delivery in Tanzania and Zambia.

The way governments manage resources through the budget cycle has important implications for health policy and whether governments achieve societal objectives such as efficiency, equity, quality, and accountability. Studies found a positive association between health service delivery outcomes and good governance of public finance; however, the mechanisms through which public financial management affects service delivery remain underexplored. This article maps the three stages of the budget cycle to common performance criteria used in health service delivery. It applies this approach to experiences in Tanzania and Zambia. The findings point to a number of stumbling blocks, including the lack of flexibility to provide additional resources for unexpected demand for care, misalignment between budgeting and planning, fragmented funding sources, rigid internal controls, insufficient budget provision leading to arrears, and a budget evaluation system that is excessively compliance driven and gives inadequate attention to issues of equity, quality, and efficiency in service delivery.

Trust in micro-health insurance: an exploratory study in Rwanda.

Micro-health insurance (MHI) has been proposed as an alternative to user fees to improve access to medical care without the threat of financial impoverishment. To enrol in health insurance and pay a premium, consumers should be able to trust that insurers use their funds to reimburse providers who will deliver quality care when needed. In 1998, shortly after the re-introduction of user fees, the Rwandan Ministry of Health in close collaboration with the local population developed and implemented MHI in three districts. Member benefits cover preventive and curative care in health centres and ambulance transport to the district hospital where a limited package of services is also covered by MHI. This paper examines trust-building structures and practices in MHI in Rwanda. It is an exploratory, descriptive analysis using information collected from focus groups. Findings suggest that MHI managers, providers and policy-makers need to think systematically about a wide range of initiatives that enhance trust and caring, and to design trust-building structures and practices in the consumer-insurance-provider arrangement.

The impact of micro health insurance on Rwandan health centre costs.

While the implications of payment mechanisms for provider behaviour and cost have been amply explored in industrialized countries, there is little empirical evidence from developing countries. This study exploits the opportunities created by a pilot study of micro health insurance with capitation in Rwanda to address this issue. Using cross-sectional data collected in 52 health centres, the paper employs an econometric cost function with payer-specific outputs to assess the cost impact of two provider payment mechanisms: (1) user fees for care paid by the uninsured, and (2) capitation payment paid by informal insurance schemes for the insured. The cost function allows payer-specific marginal and average costs and scale measures to be calculated. Findings point to significant differences in cost between the two payment forms. These may be due to the incentives embodied in the capitation provider payment or the less severe case-mix among insured patients arising from improved access to care for this group, or both. For both payment types there are important short-run economies of scale, which could be exploited through more intensive use of idle resources in health centres.

Horizontal equity in utilisation of care and fairness of health financing: a comparison of micro-health insurance and user fees in Rwanda.

This paper uses two methods to compare the impact of health care payments under insurance and user fees. Concentration indices for insured and uninsured groups are computed following the indirect standardisation method to evaluate horizontal inequity in utilisation of basic health care services. The minimum standard approach analyses the extent to which out-of-pocket health spending contributed to increased poverty. The analysis uses cross-sectional household survey data collected in Rwanda in 2000 in the context of the introduction of community-based health insurance. Results indicate that health spending had a small impact on the socio-economic situation of uninsured and insured households; however, this is at the expense of horizontal inequity in utilisation of care for user-fee paying individuals who reported significantly lower visit rates than the insured.

Why should the poor insure? Theories of decision-making in the context of health insurance.

Increasingly, low- and middle-income countries are looking to community-based health insurance (CBHI) as a means of ensuring access to health care for the poor. However, little evidence exists about the determining factors that affect poor individuals' insurance decisions. This article reviews the economic and social literature on theories of decision-making, and presents empirical findings from different socio-economic contexts to describe individuals' insurance enrolment decisions in a low-income environment. Evidence from these studies suggests that several factors may explain poor households' decision to insure or remain uninsured. Combining empirical evidence with theories may serve to develop health policies to address issues related to the insurance design, the socio-economic and the informational context; with the overall objective of improving access to care for the poor.