Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.

Sonic hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors commonly cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that Nestin Cre-driven conditional knock-out (CKO) of a Shh pathway repressor-Rab23 in the mouse brain of both genders caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly, Rab23-depleted GCPs exhibited upregulated basal level of Shh pathway activities despite showing an abnormal ciliogenesis of primary cilia. In line with the compromised ciliation, Rab23-depleted GCPs were desensitized against Hh pathway activity stimulations by Shh ligand and Smoothened (Smo) agonist-SAG, and exhibited attenuated stimulation of Smo-localization on the primary cilium in response to SAG. These results implicate multidimensional actions of Rab23 on Hh signaling cascade. Rab23 represses the basal level of Shh signaling, while facilitating primary cilium-dependent extrinsic Shh signaling activation. Collectively, our findings unravel instrumental roles of Rab23 in GCP proliferation and ciliogenesis. Furthermore, Rab23's potentiation of Shh signaling pathway through the primary cilium and Smo suggests a potential new therapeutic strategy for Smo/primary cilium-driven medulloblastoma.SIGNIFICANCE STATEMENT Primary cilium and Sonic hedgehog (Shh) signaling are known to regulate granule cell precursor (GCP) proliferation. Aberrant overactivation of Shh signaling pathway ectopically increases GCP proliferation and causes malignant childhood tumor called medulloblastoma. However, the genetic and molecular regulatory cascade of GCP tumorigenesis remains incompletely understood. Our finding uncovers Rab23 as a novel regulator of hedgehog (Hh) signaling pathway activity and cell proliferation in GCP. Intriguingly, we demonstrated that Rab23 confers dual functions in regulating Shh signaling; it potentiates primary cilium and Shh/Smoothened (Smo)-dependent signaling activation, while antagonizes basal level Hh activity. Our data present a previously underappreciated aspect of Rab23 in mediating extrinsic Shh signaling upstream of Smo. This study sheds new light on the mechanistic insights underpinning Shh signaling-mediated GCP proliferation and tumorigenesis.

Barriers to implementing a national health screening program for men in Malaysia: An online survey of healthcare providers.

INTRODUCTION: This study aimed to determine the views and practices of healthcare providers and barriers they encountered when implementing the national health screening program for men in a public primary care setting in Malaysia. METHODS: An online survey was conducted among healthcare providers across public health clinics in Malaysia. All family medicine specialists, medical officers, nurses and assistant medical officers involved in the screening program for adult men were invited to answer a 51-item questionnaire via email or WhatsApp. The questionnaire comprised five sections: participants' socio-demographic information, current screening practices, barriers and facilitators to using the screening tool, and views on the content and format of the screening tool. RESULTS: A total of 231 healthcare providers from 129 health clinics participated in this survey. Among them, 37.44% perceived the implementation of the screening program as a "top-down decision." Although 37.44% found the screening tool for adult men "useful," some felt that it was "time consuming" to fill out (38.2%) and "lengthy" (28.3%). In addition, 'adult men refuse to answer' (24.1%) was cited as the most common patient-related barrier. CONCLUSIONS: This study provided useful insights into the challenges encountered by the public healthcare providers when implementing a national screening program for men. The screening tool for adult men should be revised to make it more user-friendly. Further studies should explore the reasons why men were reluctant to participate in health screenings, thus enhancing the implementation of screening programs in primary care.

Fluid flow characteristics within an oscillating lower spherical surface and a stationary concentric upper surface for application to the artificial hip joint.

The synovial fluid motion in an artificial hip joint is important in understanding the thermo-fluids effects that can affect the reliability of the joint, although it is difficult to be studied theoretically, as the modelling involves the viscous fluid interacting with a moving surface. A new analytical solution has been derived for the maximum induced fluid motion within a spherical gap with an oscillating lower surface and a stationary upper surface, assuming one-dimensional incompressible laminar Newtonian flow with constant properties, and using the Navier-Stokes equation. The resulting time-dependent motion is analysed in terms of two dimensionless parameters R and ß, which are functions of geometry, fluid properties and the oscillation rate. The model is then applied to the conditions of the synovial fluid enclosed in the artificial hip joint and it is found that the motion may be described by a simpler velocity variation, whereby laying the foundation to thermal studies in the joint.

A Review of Stroke Research in Malaysia from 2000 - 2014.

Over 100 articles related to stroke were found in a search through a database dedicated to indexing all literature with original data involving the Malaysian population between years 2000 and 2014. Stroke is emerging as a major public health problem. The development of the National Stroke Registry in the year 2009 aims to coordinate and improve stroke care, as well as to generate more data on various aspects of stroke in the country. Studies on predictors of survival after strokes have shown potential to improve the overall management of stroke, both during acute event and long term care. Stroke units were shown to be effective locally in stroke outcomes and prevention of stroke-related complications. The limited data looking at direct cost of stroke management suggests that the health economic burden in stroke management may be even higher. Innovative rehabilitation programmes including braincomputer interface technology were studied with encouraging results. Studies in traditional complementary medicine for strokes such as acupuncture, Urut Melayu and herbal medicine were still limited.

Measles-Mumps-Rubella vaccine for children with egg allergy: Is admission for inpatient vaccination necessary?

INTRODUCTION: Children who develop any hypersensitivity reaction to eggs are routinely referred to hospital for Measles-Mumps-Rubella (MMR) vaccination as inpatients to prevent anaphylaxis. We aimed to study the association between hypersensitivity reactions after egg exposure and similar reactions after MMR immunisation; and examine the necessity of hospital admission for vaccination. METHODS: A prospective observational study was conducted in Paediatric Department in Bukit Mertajam Hospital, Penang, between March and December 2014. Children referred from local polyclinics for inpatient MMR vaccination because of a history of egg allergy were recruited. The children were observed in the ward for post vaccination allergic reactions. Concurrently, a group of children without egg allergy was recruited from those admitted for other illnesses but had recent MMR vaccination at polyclinics. Parents of these children were interviewed and asked if they had observed any reactions post vaccination. In both groups, sociodemographics, medical history and family history of atopy were collected. RESULTS: Eighty-seven subjects were recruited in this study. Fifty-four infants with egg allergy had previous mild allergic reactions after exposure to eggs or egg-related products. They were associated with a family history of egg hypersensitivity, personal history of acute gastroenteritis and upper respiratory tract infections. Two of them developed cutaneous rashes post vaccination during observation, but none developed anaphylactic or anaphylactoid reactions. Two infants among those without egg allergy had post vaccination fever. There was no association between egg allergy and hypersensitivity reactions to MMR vaccine (p=0.632). CONCLUSIONS: MMR vaccine can be safely administered to children with mild egg allergy, hence admission for vaccination in the hospital is not warranted. Risk stratification is required to ensure only infants with severe reactions will be admitted for vaccination.

Implementing global knowledge in local practice: a WHO lung health initiative in Nepal.

Clinical practice guidelines are used widely to improve the quality of primary health care in different health systems, including those of low-income countries. Often developed at international level and adapted to national contexts to increase the feasibility of effective uptake, guideline initiatives aim to transfer global scientific knowledge into local practice. The WHO's Practical Approach to Lung Health (PAL) is an example of such an initiative and is currently being developed to improve the quality of care for youths and adults with respiratory diseases. We assessed ex-ante the feasibility of successful implementation of PAL in a pilot programme in rural Nepal, studying three components: the quality of the innovation (i.e. the guidelines), the effectiveness of the implementation strategy (i.e. training) and the receptiveness of the social system of health staff at all levels (i.e. social and organizational characteristics). We assessed the guideline innovation with the AGREE instrument for guidelines, the intended implementation strategy by critical comparison with literature on effective strategies, and the social system with both a stakeholder analysis and a descriptive analysis of the health care system at district level. This ex-ante assessment of an adaptive local implementation of international WHO guidelines showed that in July 2002 the 'implementability' of the package was challenged on the three components studied. To increase the chances of successful implementation, the national guideline development process should be improved and the implementation strategy needs to be upgraded. In order to successfully transfer global knowledge into local practice, we need to develop additional multifactorial sustained interventions that tackle other culture-specific and health system-specific barriers as well. The primary health workers are key informants for these barriers.

Expression patterns of CRH, CRH receptors, and CRH binding protein in human gestational tissue at term.

Recent research suggests a significant role for placental corticotropin-releasing hormone (CRH) in controlling human parturition. This paper describes the expression of CRH, CRH receptors 1 and 2, and CRH binding protein (CRH-BP) in gestational tissue in late pregnancy. Placenta, myometrium, decidua, and fetal membranes were collected after uncomplicated pregnancies at term caesarian section before the onset of labour. The localisation and mRNA expression of CRH, CRH receptors, and CRH-BP were studied by immunohistochemistry and reverse transcription (RT)-PCR. CRH receptors were detected in placenta, myometrium, decidua, and fetal membranes. We demonstrated for the first time the presence of CRH receptors on resident macrophages and on endothelial cells. CRH receptor 1 mRNA was detected in all tissues investigated by RT-PCR, whereas CRH receptor 2 mRNA was restricted to myometrium and decidua. CRH mRNA was widely expressed in all tissue under study. Novel findings are also presented on the expression of CRH-BP in the myometrium. This widespread expression of the CRH system in gestational tissue suggests a paracrine role for CRH in the birth process (e.g. effects on macrophages and endothelial cells).