How Labor Laws Can Transform Health Systems: The Case of Saudi Arabia.

Abstract-In 1999, the Kingdom of Saudi Arabia enacted a law that compels private employers to cover non-Saudi employees with health insurance. In the 16 years that followed, the health sector in the Kingdom has seen a dramatic shift in how services are provided and paid for, and the change continues at an accelerated speed. Based on interviews with 12 large private sector providers in Riyadh, Jeddah, and Khobar, we found that a labor law enacted in 1999 led to rapid expansion of the insured population, both expatriates and Saudis, which led to a drastic change in how hospitals and other facilities are paid, and considerable more consistency in revenue stream. This article describes how the 1999 labor law, combined with other market conditions and public incentives, led to unprecedented growth in private sector capacity and how the insurance system changed the labor market for health care providers and put more pressure on physicians to engage in dual job holding in both the public and private sectors. The Kingdom later introduced another labor program, known as Nitaqat, designed to implement the Saudization initiative that started in 2011, which put pressure on all private companies to hire Saudi nationals. The interviews with large private health providers found the Nitaqat program to be the largest barrier to the growth of the sector. The Kingdom presents a striking case of how the health sector can be drastically impacted by laws and policies outside the sector and how health systems and reforms can, and should, take into account the whole range of policy instruments available to a country.

Do public health services in Egypt help young married women exercise their reproductive rights?

OBJECTIVE: To assess supply and demand of family planning services from a reproductive rights perspective among young married women (YMW) in Egypt. METHODS: Data sources related to family planning included structured interviews with service providers (n=216); an inventory of equipment and supplies (n=40); exit interviews with YMW (n=147); and focus group discussions (n=12) with YMW, husbands, and mothers and/or mothers in law. YMW, husbands and mothers in law were not necessarily related. RESULTS: Although family planning services were readily available and affordable, YMW had limited access to information and services. Shortfalls were noted regarding respect for privacy, choice of family planning method, access to fertility services, and premarital counseling. Few YMW had sufficient autonomy to make informed reproductive decisions. Effective accountability mechanisms and processes for redress were also lacking. CONCLUSION: Implementation of a rights-based approach and structural changes to family planning service delivery are recommended to empower YMW in Egypt to demand and exercise their reproductive rights.

Differential effects of paracrine factors on the survival of cells of the neurovascular unit during oxygen glucose deprivation.

BACKGROUND: Disruption of the neurovascular unit following cerebral ischemia affects protective function of the blood-brain barrier, thus contributing to vasogenic edema and hemorrhagic transformation. AIMS: This study explored the effects of mediators released from neurovascular unit cells on death of brain endothelial cells, astrocytes, pericytes, and microglia during oxygen glucose deprivation. METHODS: Rat primary cell cultures were exposed either to oxygen glucose deprivation or control conditions. Cell death and released angiogenic factors were assessed from media collected from cultures. For some experiments, astrocyte-conditioned media, pericyte-conditioned media, and microglia-conditioned media, collected from the corresponding cell culture after six-hour oxygen glucose deprivation, were added to the media during oxygen glucose deprivation incubations. RESULTS: Brain endothelial cells were more susceptible to death following oxygen glucose deprivation than other neurovascular unit cells. Neither astrocyte-conditioned media nor vascular endothelial growth factor165 were protective for pericytes or brain endothelial cells during oxygen glucose deprivation. Vascular endothelial growth factor receptor antagonist significantly reduced cell death of brain endothelial cells treated with astrocyte-conditioned media or vascular endothelial growth factor165. Pericyte-conditioned media were protective for brain endothelial cells and microglia, but this was not mediated by pericyte-released angiopoietin 1. Soluble angiopoietin 1/angiopoietin 2 receptor Tie2 was protective for brain endothelial cells. Microglia-conditioned media were protective for astrocytes and brain endothelial cells, possibly through transforming growth factor ß1 or interleukin 6. CONCLUSION: Microglia-derived signaling molecules, but not angiogenic factors, were protective for neurovascular unit cells during oxygen glucose deprivation. This finding could identify a potential therapeutic target for ischemic stroke.

Importance of preclinical research in the development of neuroprotective strategies for ischemic stroke.

IMPORTANCE: Preclinical stroke research has had a remarkably low translational success rate, and the clinical need for novel neuroprotective therapeutics has gone largely unmet, especially in light of the severe underuse of thrombolysis in acute ischemic stroke. OBJECTIVE: In this review, we aim to provide a brief overview of the commonly used stroke models, their merits and shortcomings, and how these have contributed to translational failures. We review some recent developments in preclinical stroke, providing examples of how improved study quality and the use of novel methods can facilitate translation into the clinical setting. EVIDENCE REVIEW: This is a narrative review of ischemic stroke neuroprotection based on electronic database searches, references of previous publications, and personal libraries. FINDINGS: The stroke research community has not been complacent in its response to criticism: preclinical stroke studies now demonstrate considerable rigor, standardization, and emphasis on minimization of experimenter bias. In addition, numerous innovative methods and strategies are providing novel avenues for investigating neuroprotection, as well as more extensive characterization of established models. CONCLUSIONS AND RELEVANCE: The improvements in preclinical stroke models and methods will make stroke research a good example for preclinical medicine, in general, and will hopefully instill greater confidence in the clinical community regarding which compounds are worthy of further investigation in a clinical setting.

Laser Doppler flowmetry to measure changes in cerebral blood flow.

Laser Doppler flowmetry (LDF) is a method by which relative cerebral blood flow (CBF) of the cortex can be measured. Although the method is easy to employ, LDF only measures relative CBF, while absolute CBF cannot be quantified. LDF is useful for investigating CBF changes in a number of different applications including neurovascular and stroke research. This chapter will prepare the reader for rodent experiments using LDF with two preparations. The closed skull preparation can be used to monitor CBF with an intact skull, but in adult rats, thinning of the skull is required to obtain an accurate cortical CBF signal. The open skull preparation requires a craniotomy to expose the surface of the brain and the LDF probe is held close to the surface to measure cerebral perfusion.

Impaired hypoxic response in senescent mouse brain.

Tissue hypoxia leads to activation of endogenous adaptive responses that involve a family of prolyl hydroxylase domain proteins (PHD1-3) with oxygen sensing properties, hypoxia inducible transcription factors (HIFs), and cytoprotective HIF target genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). The hypoxic induction of these genes is regulated by oxygen-dependent hydroxylation of HIFα subunits by PHDs, which signals their proteasomal degradation. In this study, mice of different age were exposed to hypoxia or subjected to cerebral ischemia after hypoxic pre-conditioning. We found an impaired hypoxic response in the brain, characterized by elevated levels and impaired downregulation of PHD1. Furthermore, an attenuated hypoxic activation of VEGF and EPO, as well as of other HIF-target genes such glucose transporter-1 and carbonic anhydrase 9 was found in senescent brain. Finally, we observed a loss of the protective effect of hypoxic pre-conditioning on subsequent cerebral ischemia with increasing age. Thus, the impaired hypoxic adaptation, resulting in compromised hypoxic activation of neuroprotective factors, could contribute to neurodegenerative processes with increasing age, and might have implications for treating age-related disorders.

Transient protective effect of B-vitamins in experimental epilepsy in the mouse brain.

The regulation of programmed cell death in the nervous system of vertebrates is a complex mechanism aimed to remove superfluous or damaged cells. Epileptic seizures can lead to an activation of pathways resulting in neuronal cell death. B-vitamins might have a neuroprotective potential reducing cell death following appropriate stimulation. Here, the role of the B-vitamins B(1) (thiamine), B(6) (pyridoxine), and B(12) (cobalamine) was investigated in a mouse model of experimental epilepsy induced by kainate. B-vitamin pre-treated animals showed a significantly reduced epileptic score during the first 15 min after kainate injection. The molecular response to kainate showed a bi-phased time course with early induction of Bcl-2 expression within 12 h and a second induction after 7 days of kainate exposure. B-vitamin pre-treatment resulted in significant higher Bcl-2 expression in control animals (no kainate) and at 12 h within the early phase. Bcl-2 expression was not affected by B-vitamins within the second phase. BAX expression was not significantly influenced during the whole experiment. Three days after kainate stimulation, the number of TdT-mediated dUTP-biotin nick end labeling-positive cells in the hippocampal region was lower in B-vitamin-treated animals. Therefore, B-vitamin pre-treatment may attenuate the response to epileptic stimulation.

Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement.

Blood-brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.

Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery.

Reducing post-stroke disability is the major goal of stroke therapy. Consequently, functional testing is essential in experimental stroke studies to increase the predictive value of animal models. We used several sensory and motor tests to assess functional disability in a mouse model of permanent distal middle cerebral artery occlusion (pdMCAO) that induced mainly cortical infarcts. Gait dynamics were transiently disturbed after pdMCAO as measured by different analysis techniques. Stance and brake duration were shorter after pdMCAO. Consistent with sensory and motor deficits the latency to move was prolonged up to 14 days after pdMCAO and the performance in the corner test and handedness were affected on day 1 or 2 after pdMCAO. Heart rate was decreased and heart rate variability were increased after pdMCAO indicating sympathetic-parasympathetic imbalance. In summary, pdMCAO-induced cortical infarcts lead to clinically relevant sensory, motor and cardiac autonomic dysfunction in mice. The present study provides a basis to explore the potential of functional testing for neuroprotection and neuroregeneration after stroke.

Brain protection by erythropoietin: a manifold task.

Many hematopoietic growth factors are produced locally in the brain. Among these, erythropoietin (Epo), has a dominant role for neuroprotection, neurogenesis, and acting as a neurotrophic factor in the central nervous system. These functions make erythropoietin a good candidate for treating diseases associated with neuronal cell death.

Vascular normalization in Rgs5-deficient tumours promotes immune destruction.

The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.

Health in our hands, but not in our heads: understanding hygiene motivation in Ghana.

Each year more than 2 million children die from diarrhoeal diseases; the same number again die from acute respiratory infections. The simple hygiene behaviour of washing hands with soap represents an effective way of preventing the transmission of many of these infections. However, rates of handwashing across the globe are low, presenting a challenge for health promotion programmes. Behaviour change is not easy, and past efforts based upon health education have met with limited success. New approaches are needed. We propose that much can be learnt from the world of consumer marketing. Rather than base communications programmes for behaviour change on increasing knowledge, marketers aim to respond to the inner desires and motivations of their target audiences. This study used consumer research to investigate the factors motivating handwashing with soap in order to inform a national communications campaign for Ghana. It revealed that the strongest motivators for handwashing with soap were related to nurturance, social acceptance and disgust of faeces and latrines, especially their smell. Protection from disease is mentioned as a driving force, but was not a key motivator of handwashing behaviour. The ways in which these findings have been translated into a handwash promotion campaign are discussed.

Interventions to improve water quality for preventing diarrhoea: systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of interventions to improve the microbial quality of drinking water for preventing diarrhoea. DESIGN: Systematic review. DATA SOURCES: Cochrane Infectious Diseases Group's trials register, CENTRAL, Medline, Embase, LILACS; hand searching; and correspondence with experts and relevant organisations. STUDY SELECTION: Randomised and quasirandomised controlled trials of interventions to improve the microbial quality of drinking water for preventing diarrhoea in adults and in children in settings with endemic disease. DATA EXTRACTION: Allocation concealment, blinding, losses to follow-up, type of intervention, outcome measures, and measures of effect. Pooled effect estimates were calculated within the appropriate subgroups. DATA SYNTHESIS: 33 reports from 21 countries documenting 42 comparisons were included. Variations in design, setting, and type and point of intervention, and variations in defining, assessing, calculating, and reporting outcomes limited the comparability of study results and pooling of results by meta-analysis. In general, interventions to improve the microbial quality of drinking water are effective in preventing diarrhoea. Effectiveness was not conditioned on the presence of improved water supplies or sanitation in the study setting and was not enhanced by combining the intervention with instructions on basic hygiene, a water storage vessel, or improved sanitation or water supplies--other common environmental interventions intended to prevent diarrhoea. CONCLUSION: Interventions to improve water quality are generally effective for preventing diarrhoea in all ages and in under 5s. Significant heterogeneity among the trials suggests that the level of effectiveness may depend on a variety of conditions that research to date cannot fully explain.

Diverging signaling events control the pathway of GPVI down-regulation in vivo.

Coronary artery thrombosis is often initiated by platelet activation on collagen-rich subendothelial layers in the disrupted atherosclerotic plaque. The activating platelet collagen receptor glycoprotein VI (GPVI) noncovalently associates with the Fc receptor gamma-chain (FcRgamma), which signals through its immunoreceptor-tyrosine-based activation motif (ITAM) via the adaptor LAT leading to the activation of phospholipase Cgamma2 (PLCgamma2). GPVI is a promising antithrombotic target as anti-GPVI antibodies induce the irreversible loss of the receptor from circulating platelets by yet undefined mechanisms in humans and mice and long-term antithrombotic protection in the latter. However, the treatment is associated with transient but severe thrombocytopenia and reduced platelet reactivity to thrombin questioning its clinical usefulness. Here we show that GPVI down-regulation occurs through 2 distinct pathways, namely ectodomain shedding or internalization/intracellular clearing, and that both processes are abrogated in mice carrying a point mutation in the FcRgamma-associated ITAM. In mice lacking LAT or PLCgamma2, GPVI shedding is abolished, but the receptor is irreversibly down-regulated through internalization/intracellular clearing. This route of GPVI loss is not associated with thrombocytopenia or altered thrombin responses. These results reveal the existence of 2 distinct signaling pathways downstream of the FcRgamma-ITAM and show that it is possible to uncouple GPVI down-regulation from undesired side effects with obvious therapeutic implications.

Handwashing and risk of respiratory infections: a quantitative systematic review.

OBJECTIVE: To determine the effect of handwashing on the risk of respiratory infection. METHODS: We searched PubMed, CAB Abstracts, Embase, Web of Science, and the Cochrane library for articles published before June 2004 in all languages. We had searched reference lists of all primary and review articles. Studies were included in the review if they reported the impact of an intervention to promote hand cleansing on respiratory infections. Studies relating to hospital-acquired infections, long-term care facilities, immuno-compromised and elderly people were excluded. We independently evaluated all studies, and inclusion decisions were reached by consensus. From a primary list of 410 articles, eight interventional studies met the eligibility criteria. RESULTS: All eight eligible studies reported that handwashing lowered risks of respiratory infection, with risk reductions ranging from 6% to 44% [pooled value 24% (95% CI 6-40%)]. Pooling the results of only the seven homogenous studies gave a relative risk of 1.19 (95% CI 1.12%-1.26%), implying that hand cleansing can cut the risk of respiratory infection by 16% (95% CI 11-21%). CONCLUSIONS: Handwashing is associated with lowered respiratory infection. However, studies were of poor quality, none related to developing countries, and only one to severe disease. Rigorous trials of the impact of handwashing on acute respiratory tract infection morbidity and mortality are urgently needed, especially in developing countries.

Robust estimation approach for blind denoising.

This work develops a new robust statistical framework for blind image denoising. Robust statistics addresses the problem of estimation when the idealized assumptions about a system are occasionally violated. The contaminating noise in an image is considered as a violation of the assumption of spatial coherence of the image intensities and is treated as an outlier random variable. A denoised image is estimated by fitting a spatially coherent stationary image model to the available noisy data using a robust estimator-based regression method within an optimal-size adaptive window. The robust formulation aims at eliminating the noise outliers while preserving the edge structures in the restored image. Several examples demonstrating the effectiveness of this robust denoising technique are reported and a comparison with other standard denoising filters is presented.

Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI.

Lipid-rich atherosclerotic plaques are vulnerable, and their rupture can cause the formation of a platelet- and fibrin-rich thrombus leading to myocardial infarction and ischemic stroke. Although the role of plaque-based tissue factor as stimulator of blood coagulation has been recognized, it is not known whether plaques can cause thrombus formation through direct activation of platelets. We isolated lipid-rich atheromatous plaques from 60 patients with carotid stenosis and identified morphologically diverse collagen type I- and type III-positive structures in the plaques that directly stimulated adhesion, dense granule secretion, and aggregation of platelets in buffer, plasma, and blood. This material also elicited platelet-monocyte aggregation and platelet-dependent blood coagulation. Plaques exposed to flowing blood at arterial wall shear rate induced platelets to adhere to and spread on the collagenous structures, triggering subsequent thrombus formation. Plaque-induced platelet thrombus formation was observed in fully anticoagulated blood (i.e., in the absence of tissue factor-mediated coagulation). Mice platelets lacking glycoprotein VI (GPVI) were unable to adhere to atheromatous plaque or form thrombi. Human platelet thrombus formation onto plaques in flowing blood was completely blocked by GPVI inhibition with the antibody 10B12 but not affected by integrin alpha2beta1 inhibition with 6F1 mAb. Moreover, the initial platelet response, shape change, induced by plaque was blocked by GPVI inhibition but not with alpha2beta1 antagonists (6F1 mAb or GFOGER-GPP peptide). Pretreatment of plaques with collagenase or anti-collagen type I and anti-collagen type III antibodies abolished plaque-induced platelet activation. Our results indicate that morphologically diverse collagen type I- and collagen type III-containing structures in lipid-rich atherosclerotic plaques stimulate thrombus formation by activating platelet GPVI. This platelet collagen receptor, essential for plaque-induced thrombus formation, presents a promising new anti-thrombotic target for the prevention of ischemic cardiovascular diseases.

Evidence for a role of ADAM17 (TACE) in the regulation of platelet glycoprotein V.

Glycoprotein V (GPV) is a subunit of the GPIb-IX-V receptor for von Willebrand factor and thrombin and has been shown to modulate platelet responses to the two strongest physiological agonists, thrombin and collagen. Thrombin directly cleaves GPV from the platelet surface, yielding a 69-kDa fragment GPV f1 of unknown function. We show here that a approximately 82-kDa fragment of GPV is shed from the platelet surface upon cellular activation with phorbol 12-myristate 13-acetate or the collagen-related peptide. This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 (ADAM17 lacking Zn-binding domain; ADAM17(DeltaZn/DeltaZn)). Furthermore, we show that recombinant ADAM17 ectodomain efficiently releases GPV from the platelet surface. GPV is known to be associated with the intracellular regulatory protein calmodulin, which has previously been shown to be involved in ADAM17-mediated shedding of l-selectin from the surface of leukocytes. As in these reports, inhibition of calmodulin led to rapid GPV shedding from the platelet surface, a process that was again blocked by GM6001 or ADAM17 inhibitors and that was absent in ADAM17(DeltaZn/DeltaZn) mice. Inhibition of outside-in signaling through GPIIb/IIIa did not significantly affect GPV shedding, excluding an essential role of this pathway for the regulation of ADAM17 activity. These results demonstrate that GPV is cleaved upon agonist-induced platelet activation and show that ADAM17 is the major enzyme mediating this process.

Evidence that disgust evolved to protect from risk of disease.

Disgust is a powerful human emotion that has been little studied until recently. Current theories do not coherently explain the purpose of disgust, nor why a wide range of stimuli can provoke a similar emotional response. Over 40 000 individuals completed a web-based survey using photo stimuli. Images of objects holding a potential disease threat were reported as significantly more disgusting than similar images with little or no disease relevance. This pattern of response was found across all regions of the world. Females reported higher disgust sensitivity than males; there was a constant decline in disgust sensitivity over the life course; and the bodily fluids of strangers were found more disgusting than those of close relatives. These data provide evidence that the human disgust emotion may be an evolved response to objects in the environment that represent threats of infectious disease.