Vitamin D Induces Cyclooxygenase 2 Dependent Prostaglandin E2 Synthesis in HaCaT Keratinocytes.

The active metabolite of vitamin D calcitriol and its analogs are well-known for their anti-inflammatory action in the skin, while their main side effect associated with topical treatment of inflammatory disorders is irritant contact dermatitis. Prostaglandin E2 (PGE2 ) is pro-inflammatory at the onset of inflammation and anti-inflammatory at its resolution. We hypothesized that induction of PGE2 synthesis by calcitriol in epidermal keratinocytes may contribute both to its pro-inflammatory and anti-inflammatory effects on the skin. Treatment of human immortalized HaCaT keratinocytes with calcitriol (3-100 nM, 2-24 h) increased PGE2 production due to increased mRNA and protein expression of COX-2, but not to increase of COX-1 or release of arachidonic acid. The effect of calcitriol on COX-2 mRNA was observed also in primary human keratinocytes. The increase in COX-2 mRNA is associated with COX-2 transcript stabilization. Calcitriol exerts this effect by a rapid (2 h) and protein synthesis independent mode of action that is dependent on PKC and Src kinase activities. Treatment with a COX-2 inhibitor partially prevented the attenuation of the keratinocyte inflammatory response by calcitriol. We conclude that upregulation of COX-2 expression with the consequent increase in PGE2 synthesis may be one of the mechanisms explaining the Janus face of calcitriol as both a promoter and attenuator of cutaneous inflammation. J. Cell. Physiol. 231: 837-843, 2016. © 2015 Wiley Periodicals, Inc.

Impact of community-based health insurance in rural India on self-medication & financial protection of the insured.

BACKGROUND & OBJECTIVES: The evidence-base of the impact of community-based health insurance (CBHI) on access to healthcare and financial protection in India is weak. We investigated the impact of CBHI in rural Uttar Pradesh and Bihar s0 tates of India on insured households' self-medication and financial position. METHODS: Data originated from (i) household surveys, and (ii) the Management Information System of each CBHI. Study design was "staggered implementation" cluster randomized controlled trial with enrollment of one-third of the treatment group in each of the years 2011, 2012 and 2013. Around 40-50 per cent of the households that were offered to enroll joined. The benefits-packages covered outpatient care in all three locations and in-patient care in two locations. To overcome self-selection enrollment bias, we constructed comparable control and treatment groups using Kernel Propensity Score Matching (K-PSM). To quantify impact, both difference-in-difference (DiD), and conditional-DiD (combined K-PSM with DiD) were used to assess robustness of results. RESULTS: Post-intervention (2013), self-medication was less practiced by insured HHs. Fewer insured households than uninsured households reported borrowing to finance care for non-hospitalization events. Being insured for two years also improved the HH's location along the income distribution, namely insured HHs were more likely to experience income quintile-upgrade in one location, and less likely to experience a quintile-downgrade in two locations. INTERPRETATION & CONCLUSIONS: The realized benefits of insurance included better access to healthcare, reduced financial risks and improved economic mobility, suggesting that in our context health insurance creates welfare gains. These findings have implications for theoretical, ethical, policy and practice considerations.

The inflammatory response of keratinocytes and its modulation by vitamin D: the role of MAPK signaling pathways.

The hormonal form of vitamin D, calcitriol, and its analogs are known for their beneficial effect in the treatment of inflammatory skin disorders. Keratinocytes play a role in epidermal inflammatory responses invoked by breeching of the epidermal barrier, by infectious agents and by infiltrating immune cells. We studied the role of calcitriol in the initiation of keratinocyte inflammatory response by the viral and injury mimic polyinosinic-polycytidylic acid (poly(I:C)) and in its maintenance by tumor-necrosis-factor α (TNFα) and investigated the role of the mitogen-activated protein kinase cascades in these processes and their regulation by calcitriol. The inflammatory response of human HaCaT keratinocytes to poly(I:C) or TNFα was assessed by measuring mRNA levels of 13 inflammation-related molecules by real-time PCR microarray and by in-depth investigation of the regulation of interleukin 8, intercellular-adhesion-molecule 1, and TNFα expression. We found that while calcitriol had only a minor effect on the keratinocyte response to poly(I:C) and a modest effect on the early response (2 h) to TNFα, it markedly attenuated the later response (16-24 h) to TNFα. The expression of CYP27B1, the enzyme responsible for calcitriol production, was marginally increased by poly(I:C) and markedly by TNFα treatment. This pattern suggests that while allowing the initial keratinocyte inflammatory response to proceed, calcitriol contributes to its timely resolution. Using pharmacological inhibitors we found that while the p38 MAPK and the extracellular signal-regulated kinase have only a minor role, c-Jun N-terminal kinase plays a pivotal role in the induction of the pro-inflammatory genes and its modulation by calcitriol.

Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes.

UNLABELLED: Vitamin D supplementation was reported to improve the probability of achieving a sustained virological response when combined with antiviral treatment against hepatitis C virus (HCV). Our aim was to determine the in vitro potential of vitamin D to inhibit HCV infectious virus production and explore the mechanism(s) of inhibition. Here we show that vitamin D(3) remarkably inhibits HCV production in Huh7.5 hepatoma cells. These cells express CYP27B1, the gene encoding for the enzyme responsible for the synthesis of the vitamin D hormonally active metabolite, calcitriol. Treatment with vitamin D(3) resulted in calcitriol production and induction of calcitriol target gene CYP24A1, indicating that these cells contain the full machinery for vitamin D metabolism and activity. Notably, treatment with calcitriol resulted in HCV inhibition. Collectively, these findings suggest that vitamin D(3) has an antiviral activity which is mediated by its active metabolite. This antiviral activity involves the induction of the interferon signaling pathway, resulting in expression of interferon-ß and the interferon-stimulated gene, MxA. Intriguingly, HCV infection increased calcitriol production by inhibiting CYP24A1 induction, the enzyme responsible for the first step in calcitriol catabolism. Importantly, the combination of vitamin D(3) or calcitriol and interferon-α synergistically inhibited viral production. CONCLUSION: This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system. It proposes an interplay between the hepatic vitamin D endocrine system and HCV, suggesting that vitamin D has a role as a natural antiviral mediator. Importantly, our study implies that vitamin D might have an interferon-sparing effect, thus improving antiviral treatment of HCV-infected patients.

Can the rural poor in India afford to treat non-communicable diseases.

OBJECTIVE: Non-communicable diseases (NCD) are on the increase in low-income countries, where healthcare costs are paid mostly out-of-pocket. We investigate the financial burden of NCD vs. communicable diseases (CD) among rural poor in India and assess whether they can afford to treat NCD. METHODS: We used data from two household surveys undertaken in 2009-2010 among 7389 rural poor households (39 205 individuals) in Odisha and Bihar. All persons from the sampled households, irrespective of age and gender, were included in the analysis. We classify self-reported illnesses as NCD, CD or 'other morbidities' following the WHO classification. RESULTS: Non-communicable diseases accounted for around 20% of the diseases in the month preceding the survey in Odisha and 30% in Bihar. The most prevalent NCD, representing the highest share in outpatient costs, were musculoskeletal, digestive and cardiovascular diseases. Cardiovascular and digestive problems also generated the highest inpatient costs. Women, older persons and less-poor households reported higher prevalence of NCD. Outpatient costs (consultations, medicines, laboratory tests and imaging) represented a bigger share of income for NCD than for CD. Patients with NCD were more likely to report a hospitalisation. CONCLUSION: Patients with NCD in rural poor settings in India pay considerably more than patients with CD. For NCD cases that are chronic, with recurring costs, this would be aggravated. The cost of NCD care consumes a big part of the per person share of household income, obliging patients with NCD to rely on informal intra-family cross-subsidisation. An alternative solution to finance NCD care for rural poor patients is needed.

Illness Mapping: a time and cost effective method to estimate healthcare data needed to establish community-based health insurance.

BACKGROUND: Most healthcare spending in developing countries is private out-of-pocket. One explanation for low penetration of health insurance is that poorer individuals doubt their ability to enforce insurance contracts. Community-based health insurance schemes (CBHI) are a solution, but launching CBHI requires obtaining accurate local data on morbidity, healthcare utilization and other details to inform package design and pricing. We developed the "Illness Mapping" method (IM) for data collection (faster and cheaper than household surveys). METHODS: IM is a modification of two non-interactive consensus group methods (Delphi and Nominal Group Technique) to operate as interactive methods. We elicited estimates from "Experts" in the target community on morbidity and healthcare utilization. Interaction between facilitator and experts became essential to bridge literacy constraints and to reach consensus.The study was conducted in Gaya District, Bihar (India) during April-June 2010. The intervention included the IM and a household survey (HHS). IM included 18 women's and 17 men's groups. The HHS was conducted in 50 villages with1,000 randomly selected households (6,656 individuals). RESULTS: We found good agreement between the two methods on overall prevalence of illness (IM: 25.9% ±3.6; HHS: 31.4%) and on prevalence of acute (IM: 76.9%; HHS: 69.2%) and chronic illnesses (IM: 20.1%; HHS: 16.6%). We also found good agreement on incidence of deliveries (IM: 3.9% ±0.4; HHS: 3.9%), and on hospital deliveries (IM: 61.0%. ± 5.4; HHS: 51.4%). For hospitalizations, we obtained a lower estimate from the IM (1.1%) than from the HHS (2.6%). The IM required less time and less person-power than a household survey, which translate into reduced costs. CONCLUSIONS: We have shown that our Illness Mapping method can be carried out at lower financial and human cost for sourcing essential local data, at acceptably accurate levels. In view of the good fit of results obtained, we assume that the method could work elsewhere as well.

Hardship financing of healthcare among rural poor in Orissa, India.

BACKGROUND: This study examines health-related "hardship financing" in order to get better insights on how poor households finance their out-of-pocket healthcare costs. We define hardship financing as having to borrow money with interest or to sell assets to pay out-of-pocket healthcare costs. METHODS: Using survey data of 5,383 low-income households in Orissa, one of the poorest states of India, we investigate factors influencing the risk of hardship financing with the use of a logistic regression. RESULTS: Overall, about 25% of the households (that had any healthcare cost) reported hardship financing during the year preceding the survey. Among households that experienced a hospitalization, this percentage was nearly 40%, but even among households with outpatient or maternity-related care around 25% experienced hardship financing.Hardship financing is explained not merely by the wealth of the household (measured by assets) or how much is spent out-of-pocket on healthcare costs, but also by when the payment occurs, its frequency and its duration (e.g. more severe in cases of chronic illnesses). The location where a household resides remains a major predictor of the likelihood to have hardship financing despite all other household features included in the model. CONCLUSIONS: Rural poor households are subjected to considerable and protracted financial hardship due to the indirect and longer-term deleterious effects of how they cope with out-of-pocket healthcare costs. The social network that households can access influences exposure to hardship financing. Our findings point to the need to develop a policy solution that would limit that exposure both in quantum and in time. We therefore conclude that policy interventions aiming to ensure health-related financial protection would have to demonstrate that they have reduced the frequency and the volume of hardship financing.

'First we go to the small doctor': first contact for curative health care sought by rural communities in Andhra Pradesh & Orissa, India.

BACKGROUND & OBJECTIVES: Against the backdrop of insufficient public supply of primary care and reports of informal providers, the present study sought to collect descriptive evidence on 1 st contact curative health care seeking choices among rural communities in two States of India - Andhra Pradesh (AP) and Orissa. METHODS: The cross-sectional study design combined a Household Survey (1,810 households in AP; 5,342 in Orissa), 48 Focus Group Discussions (19 in AP; 29 in Orissa), and 61 Key Informant Interviews with healthcare providers (22 in AP; 39 in Orissa). RESULTS: In AP, 69.5 per cent of respondents accessed non-degree allopathic practitioners (NDAPs) practicing in or near their village; in Orissa, 40.2 per cent chose first curative contact with NDAPs and 36.2 per cent with traditional healers. In AP, all NDAPs were private practitioners, in Orissa some pharmacists and nurses employed in health facilities, also practiced privately. Respondents explained their choice by proximity and providers' readiness to make house-calls when needed. Less than a quarter of respondents chose qualified doctors as their first point of call: mostly private practitioners in AP, and public practitioners in Orissa. Amongst those who chose a qualified practitioner, the most frequent reason was doctors' quality rather than proximity. INTERPRETATION & CONCLUSIONS: The results of this study show that most rural persons seek first level of curative healthcare close to home, and pay for a composite convenient service of consulting-cum-dispensing of medicines. NDAPs fill a huge demand for primary curative care which the public system does not satisfy, and are the de facto first level access in most cases.

Incidence of illness among resource-poor households: evidence from five locations in India.

BACKGROUND & OBJECTIVE: This study examines the association between household attributes and perceived morbidity within resource-poor house holds (HHs) in India at five locations. This presents an innovation compared to most epidemiological studies, which focus on associations between the incidence of an illness and characteristics of the ill person. METHODS: Perceived morbidity was represented by a variable called "Incidence of illness in a HH" (IIH) = the number of self reported illness episodes during three months preceding the survey, divided by household size. Variables were analyzed through bivariate correlation and multivariate linear regression. The evidence was based on a HH survey conducted in 2005 in Maharashtra, Bihar, and Tamil Nadu. Data yield reflected responses of 3,531 HHs, representing 17,323 individuals and 4,316 illness episodes. RESULTS: Analysis showed that incidence of illness among women was higher; the under 5 yr olds and elderly (+55) were particularly vulnerable. However, in the multivariate linear regression model, gender ratio within HHs became an insignificant explanatory variable. Age distribution had a small but significant effect. Household size and the level of education in the HH were negatively and significantly associated with IIH. The regression analysis showed that income had a modest positive effect, but improved housing was associated with reduced IIH. Large differences were noted in IIH across locations. INTERPRETATION & CONCLUSION: Our findings showed that attributes of the unit household, including type of house, income, education and size, have significant effects on IIH; variability in IIH cannot solely be explained by age and gender of HH members.

Two modes of ERK activation by TNF in keratinocytes: different cellular outcomes and bi-directional modulation by vitamin D.

Inflammation, elicited in the skin following tissue damage or pathogen invasion, may become chronic with deleterious consequences. Tumor necrosis factor (TNF) is a key mediator of cutaneous inflammation and the keratinocyte an important protagonist of skin immunity. Calcitriol, the hormonally active vitamin D metabolite, and its analogs attenuate epidermal inflammation and inhibit the hyperproliferation of keratinocytes associated with the inflammatory disorder, psoriasis. Since activation of extracellular signal-regulated kinase (ERK) promotes keratinocyte proliferation and mediates epidermal inflammation, we studied the effect of calcitriol on ERK activation in HaCaT keratinocytes exposed to the ubiquitous inflammatory cytokine TNF. By using the EGF receptor (EGFR) tyrosine kinase inhibitor, AG1487 and the Src family inhibitor, PP-1, we established that TNF activated ERK in an EGFR and Src dependent and an EGFR and Src independent modes. EGFR dependent activation resulted in the upregulation of the transcription factor, c-Fos, while the EGFR independent activation mode was of a shorter duration, did not affect c-Fos expression but induced IL-8 mRNA expression. Pretreatment with calcitriol, enhanced TNF-induced EGFR-Src dependent ERK activation and tyrosine phosphorylation of the EGFR, but abolished the EGFR-Src independent ERK activation. These effects were mirrored by enhancement of c-Fos and inhibition of IL-8 induction by TNF. Treatment with calcitriol increased the rate of the de-phosphorylation of activated ERK, accounting for the inhibition of EGFR-Src independent ERK activation by TNF. It is possible that effects on the ERK cascade contribute to the effects of calcitriol and its synthetic analogs on cutaneous inflammation and keratinocyte proliferation.

Cost of illness: evidence from a study in five resource-poor locations in India.

BACKGROUND & OBJECTIVE: In India, health services are funded largely through out-of-pocket spendings (OOPS). We carried out this study to collect data on the cost of an illness episode and parameters affecting cost in five locations in India. METHODS: The data were obtained through a household survey carried out in 2005 in five locations among resource-poor persons in rural India. The analysis was based on self-reported illness episodes and their costs. The study was based on 3,531 households (representing 17,323 persons) and 4,316 illness episodes. RESULTS: The median cost of one illness episode was INR 340. When costs were calculated as per cent of monthly income per person, the median value was 73 per cent of that monthly income, and could reach as much as 780 per cent among the 10 per cent most exposed households. The estimated median per-capita cost of illness was 6 per cent of annual per-capita income. The ratio of direct costs to indirect costs was 67:30. The cost of illness was lower among females in all age groups, due to lower indirect costs. 61 per cent of total illnesses, costing 37.4 per cent of total OOPS, were due to acute illnesses; chronic diseases represented 17.7 per cent of illnesses but 32 per cent of costs. Our study showed that hospitalizations were the single most costly component on average, yet accounted for only 11 per cent of total on an aggregated basis, compared to drugs that accounted for 49 per cent of total aggregated costs. Locations differed from each other in the absolute cost of care, in distribution of items composing the total cost of care, and in supply. INTERPRETATION & CONCLUSION: Interventions to reduce the cost of illness should be context-specific, as there is no "one-size-fits-all" model to establish the cost of healthcare for the entire sub-continent. Aggregated expenses, rather than only hospitalizations, can cause catastrophic consequences of illness.

Health insurance benefit packages prioritized by low-income clients in India: three criteria to estimate effectiveness of choice.

We applied a decision tool for rationing choices, with a predetermined budget of about 11 US dollars per household per year, to identify priorities of poor people regarding health insurance benefits in India in late 2005. A total of 302 individuals, organized in 24 groups, participated from a number of villages and neighborhoods of towns in Karnataka and Maharashtra. Many individuals were illiterate, innumerate and without insurance experience. Involving clients in insurance package design is based on an implied assumption that people can make judicious rationing decisions. Judiciousness was assessed by examining the association between the frequency of choosing a package and its perceived effectiveness. Perceived effectiveness was evaluated by comparing respondents' choices to the costs registered in 2049 illness episodes among a comparable cohort, using three criteria: 'reimbursement' (reimbursement regardless of the absolute level of expenditure), 'fairness' (higher reimbursement rate for higher expenses) and 'catastrophic coverage' (insurance for catastrophic exposure). The most frequently chosen packages scored highly on all three criteria; thus, rationing choices were confirmed as judicious. Fully 88.4% of the respondents selected at least three of the following benefits: outpatient, inpatient, drugs and tests, with a clear preference to cover high aggregate costs regardless of their probability. The results show that involving prospective clients in benefit package design can be done without compromising the judiciousness of rationing choices, even with people who have low education, low-income and no previous experience in similar exercises.

Willingness to pay for health insurance among rural and poor persons: field evidence from seven micro health insurance units in India.

This study, conducted in India in 2005, provides evidence on Willingness to pay (WTP), gathered through a unidirectional (descending) bidding game among 3024 households (HH) in seven locations where micro health insurance units are in operation. Insured persons reported slightly higher WTP values than uninsured. About two-thirds of the sample agreed to pay at least 1%; about half the sample was willing to pay at least 1.35%; 30% was willing to pay about 2.0% of annual HH income as health insurance premium. Nominal WTP correlates positively with income but relative WTP (expressed as percent of HH income) correlates negatively. The correlation between WTP and education is secondary to that of WTP with HH income. Household composition did not affect WTP. However, HHs that experienced a high-cost health event and male respondents reported slightly higher WTP. The observed nominal levels of WTP are higher than has been estimated hitherto.

Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients.

Radiation dermatitis occurs frequently during adjuvant radiation therapy for breast cancer. Prevention of radiation dermatitis by applying various creams and ointments has a limited success, and Aqua cream which has urea as one of its active ingredients is used in many institutions as a preventive treatment. The primary goal of this study is to assess the effect of vitamin D (calcipotriol) ointment in prevention of radiodermatitis in breast cancer patients compared to Aqua cream. Twenty-three women with localized breast cancer who underwent breast-conserving surgery and opted to receive adjuvant radiotherapy to breast only were enrolled in this study. A cream containing an active vitamin D analog, calcipotriol (Daivonex), was randomly applied either to the medial or to the lateral half of the irradiated breast, while Aqua cream was applied to the complimentary half of the same breast along the whole treatment days, each day, after the delivery of radiation. Skin reaction was recorded and compared between the two halves of the breast. Vitamin D was well tolerated by patients with no local or systemic allergic reactions. Radiation dermatitis was not significantly different between both treatment arms. Topical vitamin D ointment is not superior to Aqua cream for prevention of radiation-induced dermatitis in women treated with adjuvant radiation for breast cancer.

Calcitriol sensitizes colon cancer cells to H2O2-induced cytotoxicity while inhibiting caspase activation.

The anti-cancer activity of calcitriol, the active metabolite of Vitamin D, in the colon is usually attributed to its anti-proliferative and pro-differentiative actions. The levels of reactive oxygen species (ROS) are high in colon carcinomas due to increased aerobic metabolism and exposure to various anti-cancer modalities. We examined whether calcitriol modulates the response of colon cancer cells to the cytotoxic action of the common mediator of ROS injury, H2O2. Pretreatment with calcitriol (100 nM, 48 h) sensitized HT-29 colon cancer cells to cell death induced by acute exposure to H2O2 or chronic exposure to the H2O2 generating system, glucose/glucose-oxidase. Although the morphological features of H2O2-induced HT-29 cell death are consistent with apoptosis, we detected no executioner caspase activation in response to cytotoxic concentrations of H2O2 and treatment with a pan-caspase inhibitor did not affect H2O2-induced cytotoxicity nor its enhancement by calcitriol. Conversely, exposure of HT-29 cells to sub-toxic concentrations of H2O2 resulted in low executioner caspase activation that was inhibited by pretreatment with calcitriol. The sensitization of colon cancer cells to ROS-induced cytotoxicity may contribute to its assumed action as a chemopreventive agent and to its therapeutic potential alone or in combination with other anti-cancer modalities.

The impact of filipino micro health-insurance units on income-related equality of access to healthcare.

BACKGROUND: This study aims to assess the impact of being insured by micro-health insurance units (MIUs) on equality of access to health care among groups with inequitable income distribution. We measure equality by relating income with access to healthcare. The analysis is based on a household survey conducted in five regions in the Philippines in 2002. METHODS: We generated concentration curves and indices (CI) for insured and uninsured households (150 for each cohort in each region). We also elaborated a method to retain the relative income rank of households when data were aggregated across regions, as the regions had quite different nominal income levels. RESULTS: We found a significant effect of household income on access to hospitalizations among the uninsured households (a positive CI), but no such effect among the insured households (CI close to zero). As regards professionally attended deliveries, an increased tendency of poorer households to deliver at home (CI slightly negative) and a lower rate of deliveries in hospital (CI slightly positive and statistically significant) were reported by both uninsured and insured households. Access to consultations was unrelated to income among the insured (CI close to 0), but negatively correlated with income among the uninsured (a positive and significant CI). CONCLUSION: We conclude that MIUs in Philippines improve income-related equality of access to hospitalization and medical consultation in cases of illness. The findings of this study strengthen a claim for government support for the operation of MIUs as successful (albeit micro) suppliers of health insurance.

Vitamin D receptor defects: the story of hereditary resistance to vitamin D.

Vitamin D, synthesized in the epidermis in response to UV radiation, is devoid of any biological activity. The hormonal activity is due to its metabolite, 1 alpha, 25-dihydroxyvitamin D, named calcitriol. The actions of calcitriol are mediated by the vitamin D receptor, VDR, a member of the nuclear receptor family. The clinical presentation of hypocalcaemia, secondary hyperparathyroidism, early onset rickets in the presence of normal levels of serum 25-hydroxyvitamin D and markedly elevated serum levels of calcitriol is indicative of hereditary vitamin D resistant rickets, HVDRR. HVDRR is a recessive autosomal disorder that has been described in approximately 60 unrelated families. Dermal fibroblasts and peripheral blood lymphocytes can serve as target organ models to evaluate the interaction of calcitriol and its effector system. Failure of calcitriol to induce the enzyme 25-hydroxyvitamin D3 24 hydroxylase in fibroblasts or to inhibit lymphocyte mitogenesis can serve as the diagnosis for HVDRR Transfection studies employing site directed mutagenesis to mimic the natural mutations in VDR, have identified mutations that interfere with the major events in VDR signaling: hormone binding; heterodimerization with RXR; binding to vitamin D response elements in the promoters of target genes; and interaction with co- activators. Interference with one or more of these steps results in the clinical syndrome of HVDRR.

TNF-α increases the expression and activity of vitamin D receptor in keratinocytes: role of c-Jun N-terminal kinase.

Several inflammatory mediators increase calcitriol production by epidermal keratinocytes. In turn calcitriol attenuates the keratinocyte inflammatory response. Since the effect of the in-situ generated calcitriol depends also on the sensitivity to the hormone we studied the effect of inflammatory cytokines on the response of HaCaT human keratinocytes to calcitriol by examining the expression and transcriptional activity of VDR. Treatment with TNF, but not with IL-1ß or interferon γ, increased VDR protein level, while decreasing the level of its heterodimerization partner RXRα. This was associated with increased VDR mRNA levels. c-Jun N-terminal kinase, but not P38 MAPK or NFκB, was found to participate in the upregulation of VDR by TNF. The functional significance of the modulation of VDR and RXRα levels by TNF is manifested by increased induction of VDR target gene CYP24A1 by calcitriol. Calcitriol, in turn, inhibited the enhanced expression of VDR by TNF. In conclusion, the inflammatory cytokine TNF increases the response of keratinocytes to calcitriol through upregulation of its receptor VDR, which in turn is subject to negative feedback by the hormone accelerating the return of the keratinocyte vitamin D system to its basal activity. We surmise that the increased generation and sensitivity to calcitriol in keratinocytes play a role in the resolution of epidermal inflammation.

Vitamin D sensitizes breast cancer cells to the action of H2O2: mitochondria as a convergence point in the death pathway.

Calcitriol, the hormonal form of vitamin D3, sensitizes breast cancer cells to reactive oxygen species (ROS)-dependent cytotoxicity induced by various anticancer modalities. This effect could be due to increased generation of ROS and/ or to increased sensitivity of the target cells to ROS. This work examined the effect of calcitriol on the damage inflicted on breast cancer cells by the direct action of ROS represented by H2O2. Treatment of MCF-7 cells with H2O2 resulted in activation of caspase 7 as well as induction of caspase-independent cell death. Both were enhanced by 48-72 h of pretreatment with calcitriol. This effect was not due to modulation of H2O2 degradation or to a specific effect on *OH-mediated cytotoxicity. The H2O2-induced drop in mitochondrial membrane potential and release of cytochrome c were enhanced by calcitriol. These findings indicate that calcitriol sensitizes breast cancer cells to ROS-induced death by affecting event(s) common to both caspase-dependent and -independent modes of cell death upstream to mitochondrial damage.

Field based evidence of enhanced healthcare utilization among persons insured by micro health insurance units in Philippines.

Underutilization of healthcare is common among rural and low-income population segments in countries with lower income or inequitable income distribution. Micro health insurance units (MIUs) are created by informal sector groups because people cannot access health insurance or are dissatisfied with the programmes they can access. The policy choice to support MIUs relies on evidence that affiliation with these schemes increases healthcare utilization. This article examines new evidence of the association between affiliation with MIUs and healthcare utilization. We analyzed field data collected in 6 MIUs in the Philippines in 2002 (through a household survey encompassing 890 insured- and 1063 uninsured households). The two cohorts did not differ in demographic parameters, and differed only marginally in income and education levels, both higher amongst the insured. Insured persons reported higher hospitalization rates, higher rates of professionally-attended deliveries, lower rates of delivery at home, a higher frequency of primary-care physician encounters, a higher rate of diagnosed chronic diseases, and better drug compliance among chronically ill. Increased utilization by the insured is not due to adverse selection, judging by two facts: morbidity of the two cohorts, as assessed by a proxy indicator (the reported number of episodes of illness) did not differ; and rates of deliveries were even slightly higher among the uninsured. We conclude that MIUs in the Philippines can alleviate underutilization of heath care.