Simulating the healthcare workforce impact and capacity for pancreatic cancer care in Victoria: a model-based analysis.

BACKGROUND: The incidence of pancreatic cancer is rising. With improvements in knowledge for screening and early detection, earlier detection of pancreatic cancer will continue to be more common. To support workforce planning, our aim is to perform a model-based analysis that simulates the potential impact on the healthcare workforce, assuming an earlier diagnosis of pancreatic cancer. METHODS: We developed a simulation model to estimate the demand (i.e. new cases of pancreatic cancer) and supply (i.e. the healthcare workforce including general surgeons, medical oncologists, radiation oncologists, pain medicine physicians, and palliative care physicians) between 2023 and 2027 in Victoria, Australia. The model compares the current scenario to one in which pancreatic cancer is diagnosed at an earlier stage. The incidence of pancreatic cancer in Victoria, five-year survival rates, and Victoria's population size were obtained from Victorian Cancer Registry, Cancer Council NSW, and Australian Bureau of Statistics respectively. The healthcare workforce data were sourced from the Australian Government Department of Health and Aged Care's Health Workforce Data. The model was constructed at the remoteness level. We analysed the new cases and the number of healthcare workforce by profession together to assess the impact on the healthcare workforce. RESULTS: In the status quo, over the next five years, there will be 198 to 220 stages I-II, 297 to 330 stage III, and 495 to 550 stage IV pancreatic cancer cases diagnosed annually, respectively. Assuming 20-70% of the shift towards pancreatic cancer's earlier diagnosis (shifting from stage IV to stages I-II pancreatic cancer within one year), the stages I-II cases could increase to 351 to 390 or 598 to 665 per year. The shift to early diagnosis led to substantial survival gains, translating into an additional 284 or 795 out of 5246 patients with pancreatic cancer remaining alive up to year 5 post-diagnosis. Workforce supply decreases significantly by the remoteness levels, and remote areas face a shortage of key medical professionals registered in delivering pancreatic cancer care, suggesting travel necessities by patients or clinicians. CONCLUSION: Improving the early detection and diagnosis of pancreatic cancer is expected to bring significant survival benefits, although there are workforce distribution imbalances in Victoria that may affect the ability to achieve the anticipated survival gain.

Protocol for integrated solutions for healthy birth, growth and development: a cluster-randomised controlled trial to evaluate the effectiveness of a mixed nutrition intervention package in reducing child undernutrition in Lao People's Democratic Republic.

INTRODUCTION: While Lao People's Democratic Republic has seen economic gains in recent years, one-third of children aged 5 years and under are stunted. There is a need for evidence around clinically effective and cost-effective integrated nutrition-specific and nutrition-sensitive interventions in the local context. METHODS AND ANALYSIS: We aim to conduct a cluster-randomised control trial to test the effectiveness of an integrated package of community-based nutrition-specific and nutrition-sensitive interventions compared with the standard government package of nutrition actions. The trial will be in six districts within the province of Vientiane. We will recruit pregnant women in their third trimester and follow the children born to them every 6 months until 18 months of age. A total of 256 villages (serviced by 34 health centres) will be randomised to a control arm or an intervention arm using a minimisation algorithm. The primary outcome is the prevalence of stunting among children aged 6, 12 and 18 months. The secondary outcomes include prevalence of low birth weight and wasting among children aged 6, 12 and 18 months. Analyses for the primary and secondary outcomes will be conducted at the mother-infant dyad level and adjusted for the cluster randomisation. The difference in prevalence of low birth weight, wasting and stunting between control and intervention groups will be assessed using Pearson's χ2 tests and 95% CIs for the group difference, adjusted for clustering. ETHICS AND DISSEMINATION: The trial protocol was approved by the Alfred Human Research Ethic Committee (Ref: 227/16) and the Lao National Ethics Committee for Health Research (Ref: 81). The trial was registered with the Australian New Zealand Clinical Trials Registry on 28 April 2020 (ACTRN12620000520932). The results will be disseminated at different levels: study participants; the local community; other Lao stakeholders including policymakers; and an international audience. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry: ACTRN12620000520932.

Cost-Effectiveness of Osteoporosis Opportunistic Screening Using Computed Tomography in China.

OBJECTIVES: Underutilization and insufficient availability of dual-energy X-ray absorptiometry (DXA) in diagnosing osteoporosis in China could be changed by adopting unindicated quantitative computed tomography. We aimed to assess the cost-effectiveness of quantitative computed tomography (QCT) as a screening tool for osteoporosis in China. METHODS: A Markov microsimulation model was developed to assess the long-term costs and quality-adjusted life-years (QALYs) saved associated with 2 examinations as opportunistic screening for osteoporosis in a general population without prior histories of fracture. The diagnostic performance of both examinations was incorporated into the model. In lifetime modeling, opportunistically screened people may face the risk of experiencing hip, vertebral, and wrist fractures depending on their osteoporosis, age, and sex. Model parameters were informed by published literature. RESULTS: The base-case result showed that QCT was associated with higher costs ($6054 vs $5883) and higher benefits (10.081 vs 10.071 QALYs) in comparison with DXA, making QCT a cost-effective option for opportunistic screening (incremental cost-effectiveness ratio of US $16 430/QALY). Screening with QCT led to fewer fractures over the lifetime simulation: for every 10 000 people screened, 129 fractures (32 hip, 78 vertebral, and 19 wrist fractures) could be avoided because of the early initiation of antiosteoporotic treatment. CONCLUSIONS: Using QCT to screen people for osteoporosis is more cost-effective than standard practice in China, where access to DXA is minimal. This finding could support opportunistic osteoporosis screening using QCT in other countries with similar status.

Impact of the Medicare Benefits Schedule Rebate (MBSR) freeze on General Practice (GP) use: multivariable regression analysis.

BACKGROUND: In 2015, the Australian government froze the Medicare Benefits Schedule Rebate (MBSR) for General Practitioner (GP) service use. This paper aimed to explore the impact of the MBSR freeze on the demand for GP services in Victoria, Australia, for three years, from 2014 to 2016. METHOD: Annual data on GP service utilisation by the Victorian State Statistical Area Level 3 (SA3) were analysed using 2015 as the reference year (MBSR freeze year). We compared annual per-person GP service use before and after the MBSR freeze for each SA3. Socioeconomic Indexes for Areas (SEIFA) scores and regions of Victoria (Greater Melbourne and the Rest of Victoria) were used to identify the most disadvantaged SA3s in Victoria. We conducted a multivariable regression analysis for the number of GP services per patient by SA3, controlling for regions of Victoria, the number of GP services, the proportion of bulk-billed visits, age group, gender and year. FINDINGS: After adjusting for age group, gender, region, SEIFA, the number of GPs and the proportion of bulk-billed GP visits, mean GP services per person per year declined steadily between 2014 and 2016, with a 3% or 0.11 visit (-0.114, 95%CI: -0.134; -0.094, P = < 0.001) reduction in mean utilisation in 2016 compared to 2014. In disadvantaged SA3s, there was a fall in the number of GP services that were bulk-billed during and after the MBSR freeze compared to 2014, and this fall was large in LOW SEIFA SA3s, with a reduction in 17% of mean bulk-billed GP services. CONCLUSION: The MBSR freeze for GP consultations in 2015 resulted in a reduction in the annual per capita demand for GP visits, with the impact of reduced demand more significant in lower socioeconomic and regional/rural areas. The GP funding policies must consider the demand differences by social-economic status and location.

Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity.

Ferroptosis is an iron-dependent form of regulated cell death associated with uncontrolled membrane lipid peroxidation and destruction. Previously, we showed that dietary dihomo-gamma-linolenic acid (DGLA; 20: 3(n-6)) triggers ferroptosis in the germ cells of the model organism, Caenorhabditis elegans. We also demonstrated that ether lipid-deficient mutant strains are sensitive to DGLA-induced ferroptosis, suggesting a protective role for ether lipids. The vinyl ether bond unique to plasmalogen lipids has been hypothesized to function as an antioxidant, but this has not been tested in animal models. In this study, we used C. elegans mutants to test the hypothesis that the vinyl ether bond in plasmalogens acts as an antioxidant to protect against germ cell ferroptosis as well as to protect from whole-body tert-butyl hydroperoxide (TBHP)-induced oxidative stress. We found no role for plasmalogens in either process. Instead, we demonstrate that ether lipid-deficiency disrupts lipid homeostasis in C. elegans, leading to altered ratios of saturated and monounsaturated fatty acid (MUFA) content in cellular membranes. We demonstrate that ferroptosis sensitivity in both wild type and ether-lipid deficient mutants can be rescued in several ways that change the relative abundance of saturated fats, MUFAs and specific polyunsaturated fatty acids (PUFAs). Specifically, we reduced ferroptosis sensitivity by (1) using mutant strains unable to synthesize DGLA, (2) using a strain carrying a gain-of-function mutation in the transcriptional mediator MDT-15, or (3) by dietary supplementation of MUFAs. Furthermore, our studies reveal important differences in how dietary lipids influence germ cell ferroptosis versus whole-body peroxide-induced oxidative stress. These studies highlight a potentially beneficial role for endogenous and dietary MUFAs in the prevention of ferroptosis.

Dietary Lipids Induce Ferroptosis in Caenorhabditiselegans and Human Cancer Cells.

Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans. Exogenous DGLA is also sufficient to induce ferroptosis in human cells, pinpointing this omega-6 PUFA as a conserved metabolic instigator of this lethal process. In both C. elegans and human cancer cells, ether-lipid synthesis protects against ferroptosis. These results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats and indicate that endogenous ether lipids act to prevent this nonapoptotic cell fate.

TEAD4, YAP1 and WWTR1 prevent the premature onset of pluripotency prior to the 16-cell stage.

In mice, pluripotent cells are thought to derive from cells buried inside the embryo around the 16-cell stage. Sox2 is the only pluripotency gene known to be expressed specifically within inside cells at this stage. To understand how pluripotency is established, we therefore investigated the mechanisms regulating the initial activation of Sox2 expression. Surprisingly, Sox2 expression initiated normally in the absence of both Nanog and Oct4 (Pou5f1), highlighting differences between embryo and stem cell models of pluripotency. However, we observed precocious ectopic expression of Sox2 prior to the 16-cell stage in the absence of Yap1, Wwtr1 and Tead4 Interestingly, the repression of premature Sox2 expression was sensitive to LATS kinase activity, even though LATS proteins normally do not limit activity of TEAD4, YAP1 and WWTR1 during these early stages. Finally, we present evidence for direct transcriptional repression of Sox2 by YAP1, WWTR1 and TEAD4. Taken together, our observations reveal that, while embryos are initially competent to express Sox2 as early as the four-cell stage, transcriptional repression prevents the premature expression of Sox2, thereby restricting the pluripotency program to the stage when inside cells are first created.

Pediatric Injuries Treated at a Level 1 Trauma Center After an F5 Tornado.

BACKGROUND: On May 22, 2011, an F5 tornado ripped through the city of Joplin, Mo, resulting in over 150 fatalities and over 750 injuries. Pediatric trauma centers in the region needed to be prepared to receive patients. Little data exist on the types of patients who are received at pediatric trauma centers after disasters such as tornados. OBJECTIVE: The purpose of this study is to describe the patients received at the nearest level 1 pediatric trauma center after the tornado. METHODS: Cases were identified through the trauma registry. Data regarding patient demographics, past medical history, characteristics of injury, treatment received, and outcomes were obtained retrospectively from medical records. RESULTS: A total of 10 patients were received at the pediatric trauma center. Traumatic brain injury was the most common diagnosis followed by orthopedic and maxillofacial injuries. Seven patients required surgical procedures in the operating room, but only 1 patient required surgery within the first 24 hours of arrival. Eight patients were intubated and were in the pediatric intensive care unit. The average length of stay in the hospital was 19.4 days with a range of 14 hours to 94 days. CONCLUSIONS: Immediately after a significant tornado in the referral region, pediatric trauma centers need to prepare to receive patients. Head injuries will likely be common, and pediatric trauma centers will likely receive multiple intubated patients. Knowledge of injuries received and resources needed can better prepare these trauma centers for future devastating tornadoes.

A Caenorhabditis elegans model for ether lipid biosynthesis and function.

Ether lipids are widespread in nature, and they are structurally and functionally important components of membranes. The roundworm, Caenorhabditis elegans, synthesizes numerous lipid species containing alkyl and alkenyl ether bonds. We isolated C. elegans strains carrying loss-of-function mutations in three genes encoding the proteins required for the initial three steps in the ether lipid biosynthetic pathway, FARD-1/FAR1, ACL-7/GNPAT, and ADS-1/AGPS. Analysis of the mutant strains show that they lack ether lipids, but possess the ability to alter their lipid composition in response to lack of ether lipids. We found that increases in de novo fatty acid synthesis and reduction of stearoyl- and palmitoyl-CoA desaturase activity, processes that are at least partially regulated transcriptionally, mediate the altered lipid composition in ether lipid-deficient mutants. Phenotypic analysis demonstrated the importance of ether lipids for optimal fertility, lifespan, survival at cold temperatures, and resistance to oxidative stress.Caenorhabditis.

s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways.

s-adenosylmethionine (SAM) is the sole methyl donor modifying histones, nucleic acids, and phospholipids. Its fluctuation affects hepatic phosphatidylcholine (PC) synthesis or may be linked to variations in DNA or histone methylation. Physiologically, low SAM is associated with lipid accumulation, tissue injury, and immune responses in fatty liver disease. However, molecular connections among SAM limitation, methyltransferases, and disease-associated phenotypes are unclear. We find that low SAM can activate or attenuate Caenorhabditis elegans immune responses. Immune pathways are stimulated downstream of PC production on a non-pathogenic diet. In contrast, distinct SAM-dependent mechanisms limit survival on pathogenic Pseudomonas aeruginosa. C. elegans undertakes a broad transcriptional response to pathogens and we find that low SAM restricts H3K4me3 at Pseudomonas-responsive promoters, limiting their expression. Furthermore, this response depends on the H3K4 methyltransferase set-16/MLL. Thus, our studies provide molecular links between SAM and innate immune functions and suggest that SAM depletion may limit stress-induced gene expression.

Myasthenia gravis exacerbation with low dose ocular botulinum toxin for epiphoria.

We present a man with clinically stable systemic myasthenia gravis (MG) which flared with a low dose of peripherally injected botulinum toxin type A (BTX-A). Botulinum toxin drugs generally have an excellent safety profile, however, they are contentious in patients with neuromuscular disorders. Despite this, there remain limited reports on the systemic effects of botulinum therapy in patients with MG. This man is one of less than 10 reported patients worldwide in whom MG was exacerbated by a peripheral BTX-A injection. This is an important reminder to Australian clinicians of the potential risks of this common place medication in patients with neuromuscular disorders, even those with stable disease.

Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo.

The Mediator is a conserved transcriptional coregulator complex required for eukaryotic gene expression. In Caenorhabditis elegans, the Mediator subunit mdt-15 is essential for the expression of genes involved in fatty acid metabolism and ingestion-associated stress responses. mdt-15 loss of function causes defects in reproduction and mobility and shortens lifespan. In the present study, we find that worms with mutated or depleted mdt-15 (mdt-15 worms) exhibit decreased membrane phospholipid desaturation, especially in phosphatidylcholine. Accordingly, mdt-15 worms exhibit disturbed endoplasmic reticulum (ER) homeostasis, as indicated by a constitutively activated ER unfolded protein response (UPR(ER)). Activation of this stress response is only partially the consequence of reduced membrane lipid desaturation, implicating other mdt-15-regulated processes in maintaining ER homeostasis. Interestingly, mdt-15 inactivation or depletion of the lipid metabolism enzymes stearoyl-CoA-desaturases (SCD) and S-adenosyl methionine synthetase (sams-1) activates the UPR(ER) without promoting misfolded protein aggregates. Moreover, these worms exhibit wild-type sensitivity to chemically induced protein misfolding, and they do not display synthetic lethality with mutations in UPR(ER) genes, which cause protein misfolding. Therefore, the constitutively activated UPR(ER) in mdt-15, SCD, and sams-1 worms is not the consequence of proteotoxic stress but likely is the direct result of changes in ER membrane fluidity and composition. Together, our data suggest that the UPR(ER) is induced directly upon membrane disequilibrium and thus monitors altered ER homeostasis.

DNA damage induced MutS homologue hMSH4 acetylation.

Acetylation of non-histone proteins is increasingly recognized as an important post-translational modification for controlling the actions of various cellular processes including DNA repair and damage response. Here, we report that the human MutS homologue hMSH4 undergoes acetylation following DNA damage induced by ionizing radiation (IR). To determine which acetyltransferases are responsible for hMSH4 acetylation in response to DNA damage, potential interactions of hMSH4 with hTip60, hGCN5, and hMof were analyzed. The results of these experiments indicate that only hMof interacts with hMSH4 in a DNA damage-dependent manner. Intriguingly, the interplay between hMSH4 and hMof manipulates the outcomes of nonhomologous end joining (NHEJ)-mediated DNA double strand break (DSB) repair and thereby controls cell survival in response to IR. This study also shows that hMSH4 interacts with HDAC3, by which HDAC3 negatively regulates the levels of hMSH4 acetylation. Interestingly, elevated levels of HDAC3 correlate with increased NHEJ-mediated DSB repair, suggesting that hMSH4 acetylation per se may not directly affect the role of hMSH4 in DSB repair.

A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans.

Sterol regulatory element-binding proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids and are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can contribute to obesity, fatty liver disease, and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls genes in the one-carbon cycle, which produces the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for the synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver, and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a feedback mechanism whereby maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.

The influence of bacterial diet on fat storage in C. elegans.

BACKGROUND: The nematode Caenorhabditis elegans has emerged as an important model for studies of the regulation of fat storage. C. elegans feed on bacteria, and various strains of E. coli are commonly used in research settings. However, it is not known whether particular bacterial diets affect fat storage and metabolism. METHODOLOGY/PRINCIPAL FINDINGS: Fat staining of fixed nematodes, as well as biochemical analysis of lipid classes, revealed considerable differences in fat stores in C. elegans growing on four different E. coli strains. Fatty acid composition and carbohydrate levels differ in the E. coli strains examined in these studies, however these nutrient differences did not appear to have a causative effect on fat storage levels in worms. Analysis of C. elegans strains carrying mutations disrupting neuroendocrine and other fat-regulatory pathways demonstrated that the intensity of Nile Red staining of live worms does not correlate well with biochemical methods of fat quantification. Several neuroendocrine pathway mutants and eating defective mutants show higher or lower fat storage levels than wild type, however, these mutants still show differences in fat stores when grown on different bacterial strains. Of all the mutants tested, only pept-1 mutants, which lack a functional intestinal peptide transporter, fail to show differential fat stores. Furthermore, fatty acid analysis of triacylglycerol stores reveals an inverse correlation between total fat stores and the levels of 15-methylpalmitic acid, derived from leucine catabolism. CONCLUSIONS: These studies demonstrate that nutritional cues perceived in the intestine regulate fat storage levels independently of neuroendocrine cues. The involvement of peptide transport and the accumulation of a fatty acid product derived from an amino acid suggest that specific peptides or amino acids may provide nutritional signals regulating fat metabolism and fat storage levels.

Vouchers for chronic disease care.

This paper explores the economic implications of vouchers for chronic disease management with respect to achieving objectives of equity and efficiency. Vouchers as a payment policy instrument for health care services have a set of properties that suggest they may address both demand-side and supply-side issues, and contribute to equity and efficiency. They provide a means whereby health care services can be targeted at selected groups, enabling consumer choice of provider, and encouraging competition in the supply of health services. This analysis suggests that, when structured appropriately, vouchers can support consumers to choose services that will meet their health care needs and encourage competition among providers. Although they may not be appropriate across the entire health care system, there are features of vouchers that make them a potentially attractive option, especially for the management of chronic disease.

Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite.

Methylselenol has been implicated as an active anticancer selenium (Se) metabolite. However, its in vivo efficacy against prostate cancer (PCa) has yet to be established. Here, we evaluated the growth inhibitory effects of two presumed methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in comparison with selenomethionine (SeMet) and selenite in DU145 and PC-3 human PCa xenografts in athymic nude mice. Each Se was given by a daily single oral dose regimen starting the day after the subcutaneous inoculation of cancer cells. We analyzed serum, liver and tumor Se content to confirm supplementation status and apoptosis indices and tumor microvessel density for association with antitumor efficacy. Furthermore, we analyzed lymphocyte DNA integrity to detect genotoxic effect of Se treatments. The data show that MSeA and MSeC exerted a dose-dependent inhibition of DU145 xenograft growth and both were more potent than SeMet and selenite, in spite of less tumor Se retention than in the SeMet-treated mice. Selenite treatment increased DNA single-strand breaks in peripheral lymphocytes, whereas the other Se forms did not. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and cleaved caspase-3 indices (apoptosis) from MSeC-treated tumors were higher than tumors from control mice or MSeA-treated mice, whereas the microvessel density index was lower in tumors from MSeA-treated mice. In the PC-3 xenograft model, only MSeA was growth inhibitory at a dose of 3 mg/kg body wt. In summary, our data demonstrated superior in vivo growth inhibitory efficacy of MSeA over SeMet and selenite, against two human PCa xenograft models without the genotoxic property of selenite.

Methylseleninic acid enhances taxane drug efficacy against human prostate cancer and down-regulates antiapoptotic proteins Bcl-XL and survivin.

PURPOSE: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (Taxol) through enhancing multiple caspases. This study aimed to (a) determine the general applicability of the sensitization effect for taxane drugs in vitro, (b) establish the enhancement of paclitaxel efficacy by MSeA in vivo, and (c) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis. EXPERIMENTAL DESIGN: DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA, and the molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance. RESULTS: MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with the equivalent efficacy of a four-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expression of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxel-induced apoptosis. CONCLUSIONS: MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part, by down-regulating the basal and paclitaxel-induced expression of both Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.

Apparent efficacy of food-based calcium supplementation in preventing rickets in Bangladesh.

To determine whether increased Ca intakes can prevent rickets in a susceptible group of children living in a rickets-endemic area of Bangladesh, we conducted a 13-month long, double-blind, clinical trial with 1-to 5-year-old children who did not present with rickets but ranked in the upper decile of plasma alkaline phosphatase (AP) activity of a screening cohort of 1,749 children. A total of 158 children were randomized to a milk-powder-based dietary supplement given daily, 6 days/week, and providing either 50, 250, or 500 mg Ca, or 500 mg Ca plus multivitamins, iron, and zinc. Upon initial screening, 194 healthy children presented with no rachitic leg signs and had serum AP in the upper decile (>260 u/dl) of the cohort. When 183 of those subjects were re-screened after a 7-month pre-trial period, 23 (12.6%) had developed rachitic leg signs, suggesting an annual risk of 21.5% in this cohort. Of those still not presenting with leg signs and completing 13 months of dietary intervention, none showed rachitic leg signs, none showed significant radiological evidence of active rickets, and all showed carpal ossification normal for age after that intervention. These results are consistent with even the lowest amount of supplemental Ca (50 mg/day) being useful in supporting normal bone development in this high-risk population.

Function of the Caenorhabditis elegans ABC transporter PGP-2 in the biogenesis of a lysosome-related fat storage organelle.

Caenorhabditis elegans gut granules are intestine specific lysosome-related organelles with birefringent and autofluorescent contents. We identified pgp-2, which encodes an ABC transporter, in screens for genes required for the proper formation of gut granules. pgp-2(-) embryos mislocalize birefringent material into the intestinal lumen and are lacking in acidified intestinal V-ATPase-containing compartments. Adults without pgp-2(+) function similarly lack organelles with gut granule characteristics. These cellular phenotypes indicate that pgp-2(-) animals are defective in gut granule biogenesis. Double mutant analysis suggests that pgp-2(+) functions in parallel with the AP-3 adaptor complex during gut granule formation. We find that pgp-2 is expressed in the intestine where it functions in gut granule biogenesis and that PGP-2 localizes to the gut granule membrane. These results support a direct role of an ABC transporter in regulating lysosome biogenesis. Previously, pgp-2(+) activity has been shown to be necessary for the accumulation of Nile Red-stained fat in C. elegans. We show that gut granules are sites of fat storage in C. elegans embryos and adults. Notably, levels of triacylglycerides are relatively normal in animals defective in the formation of gut granules. Our results provide an explanation for the loss of Nile Red-stained fat in pgp-2(-) animals as well as insight into the specialized function of this lysosome-related organelle.