JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cells.

The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3',4':6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of ß-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.

p21WAF1/CIP1 promotes p53 protein degradation by facilitating p53-Wip1 and p53-Mdm2 interaction.

Downregulation of the p53 tumor suppressor in cancers is frequently accompanied by the upregulation of Wip1 (a phosphatase) and Mdm2 (an E3 ubiquitin ligase). Mdm2 binds and ubiquitinates p53, promoting its degradation by the proteasome. As the p53/Mdm2 interaction is alleviated by the phosphorylation of the serine-15 (S15) residue of p53, Wip1, which can directly dephosphorylate phospho-S15, facilitates the Mdm2-mediated degradation of p53. Here, we found that p21WAF1/CIP1, previously shown to bind p53 and Mdm2, reduces the cellular levels of p53 protein by decreasing its stability. This is accompanied by a decrease in p53-S15 phosphorylation levels. In agreement, p21 promotes the p53/Wip1 interaction. Additionally, p21 interacts with Wip1, forming a trimeric complex of p53, p21, and Wip1. Studies using a p21 deletion mutant that cannot bind p53 revealed that the p53/p21 complex is more efficient than p53 alone in facilitating the binding of p53 to Wip1 and Mdm2. These findings indicate that p21 is a novel negative regulator of p53 stability and therefore, may be used as a target to restore p53 activity by preventing the action of Wip1 and Mdm2 on p53.

Radiation-induced IL-1ß expression and secretion promote cancer cell migration/invasion via activation of the NF-κB-RIP1 pathway.

Here, we demonstrate that interleukin-1ß (IL-1ß) contributes to the γ-ionizing radiation (IR)-induced increase of migration/invasion in A549 lung cancer cells, and that this occurs via RIP1 upregulation. We initially observed that the protein expression and secreted concentration of IL-1ß were increased upon exposure of A549 cells to IR. We then demonstrated that IR-induced IL-1ß is located downstream of the NF-κB-RIP1 signaling pathway. Treatments with siRNA and specific pharmaceutical inhibitors of RIP1 and NF-κB suppressed the IR-induced increases in the protein expression and secreted concentration of IL-1ß. IL-1Ra, an antagonist of IL-1ß, treatment suppressed the IR-induced epithelial-mesenchymal transition (EMT) and IR-induced invasion/migration in vitro. These results suggest that IL-1ß could regulate IR-induced EMT. We also found that IR could induce the expression of IL-1ß expression in vivo and that of IL-1 receptor (R) I/II in vitro and in vivo. The IR-induced increases in the protein levels of IL-1 RI/II and IL-1ß suggest that an autocrine loop between IL-1ß and IL-1 RI/II might play important roles in IR-induced EMT and migration/invasion. Based on these collective results, we propose that IR concomitantly activates NF-κB and RIP1 to trigger the NF-κB-RIP1-IL-1ß-IL-1RI/II-EMT pathway, ultimately promoting metastasis.

Oral anticoagulants for nonvalvular atrial fibrillation in frail elderly patients: insights from the ARISTOPHANES study.

BACKGROUND: Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population. OBJECTIVES: This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin. METHODS: This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB. RESULTS: Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55-0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72-0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57-0.66) and dabigatran (HR: 0.79, 95% CI: 0.70-0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08-1.21) was associated with a higher risk vs warfarin. CONCLUSION: Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.

Radiosensitizer Effect of ß-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.

ß-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

Changes in quality of life and sleep across the perinatal period in women with mood disorders.

INTRODUCTION: The perinatal period represents a time of significant life changes associated with increases in sleep difficulties, depression, and potentially impaired quality of life (QoL). Associations between QoL and sleep among women with perinatal depression are poorly understood, and changes in QoL across the perinatal period have received little attention. METHODS: Participants were the treatment-as-usual group (n = 23) from a clinical trial testing an intervention for perinatal mood disorders. They completed the WHOQOL-Bref, had depression assessed with the HAM-D-17, and wore wrist actigraphs to estimate sleep for 1 week during third trimester and at 6 weeks postpartum. RESULTS: Higher education level was associated with better environmental QoL during pregnancy (p = .044) and presence of older children was associated with worse social QoL postpartum (p = .045). Psychological health QoL worsened (p = .014) across the perinatal period. Total sleep time (p = .001) and sleep efficiency (p = .008) decreased from third trimester to postpartum week 6, but sleep measures were not associated with QoL at either time point. Depressive symptoms decreased from pregnancy to postpartum week 6 and were inversely associated with postpartum physical and social QoL (p = .031 and .048). DISCUSSION: Factors contributing to self-rated QoL are variable across multiple domains during the perinatal period. QoL among our participants was lower than population norms. In our sample of women with depression and/or anxiety, QoL was related to postpartum depressive symptoms, but not to objectively measured sleep quality, quantity, or timing. Links between QoL and sleep may be inherently complex in perinatal women.

RIP1 Is a Novel Component of γ-ionizing Radiation-Induced Invasion of Non-Small Cell Lung Cancer Cells.

Abstract: Previously, we demonstrated that γ-ionizing radiation (IR) triggers the invasion/migration of A549 cells via activation of an EGFR-p38/ERK-STAT3/CREB-1-EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9 and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression, followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1-Src/STAT3-EMT pathway, ultimately promoting metastasis.

Evaluation of the Inhibitory Effects of (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (DiNap), a Natural Product Analog, on the Replication of Type 2 PRRSV In Vitro and In Vivo.

DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.

The current role for clinical and renal histological findings as predictor for outcome in Australian patients with lupus nephritis.

Objectives To investigate the current demographic, clinical and histological characteristics of patients with lupus nephritis (LN) in Western Australia (WA) with regards to their predictive value for patient and renal outcome. Methods Retrospective study of adult systemic lupus erythematosus (SLE) patients with a first renal biopsy demonstrating LN between 1997 and 2017 at a metropolitan tertiary hospital in WA. Clinical data were collected at baseline and last follow-up with renal biopsy findings classified by International Society of Nephrology (ISN) criteria. Annual incidence rates (AIRs)/100,000, Kaplan-Meyer curves and Cox regression hazard ratio for independent predictors for patient and renal survival were applied. Results The AIR was 3.3, 3.1 and 0.4 for Asian ( n = 29), Indigenous Australian (IA) ( n = 11) and Caucasian ( n = 43) patients, respectively ( p < 0.01). There was no significant subgroup difference regarding ISN class (proliferative 66%, membranous 19%, mesangial 15%), levels of proteinuria (median PCR 300 mg/mmol) or frequency of raised creatinine (31%), anti-dsDNA antibody (89%) or hypocomplementaemia (88%). Treatment included corticosteroids (91%), cyclophosphamide (30%), mycophenolate (67%) and antihypertensive drugs (67%). Five- (81%) and 10-year (70%) survival was lower for IAs than for Caucasians and Asians (95% each at both time points) ( p = 0.016). Five- and 10-year renal survival (endpoint renal replacement therapy (RRT)) was 86% and 64% for IA vs 100% for Asian, 100% and 96% for Caucasian patients ( p = 0.02). IA background was the only independent predictor for poor patient survival and together with male gender also for renal survival. Only 25% of all patients remained free of any organ damage with non-renal damage observed in 53% of survivors. Conclusions LN incidence in WA was 0.75/100,000 with the lowest rate observed in Caucasians. While Asian patients have the same favourable outlook as Caucasians, the outcome is much bleaker for IA patients. Other clinical and histological findings did not predict outcomes, and importantly more than half of all surviving patients accrued non-renal damage.

Production of a monoclonal antibody against a mannose-binding protein of Acanthamoeba culbertsoni and its localization.

Amoebae from the genus Acanthamoeba are facultative pathogens of humans and other animals. In humans they most frequently infect the eye causing a sight threatening infection known as Acanthamoeba keratitis (AK), and also cause an often fatal encephalitis (GAE). A mannose-binding protein (MBP) has been identified as being important for Acanthamoeba infection especially in AK. This lectin has previously been characterized from Acanthamoeba castellanii as consisting of multiple 130 kDa subunits. MBP expression correlates with pathogenic potential and is expressed in a number of Acanthamoeba species. Here we report the purification of a similar lectin from Acanthamoeba culbertsoni and the production of a monoclonal antibody to it. The A. culbertsoni MBP was isolated by affinity chromatography using α-D-mannose agarose and has an apparent molecular weight of 83 kDa. The monoclonal antibody is an IgM that is useful in both western blots and immunofluorescence. We expect that this antibody will be useful in the study of the pathology of A. culbertsoni and in its identification in clinical samples.

Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients.

Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor-specific antibodies (DSAs) posttransplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL-6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti-IL-6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes. Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL-6-IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.

Geographic Distribution of Scorpion Exposures in the United States, 2010-2015.

OBJECTIVES: To determine the geographic distribution of scorpion envenomations in the United States by zip code, with particular attention to the neurotoxic Centruroides sculpturatus (Arizona bark scorpion), for which an antivenom is available. METHODS: We obtained scorpion exposure cases for 2010 to 2015 from the National Poison Data System. Using geographic information systems software, we mapped total exposures and incidence rates for 9 states that reported more than 100 annual calls. We also mapped cases that reported fasciculations and nystagmus (unique to C. sculpturatus among native scorpions). RESULTS: The highest exposure incidences occurred in Phoenix (up to 677 per 100 000 population) and Tucson (584), both in Arizona. Elsewhere, high incidences were found in El Paso, Texas (213); Oklahoma City (209) and Tulsa (178), Oklahoma; and Las Vegas, Nevada (170). Fasciculations and nystagmus were reported in Arizona and southeastern Nevada, with small numbers in surrounding states, including Utah. CONCLUSIONS: Scorpion exposures occurred at baseline rates throughout many of the southern states, whereas several states reported effects indicative of Arizona bark scorpion envenomation. Public Health Implications. Public and health care provider education, as well as the stocking of antivenom, should be targeted based on these findings.

Risk factors associated with in-hospital mortality in elderly patients admitted to a regional trauma center after sustaining a fall.

BACKGROUND AND AIMS: Falls are a significant cause of mortality in the elderly patients. Despite this, the literature on in-hospital mortality related to elderly falls remains sparse. Our study aims to determine the risk factors associated with in-hospital mortality in elderly patients admitted to a regional trauma center after sustaining a fall. METHODS: All elderly case records with fall-related injuries between 2003 and 2013 were retrospectively analyzed for demographic characteristics, injury severities, comorbidity factors and clinical outcomes. Logistic regression analysis was used to examine the risk factors associated with in-hospital mortality. RESULTS: In total, 1026 elderly patients with fall-related injuries were included in the study. The average age of patients was 80.94 ± 8.16 years. Seventy seven percent of the patients had at least one comorbid condition. Majority of the falls occurred at home. More than half of the patients fell from ground level. Overall, the in-hospital mortality rate was 16 %. Head injury constituted the most common injury sustained in patients who died (77 %). In addition to age, ISS, GCS, ICU admission and anemia were significantly (P < 0.05) associated with in-hospital deaths in elderly fall patients. CONCLUSION: Ground-level falls in the elderly can be devastating and carry a significant mortality rate. Elderly patients with anemia were two times more likely to die in the hospital after sustaining a fall in our study population. Increased focus on anemia which is often underappreciated in elderly fall patients can be beneficial in improving outcomes and reducing in-hospital mortality.

A key lysine residue in the AXH domain of ataxin-1 is essential for its ubiquitylation.

Spinocerebellar ataxia type 1 (SCA1), an autosomal-dominant neurodegenerative disorder, is caused by expansion of the polyglutamine tract within ataxin-1 (ATXN1). The AXH domain of ATXN1 can mediate neurodegeneration through its interaction with other proteins. We have previously showed that the ubiquitin-conjugating enzyme UbcH6 modulates the transcriptional repression activity of ATXN1 through ubiquitylation. In the present study, we sought to identify sites in the AXH domain that are ubiquitylated by UbcH6. Systematic replacement of each lysine residue in the AXH domain revealed that the lysine at 589 (K589) of ATXN1 is essential for its ubiquitylation by UbcH6. Mass spectrometry studies further confirmed the ubiquitylation site. Interestingly, protein aggregation was significantly enhanced in mutant AXH K589R, implying that the aggregation is strongly associated with the level of ATXN1 expression. Our study may suggest a therapeutic potential of UbcH6 in the treatment of SCA1.

Herpesvirus-associated ubiquitin-specific protease (HAUSP) modulates peroxisome proliferator-activated receptor γ (PPARγ) stability through its deubiquitinating activity.

The peroxisome proliferator-activated receptor γ (PPARγ) is a central regulator of adipogenesis and modulates glucose and lipid metabolism. In this study, herpesvirus-associated ubiquitin-specific protease (HAUSP) was isolated as a binding partner of PPARγ. Both endogenous and exogenous PPARγ associated with HAUSP in co-immunoprecipitation analysis. HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenous PPARγ through its deubiquitinating activity. Site-directed mutagenesis experiments showed that the Lys(462) residue of PPARγ is critical for ubiquitination. HBX 41,108, a specific inhibitor of HAUSP, abolished the increase in PPARγ stability induced by HAUSP. In addition, knockdown of endogenous HAUSP using siRNA decreased PPARγ protein levels. HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPARγ in luciferase activity assays. Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPARγ target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP. In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARγ and lipid accumulation in the liver. Our results demonstrate that the stability and activity of PPARγ are modulated by the deubiquitinating activity of HAUSP, which may be a target for the development of anti-diabetic drugs.

Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.

Quality of life and emotional distress between patients on peritoneal dialysis versus community-based hemodialysis.

PURPOSE: Patient-reported outcomes are important endpoints to evaluate new models of renal delivery. This is the first study to compare Quality of Life (QOL) and emotional adjustment outcomes between patients on community-based hemodialysis (HD) and those on peritoneal dialysis (PD). METHODS: Data were collected between 2009 and 2011 from a cross-sectional sample of 232 HD patients and 201 PD patients recruited through community dialysis centers and outpatient PD clinics in Singapore. Participants completed the Hospital Anxiety and Depression Scale, World Health Organization Quality of Life Brief and the Short form for the Kidney Disease Quality of Life. Measures of ESRD severity, comorbidity and biochemistry were also collected. RESULTS: Physical and emotional QOL impairments were noted for both dialysis groups. Case-mix-adjusted comparisons indicated higher symptoms of depression (p = 0.027), and poorer physical health yet higher satisfaction with care (p = 0.001) in PD relative to community-based HD. CONCLUSIONS: Peritoneal dialysis regimes offer flexibility and autonomy under the support of PD teams. Although outcomes for most QOL domains measured were equivalent, PD patients are more satisfied with care but are at risk for emotional distress and provide poor ratings of physical health. Further research is needed to explore the expansion of standards of care to address psychosocial needs in PD populations.

Neonatal and Maternal Ichthyosiform Dermopathy in Association with Kava Use during Pregnancy.

INTRODUCTION: Kava, a substance derived from the Piper methysticum plant, is enjoying a surge in popularity in the United States due to its purported anxiolytic and analgesic effects. Though ichthyosiform dermopathy is a known adverse effect associated with chronic kava exposure in adults, dermopathy in a newborn due to maternal kava use has not yet been described. CASE REPORT: This is a case of a 41-year-old woman who was taking a combination kava/kratom product throughout her pregnancy. She developed an ichthyosiform dermopathy that resolved after she stopped using the product postpartum. Her male infant had a neonatal course complicated by both neonatal opioid withdrawal syndrome, attributed to maternal kratom and buprenorphine use, as well as a diffuse ichthyosiform rash similar to descriptions of kava ichthyosiform dermopathy in adults. His neonatal course was complicated by Group B streptococcus and Serratia marscecens bacteremia (treated with antibiotics) and seizures (treated with lorazepam and phenobarbital). His rash resolved completely by day of life 22. At 9-month outpatient follow-up, he had no dermatologic abnormalities or rash recurrence. DISCUSSION: Maternal kava use during pregnancy may cause fetal dermopathy presenting as an acquired ichthyosis. More public education is needed about the potential consequences of kava use, particularly during pregnancy.