Vitamin D status and clinical implications in the adult population of Malaysia: a position paper by the Malaysian Vitamin D Special Interest Group.

PURPOSE: Vitamin D deficiency and insufficiency is common among populations globally, and in Asia and Malaysia. The purpose of this Position Paper is to propose recommendations for both clinicians and non-clinicians to promote vitamin D sufficiency in Malaysian adults. Formation of a national multisector, multidisciplinary alliance is also proposed to progress initiatives relating to safe sun exposure, adequate vitamin D intake through food fortification, and vitamin D supplementation for high-risk groups. METHODS: Literature reviews were undertaken to inform summaries of the following: vitamin D status globally and in Asian and Malaysian populations, vitamin D status among individuals with common medical conditions, and current recommendations to achieve vitamin D sufficiency through sun exposure, food intake and supplementation. Recommendations were based on the findings of the literature reviews, recent European guidance on vitamin D supplementation, the 2018 road map for action on vitamin D in low- and middle-income countries, and research recommendations proposed by the Malaysian Ministry of Health in 2017. RESULTS: Recommendations on assessment of vitamin D in the adult Malaysian population include using serum or plasma 25-hydroxyvitamin D concentration as a biomarker, widespread participation by Malaysian laboratories in the Vitamin D Standardization Program, adoption of the US Endocrine Society definitions of vitamin D deficiency and insufficiency, and development of a comprehensive nationwide vitamin D status study. Specific high-risk groups are identified for vitamin D assessment and recommendations relating to loading doses and ongoing management are also made. CONCLUSION: This Position Paper provides individual clinicians and national stakeholder organisations with clear recommendations to achieve vitamin D sufficiency in the adult population of Malaysia.

Effect of screening, brief intervention and referral to treatment for unhealthy alcohol and other drug use in mental health treatment settings: a randomized controlled trial.

AIMS: To test the efficacy of a brief intervention to reduce alcohol or drug use and to promote use of addiction services among patients seeking mental health treatment. DESIGN AND SETTING: A multi-centre, longitudinal, two-group randomized controlled trial with randomization within each of two mental health treatment systems located in Ventura County and Los Angeles County in California, USA. PARTICIPANTS: A total of 718 patients (49.2% female) aged 18 and older with a mental health diagnosis and either a heavy drinking day or any use of cannabis or stimulants in the past 90 days. INTERVENTION AND COMPARATOR: A motivation-based brief intervention with personalized feedback (screening, brief intervention and referral to treatment (SBIRT) condition) (n = 354) or a health education session (control condition) (n = 364). MEASUREMENTS: Primary outcomes included frequency of heavy drinking days, days of cannabis use and days of stimulant use at the primary end-point 3 months post-baseline. Secondary outcomes included frequency and abstinence from substance use out to a 12-month follow-up and the use of addiction treatment services. FINDINGS: Participants in the SBIRT condition had fewer heavy drinking days [odds ratio (OR) = 0.53; 95% credible interval (CrI) = 0.48-0.6] and fewer days of stimulant use (OR = 0.58; 95% CrI = 0.50-0.66) at the 3-month follow-up compared with participants in the health education condition. Participants in the SBIRT condition did not comparatively reduce days of cannabis use at the 3-month follow-up (OR = 0.93; 95% CrI = 0.85-1.01). Secondary outcomes indicated sustained effects of SBIRT on reducing the frequency of heavy drinking days and days of stimulant use. No effects were observed on abstinence rates or use of addiction treatment services. CONCLUSIONS: Screening and brief intervention for unhealthy alcohol and drug use in mental health treatment settings were effective at reducing the frequency of heavy drinking and stimulant use.

A pilot study of 4CYTE™ Epiitalis® Forte, a novel nutraceutical, in the management of naturally occurring osteoarthritis in dogs.

The primary goal of this pilot study was to assess, the efficacy of a new nutraceutical, 4CYTE™ Epiitalis® Forte, containing, as a standalone, a proprietary plant oil extract, Epiitalis, in dogs presenting with signs of osteoarthritis (OA). Fifty dogs aged 9.2 (±3.2) years with signs of naturally occurring OA were included in this report. They were free of other comorbidities and were not on any medications except for those utilised for managing their OA. In these dogs, the current treatments were continued to avoid any sudden changes in their disease management. The effects of the 4CYTE Epiitalis Forte were assessed both at the beginning and at the end of a 1 month-long treatment period. The evaluation consisted of an objective lameness assessment (TPI%[total pressure index]) using a gait analysis (GAITRite® Portable Walkway System) and a subjective quality-of-life questionnaire, the Helsinki Chronic Pain Index (HCPI). Additional exploratory objective measurements included the Symmetry Index (SI) and the fore/hind limb ratio (T/P TPI%). Of dogs, 74% (34/46) registered a numerical improvement in TPI% in their worse limb. In addition, of the 93.5% of the dogs that demonstrated improvement in their HCPI scores by at least 5% on the quality-of-life questionnaire, 79% demonstrated improvements in gait based on TPI%. Finally, there were improvements measured in both exploratory objective endpoints SI and T/P TPI%. These encouraging results will be used to develop a protocol for a follow-up placebo-controlled randomised study to confirm the efficacy of this new nutraceutical for dogs suffering from OA.

IQ driving QI: the Asia Pacific Consortium on Osteoporosis (APCO): an innovative and collaborative initiative to improve osteoporosis care in the Asia Pacific.

Asia Pacific Consortium on Osteoporosis (APCO) comprises of clinical experts from across the Asia Pacific region, uniting to develop solutions to problems facing osteoporosis management and care. The vision of APCO is to reduce the burden of osteoporosis and fragility fractures in the Asia Pacific region. INTRODUCTION: The Asia Pacific (AP) region comprises 71 countries with vastly different healthcare systems. It is predicted that by 2050, more than half the world's hip fractures will occur in this region. The Asia Pacific Consortium on Osteoporosis (APCO) was set up in May 2019 with the vision of reducing the burden of osteoporosis and fragility fractures in the AP region. METHODS: APCO has so far brought together 39 clinical experts from countries and regions across the AP to develop solutions to challenges facing osteoporosis management and fracture prevention in this highly populous region of the world. APCO aims to achieve its vision by engaging with relevant stakeholders including healthcare providers, policy makers and the public. The initial APCO project is to develop and implement a Framework of pan-AP minimum clinical standards for the screening, diagnosis and management of osteoporosis. RESULTS AND CONCLUSIONS: The Framework will serve as a platform upon which new national clinical guidelines can be developed or existing guidelines be revised, in a standardised fashion. The Framework will also facilitate benchmarking for provision of quality of care. It is hoped that the principles underlying the formation and functioning of APCO can be adopted by other regions and that every health care facility and progressively every country in the world can follow our aspirational path and progress towards best practice.

Yin Yang 1 Orchestrates a Metabolic Program Required for Both Neural Crest Development and Melanoma Formation.

Increasing evidence suggests that cancer cells highjack developmental programs for disease initiation and progression. Melanoma arises from melanocytes that originate during development from neural crest stem cells (NCSCs). Here, we identified the transcription factor Yin Yang 1 (Yy1) as an NCSCs regulator. Conditional deletion of Yy1 in NCSCs resulted in stage-dependent hypoplasia of all major neural crest derivatives due to decreased proliferation and increased cell death. Moreover, conditional ablation of one Yy1 allele in a melanoma mouse model prevented tumorigenesis, indicating a particular susceptibility of melanoma cells to reduced Yy1 levels. Combined RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and untargeted metabolomics demonstrated that YY1 governs multiple metabolic pathways and protein synthesis in both NCSCs and melanoma. In addition to directly regulating a metabolic gene set, YY1 can act upstream of MITF/c-MYC as part of a gene regulatory network controlling metabolism. Thus, both NCSC development and melanoma formation depend on an intricate YY1-controlled metabolic program.

Browning Index of Anthocyanin-Rich Fruit Juice Depends on pH and Anthocyanin Loss More Than the Gain of Soluble Polymeric Pigments.

Browning index (BI, ABS520 nm /ABS420 nm ) is a measure of anthocyanin-rich fruit juice pigmentation quality. This study sought to determine the extent to which BI describes anthocyanin quality and degradation in fruit juices. Commercial fruit juices were assayed for monomeric anthocyanin (MA) content, percent polymeric color (%PC), pH, and BI. BI varied, 0.29 to 1.72, among cranberry, cherry, grape, aronia, and pomegranate juices. Principal component analysis (PCA) revealed that BI was strongly inversely associated with %PC, and positively correlated with MAs to a lesser extent. The BI of grape and cherry juices varied linearly with pH from 2.0 to 4.0 in pH-adjusted juices. Cherry and grape juices at pH approximately 2.0 to 4.0 were incubated at 50 °C to induce juice browning. BI and MA decreased, and %PC increased, but the amount of MA degradation was not explained by %PC. In the aged juices, BI and MA were strongly correlated using PCA. In aged grape juice, chromatographic analysis was used characterize anthocyanins, proanthocyanidins, and anthocyanin scission products. Anthocyanin loss and a gain of unresolved components absorbing at 420 nm decreased BI. Proanthocyanidins and co-eluting pigments with varying BI decreased during aging. Scission products did not account for anthocyanin loss. Thus, MA loss more so than the gain in pigments associated with juice proanthocyanidins contribute to the increase in %PC and decline of the BI during accelerated aging of grape juice. Thus, BI is a useful marker of fruit juice quality within juices of the same pH and anthocyanin composition. PRACTICAL APPLICATION: Fruit juice pigmentation depends on anthocyanins, pH, and other matrix components. Spectrophotometric methods to determine pigmentation include the browning index (ABS520 nm /ABS420 nm ), pH differential method for monomeric anthocyanin (MA) content, and bisulfite bleaching to determine percent polymeric color (%PC). In this study, anthocyanin-rich fruit juice browning index was strongly dependent on pH and MA content. MA loss, and to a lesser extent, a gain in newly-formed pigments at 420 nm contributed to the browning index change during aging. Therefore, browning index is strongly associated with MA content and is useful for assessing fruit juice quality.

Long-term hypovitaminosis D and secondary hyperparathyroidism outcomes of the Roux-en-Y gastric bypass: a systematic review.

INTRODUCTION: Pre-operative Vitamin D deficiency is markedly prevalent in prospective bariatric surgery patients. While bariatric surgery leads to significant weight loss, it can exacerbate or prolong Vitamin D deficiency. We systematically reviewed the literature to assess whether secondary hyperparathyroidism is maintained in the medium to long term in patients following the Roux-en-Y gastric bypass. METHODS: A comprehensive literature search was conducted through Medline, Embase, Scopus, Web of Science, Dare, Cochrane library and HTA database. The search terms used were bariatric surgery, gastric bypass and hyperparathyroidism. RESULTS: Fourteen studies were included (n = 2688 subjects). Parathyroid hormone levels rose gradually from a mean pre-operative level of 5.69 ± 1.2 pmol/L to 6.36 ± 0.77 pmol/L, 7.59 ± 0.73 pmol/L and 8.29 ± 1.41 pmol/L at 2 years, between 2 and 5 years, and beyond 5 years, respectively. Vitamin D levels slowly fell to a mean of 20.50 ± 4.37 ng/mL and 20.76 ± 3.80 ng/mL between follow-up intervals 2-5 years and beyond 5, respectively. CONCLUSION: It appears that hyperparathyroidism persists at 5-year follow-up after gastric bypass, despite most patients being supplemented with calcium and Vitamin D.

Identification and pharmacological characterization of a novel inhibitor of autotaxin in rodent models of joint pain.

OBJECTIVE: Autotaxin is a secreted lysophospholipase that mediates the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a bioactive lipid mediator. Autotaxin levels in plasma and synovial fluid correlate with disease severity in patients with knee osteoarthritis (OA). The goal of this study was to develop and characterize a novel small molecule inhibitor of autotaxin to inhibit LPA production in vivo and determine its efficacy in animal models of musculoskeletal pain. DESIGN: Compound libraries were screened using an LPC coupled enzyme assay that measures the amount of choline released from LPC by the action of autotaxin. Hits from this assay were tested in a plasma assay to assess inhibition of endogenous plasma autotaxin and subsequently tested for their ability to lower plasma LPA levels upon oral dosing of rats. The best compounds were then tested in animal models of musculoskeletal pain. RESULTS: Compound screening led to the identification of compounds with nanomolar potency for inhibition of autotaxin activity. Studies in rats demonstrated a good correlation between compound exposure levels and a decrease in LPA levels in plasma. The leading molecule (compound-1) resulted in a dose dependent decrease in joint pain in the mono-sodium iodoacetate (MIA) and meniscal tear models and a decrease in bone fracture pain in the osteotomy model in rats. CONCLUSION: We have identified and characterized a novel small molecule inhibitor of autotaxin and demonstrated its efficacy in animal models of musculoskeletal pain. The inhibitor has the potential to serve as an analgesic for human OA and bone fracture.

Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality using the IOF Capture the Fracture® Best Practice Framework tool.

UNLABELLED: Fracture Liaison Services are the best model to prevent secondary fractures. The International Osteoporosis Foundation developed a Best Practice Framework to provide a quality benchmark. After a year of implementation, we confirmed that a single framework with set criteria is able to benchmark services across healthcare systems worldwide. INTRODUCTION: Despite evidence for the clinical effectiveness of secondary fracture prevention, translation in the real-world setting remains disappointing. Where implemented, a wide variety of service models are used to deliver effective secondary fracture prevention. To support use of effective models of care across the globe, the International Osteoporosis Foundation's Capture the Fracture® programme developed a Best Practice Framework (BPF) tool of criteria and standards to provide a quality benchmark. We now report findings after the first 12 months of implementation. METHODS: A questionnaire for the BPF was created and made available to institutions on the Capture the Fracture website. Responses from institutions were used to assign gold, silver, bronze or black (insufficient) level of achievements mapped across five domains. Through an interactive process with the institution, a final score was determined and published on the Capture the Fracture website Fracture Liaison Service (FLS) map. RESULTS: Sixty hospitals across six continents submitted their questionnaires. The hospitals served populations from 20,000 to 15 million and were a mix of private and publicly funded. Each FLS managed 146 to 6200 fragility fracture patients per year with a total of 55,160 patients across all sites. Overall, 27 hospitals scored gold, 23 silver and 10 bronze. The pathway for the hip fracture patients had the highest proportion of gold grading while vertebral fracture the lowest. CONCLUSION: In the first 12 months, we have successfully tested the BPF tool in a range of health settings across the globe. Initial findings confirm a significant heterogeneity in service provision and highlight the importance of a global approach to ensure high quality secondary fracture prevention services.

Anal acoustic reflectometry predicts the outcome of percutaneous nerve evaluation for faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is effective for some patients with faecal incontinence. Before insertion of a costly implant, percutaneous nerve evaluation (PNE) is undertaken to identify patients likely to report success from SNS. The aim of this study was to determine whether variables of anal sphincter function measured by anal acoustic reflectometry (AAR) could predict the outcome of PNE for faecal incontinence. METHODS: Women with faecal incontinence undergoing PNE were recruited. AAR, followed by anal manometry, was performed on the day of surgery, immediately before PNE. The outcome of PNE was determined by bowel diary results and incontinence severity score. Patients with a successful PNE outcome were compared with those with an unsuccessful outcome; logistic regression analysis was used to identify any independent predictors of success. RESULTS: Fifty-two patients were recruited, of whom 32 (62 per cent) had a successful PNE outcome and 20 (38 per cent) an unsuccessful outcome. The AAR variable opening pressure was significantly greater in patients who subsequently had a successful PNE result compared with the pressure in patients who did not (28 versus 17 cmH2 O; P = 0·008). No difference was seen in the manometric equivalent, maximum resting pressure. Opening pressure was an independent predictor of success with an odds ratio of 1·08 (95 per cent confidence interval 1·01 to 1·16; P = 0·018). CONCLUSION: AAR is a sensitive test of sphincter function and can identify differences between patients who respond to PNE and those who do not. Opening pressure is an independent predictor of success in PNE, and may be of value in the selection of patients for this expensive treatment option.

Identification of the GPR55 antagonist binding site using a novel set of high-potency GPR55 selective ligands.

GPR55 is a class A G protein-coupled receptor (GPCR) that has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Initially deorphanized as a cannabinoid receptor, GPR55 has been shown to be activated by non-cannabinoid ligands such as l-α-lysophosphatidylinositol (LPI). While there is a growing body of evidence of physiological and pathophysiological roles for GPR55, the paucity of specific antagonists has limited its study. In collaboration with the Molecular Libraries Probe Production Centers Network initiative, we identified a series of GPR55 antagonists using a ß-arrestin, high-throughput, high-content screen of ~300000 compounds. This screen yielded novel, GPR55 antagonist chemotypes with IC50 values in the range of 0.16-2.72 µM [Heynen-Genel, S., et al. (2010) Screening for Selective Ligands for GPR55: Antagonists (ML191, ML192, ML193) (Bookshelf ID NBK66153; PMID entry 22091481)]. Importantly, many of the GPR55 antagonists were completely selective, with no agonism or antagonism against GPR35, CB1, or CB2 up to 20 µM. Using a model of the GPR55 inactive state, we studied the binding of an antagonist series that emerged from this screen. These studies suggest that GPR55 antagonists possess a head region that occupies a horizontal binding pocket extending into the extracellular loop region, a central ligand portion that fits vertically in the receptor binding pocket and terminates with a pendant aromatic or heterocyclic ring that juts out. Both the region that extends extracellularly and the pendant ring are features associated with antagonism. Taken together, our results provide a set of design rules for the development of second-generation GPR55 selective antagonists.

Long-term Supplementation With n-6 and n-3 PUFAs Improves Moderate-to-Severe Keratoconjunctivitis Sicca: A Randomized Double-Blind Clinical Trial.

PURPOSE: Supplementation with gamma-linolenic acid (GLA) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) has been found to decrease the production of disease-relevant inflammatory mediators that are implicated in the pathogenesis of chronic dry eye. This study evaluated the effect of a supplement containing both GLA and n-3 PUFAs on signs and symptoms of moderate-to-severe keratoconjunctivitis sicca in postmenopausal patients. METHODS: This multicenter, double-masked placebo-controlled clinical trial enrolled 38 patients (both eyes) with tear dysfunction who were randomized to supplemental GLA + n-3 PUFAs or placebo for 6 months. Disease parameters, including Ocular Surface Disease Index, Schirmer test, tear breakup time, conjunctival fluorescein and lissamine green staining, and topographic corneal smoothness indexes (surface asymmetry index and surface regularity index), were assessed at baseline and at 4, 12, and 24 weeks. The intensity of dendritic cell CD11c integrin and HLA-DR expression was measured in conjunctival impression cytologies. RESULTS: The Ocular Surface Disease Index score improved with supplementation and was significantly lower than placebo (21 ± 4 vs. 34 ± 5) after 24 weeks (P = 0.05, n = 19 per group). The surface asymmetry index was significantly lower in supplement-treated subjects (0.37 ± 0.03, n = 15) than placebo (0.51 ± 0.03, n = 16) at 24 weeks (P = 0.005). Placebo treatment also significantly increased HLA-DR intensity by 36% ± 9% and CD11c by 34% ± 7% when compared with supplement treatment (n = 19 per group, P = 0.001, 24 weeks). Neither treatment had any effect on tear production, tear breakup time, or corneal or conjunctival staining. CONCLUSIONS: Supplemental GLA and n-3 PUFAs for 6 months improved ocular irritation symptoms, maintained corneal surface smoothness, and inhibited conjunctival dendritic cell maturation in patients with postmenopausal keratoconjunctivitis sicca.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00883649.

Infectious complications related to intrathecal drug delivery system and spinal cord stimulator system implantations at a comprehensive cancer pain center.

BACKGROUND: Intrathecal drug delivery (IDD) and spinal cord stimulator (SCS) systems are implantable devices for the management of both chronic and cancer pain. Although these therapies have favorable long-term outcomes, they are associated with occasional complications including infection. The incidence of infectious complications varies from 2 - 8% and frequently requires prolonged antibiotics and device revision or removal. Cancer patients are particularly susceptible to infectious complications because they are immunocompromised, malnourished, and receiving cytotoxic cancer-related therapies. OBJECTIVE: Determine if cancer pain patients have a higher incidence of infectious complications following implantation of IDD or SCS systems than non-cancer pain patients. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary comprehensive cancer hospital. METHODS: Following local Institutional Review Board (IRB) approval, we collected data on infectious complications for IDD and SCS systems implanted at MD Anderson Cancer Center for the treatment of cancer and chronic pain. The examined implants were performed from July 15, 2006, to July 14, 2009. In addition, we obtained data regarding patient comorbidities and perioperative risk factors to assess their impact on infectious complications. RESULTS: One hundred forty-two devices were implanted in 131 patients during the examined period. Eighty-three of the devices were IDD systems and 59 were SCS systems. Eighty percent of the patients had a diagnosis of cancer. Four infectious complications were noted with an overall infectious risk of 2.8%. The infection rate was 2.4% for IDD systems versus 3.4% for SCS systems (P = 1). All infections were at the implantable pulse generator (IPG) or pump pocket site. The rate of infection was 2.7% for cancer patients and 3.3% for non-cancer patients (P = 1). Neither the perioperative administration of prophylactic antibiotics (P = 0.4) nor the National Nosocomial Infection Surveillance (NNIS) risk level for individual patients (P = 0.15) were statistically associated with infectious complication. The mean surgical time was longer for cases with infection at 215 ± 93 minutes versus 132 ± 52 minutes for those without infection which was statistically significant (P = 0.02). LIMITATIONS: The major limitation of this study is that it was a retrospective analysis. An additional limitation is that 51(38.9%) of our patients either died or were lost to follow-up during the year following implantation which may have led to an underestimation of our infection rates. CONCLUSIONS: The experience of this tertiary cancer pain center demonstrates that infectious complications following implantation of IDD and SCS systems are relatively rare events in cancer patients. Contrary to our initial hypothesis, no difference was found in the infection rate between cancer and non-cancer patients. The main factor associated with increased risk of infectious complications was increased surgical time, indicating a need to minimize patient time in the operating room. The low infectious complication rate seen in this series compared to previous reports in non-cancer patients is likely multifactorial in nature.

Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients.

CONTEXT: The stool softener docusate is widely used in the management of constipation in hospice patients. There is little experimental evidence to support this practice, and no randomized trials have been conducted in the hospice setting. OBJECTIVES: To assess the efficacy of docusate in hospice patients. METHODS: This was a 10-day, prospective, randomized, double-blind, placebo-controlled trial of docusate and sennosides vs. placebo and sennosides in hospice patients in Edmonton, Alberta. Patients were included if they were age 18 years or older, able to take oral medications, did not have a gastrointestinal stoma, and had a Palliative Performance Scale score of 20% or more. The primary outcome measures were stool frequency, volume, and consistency. Secondary outcomes were patient perceptions of bowel movements (difficulty and completeness of evacuation) and bowel-related interventions. RESULTS: A total of 74 patients were randomized into the study (35 to the docusate group and 39 to the placebo group). There were neither significant differences between the groups in stool frequency, volume, or consistency, nor in difficulty or completeness of evacuation. On the Bristol Stool Form Scale, more patients in the placebo group had Type 4 (smooth and soft) and Type 5 (soft blobs) stool, whereas in the docusate group, more had Type 3 (sausage like) and Type 6 (mushy) stool (P=0.01). CONCLUSION: There was no significant benefit of docusate plus sennosides compared with placebo plus sennosides in managing constipation in hospice patients. Docusate use should be considered on an individual basis.

A randomized controlled trial of mindfulness-based cognitive therapy for bipolar disorder.

OBJECTIVE: To compare the efficacy of mindfulness-based cognitive therapy (MBCT) plus treatment as usual (TAU) to TAU alone for patients with bipolar disorder over a 12-month follow-up period. METHOD: Participants with a DSM-IV diagnosis of bipolar disorder were randomly allocated to either MBCT plus TAU or TAU alone. Primary outcome measures were time to recurrence of a DSM-IV major depressive, hypomanic or manic episode; the Montgomery-Åsberg Depression Rating Scale (MADRS); and Young Mania Rating Scale (YMRS). Secondary outcome measures were number of recurrences, the Depression Anxiety Stress Scales (DASS), and the State Trait Anxiety Inventory (STAI). RESULTS: Ninety-five participants with bipolar disorder were recruited to the study (MBCT = 48; TAU = 47). Intention-to-treat (ITT) analysis found no significant differences between the groups on either time to first recurrence of a mood episode or total number of recurrences over the 12-month period. Furthermore, there were no significant between-group differences on the MADRS or YMRS scales. A significant between-group difference was found in STAI - state anxiety scores. There was a significant treatment by time interaction for the DAS - achievement subscale. CONCLUSION: While MBCT did not lead to significant reductions in time to depressive or hypo/manic relapse, total number of episodes, or mood symptom severity at 12-month follow-up, there was some evidence for an effect on anxiety symptoms. This finding suggests a potential role of MBCT in reducing anxiety comorbid with bipolar disorder.

Sorafenib in melanoma.

INTRODUCTION: Sorafenib is an orally available multi-kinase inhibitor that inhibits tumor proliferation by targeting multiple kinases including the vascular endothelial growth factor receptors VEGFR1, VEGFR2, VEGFR3 and the platelet-derived growth factor receptor PDGFR, and it targets tumor progression by inhibiting FLT3, C-Kit and BRAF. Since BRAF mutations are frequent in melanoma, sorafenib was investigated in various Phase I, II and III clinical trials. The drug is well tolerated with mild to moderate adverse effects, which are mostly limited to cutaneous toxicity, diarrhea and fatigue. AREAS COVERED: Systematic literature review of the randomized trials using PubMed was performed. Original articles were reviewed and citations from those were also considered. Additionally, clinical trial databases were examined to identify and summarize ongoing trials of sorafenib in melanoma patients. EXPERT OPINION: Sorafenib as a monotherapy or in combination with chemotherapy is of limited use. Combining it with dacarbazine doubled the response rate and the progression-free survival in metastatic melanoma patients. Unfortunately, these results have never been evaluated in large randomized Phase III clinical trials. According to the trials conducted so far a subpopulation of patients experience substantial benefit, therefore it is essential to identify biomarkers to select the subgroups of patients that are more likely to respond to sorafenib. Furthermore, other less frequent subtypes such as mucosal or ocular melanoma still constitute promising targets; academic institutions are currently launching investigator-initiated trials in these indications.

L-arginine is a radioprotector for hematopoietic progenitor cells.

L-arginine is shown to protect hematopoietic progenitor (32D cl 3) cells from death due to exposure to γ radiation ((137)Cs). Some of the other intermediates in the urea cycle, namely ornithine and citrulline, plus urea itself, were not found to have any significant impact on cell survival after irradiation. Intriguingly, supplementation of irradiated cells with L-arginine results in decreased production of peroxynitrite, suggesting that suppression of superoxide generation by nitric oxide synthase in one or more microenvironments is an important factor in the observed radioprotection. The absence of any radioprotective effect of L-arginine in cells at 3% oxygen also confirms the involvement of one or more oxygen-derived species. Knockdown experiments with nitric oxide synthase (NOS) siRNAs in cells and NOS knockout animals confirm that the observed radioprotection is associated with nNOS (NOS-1). L-arginine also ameliorates the transient inhibition of the electron-transport chain complex I that occurs within 30 min of completing the dose (10 Gy) and that appears to be a functional marker for postirradiation mitochondrial oxidant production.

Dietary antioxidant intake is associated with the prevalence but not incidence of age-related hearing loss.

OBJECTIVES: Diet is one of the few modifiable risk factors for age-related hearing loss. We aimed to examine the link between dietary and supplement intakes of antioxidants, and both the prevalence and 5-year incidence of measured hearing loss. DESIGN: Cross-sectional and 5-year longitudinal analyses. SETTING: Blue Mountains, Sydney, Australia. PARTICIPANTS: 2,956 Blue Mountains Hearing Study participants aged 50+ at baseline, examined during 1997-9 to 2002-4. MEASUREMENTS: Age-related hearing loss was measured and defined as the pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz >25 dB HL. Dietary data were collected in a semi-quantitative food frequency questionnaire, and intakes of α-carotene; ß-carotene; ß-cryptoxanthin; lutein and zeaxanthin; lycopene; vitamins A, C and E; iron and zinc were calculated. RESULTS: After adjusting for age, sex, smoking, education, occupational noise exposure, family history of hearing loss, history of diagnosed diabetes and stroke, each standard deviation (SD) increase in dietary vitamin E intake was associated with a 14% reduced likelihood of prevalent hearing loss, odds ratio, OR, 0.86 (95% confidence interval, CI, 0.78-0.98). Those in the highest quintile of dietary vitamin A intake had a 47% reduced risk of having moderate or greater hearing loss (>40 dB HL) compared to those in the lowest quintile of intake, multivariable-adjusted OR 0.53 (CI 0.30-0.92), P for trend = 0.04. However, dietary antioxidant intake was not associated with the 5-year incidence of hearing loss. CONCLUSIONS: Dietary vitamin A and vitamin E intake were significantly associated with the prevalence of hearing loss. However, dietary antioxidant intake did not increase the risk of incident hearing loss. Further large, prospective studies are warranted to assess these relationships in older adults.

A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis.

OBJECTIVE: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS. METHODS: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses. RESULTS: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04). CONCLUSION: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.