Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial.

AIM: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. METHODS: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. RESULTS: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib. CONCLUSIONS: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss.

Novel inactivating mutation of the calcium-sensing receptor in a young woman with mild hypercalcaemia.

A young woman with mild hypercalcaemia and an inappropriately normal serum parathyroid hormone had parathyroid scintigraphy suggestive of an active ectopic parathyroid tissue in the superior mediastinum. Urinary calcium to creatinine clearance ratio was low, and a subsequent genetic analysis confirmed a novel mutation (Q164K) in the calcium sensing receptor gene, consistent with familial hypocalciuric hypercalcaemia. We propose that this mutation accounts for her clinical and investigational findings, although a double pathology of Q164K and an ectopic parathyroid adenoma is also conceivable.

A study of venous thrombosis incidence in patients with acute hyperthyroidism.

BACKGROUND: Hyperthyroidism is not a widely acknowledged risk factor for venous thrombosis (VT), such as deep vein thrombosis, pulmonary embolism and cerebral VT. Several case reports and case-control studies support an association between VT and hyperthyroidism. Prothrombotic changes in the coagulation pathway in thyrotoxic subjects include reversible elevation of factor VIII and von Willebrand factor, and give biological plausibility to the association and possibly causation for VT. AIM: We sought to determine the incidence of symptomatic VT in acute hyperthyroidism. METHODS: A retrospective review of consecutive outpatients presenting to the endocrinology clinic at our district hospitals from January 2006 to December 2008 with acute hyperthyroidism was carried out. All occurrences of objectively proven symptomatic VT (deep vein thrombosis, pulmonary embolism and cerebral vein thrombosis) in the 6 months following the diagnosis of hyperthyroidism were sought. RESULTS: Four hundred and twenty-eight patients were identified, of whom most were female (80%) and relatively young (mean age 47 years). Three patients (0.70%: 95% confidence interval 0.14-2.0%) were identified with a confirmed VT within 6 months of the diagnosis of hyperthyroidism. CONCLUSIONS: Although the literature suggests moderate association between VT and acute hyperthyroidism, our data show that the absolute risk is low. Furthermore, our data suggest that hyperthyroidism is usually an additional risk factor but rarely the sole risk factor for VT.

Effect of soil pH on as hyperaccumulation capacity in fern species, Pityrogramma calomelanos.

Arsenic uptake by hyperaccumulator plant species depends on many different environmental factors. Soil pH is one of the most important factors due to its combined effect on both chemical and biological processes. In greenhouse experiment, the effect of pH (within the pH range 3.6 - 8.9) on As uptake as well as biomass of Pityrogramma calomelanos was evaluated. The plants were grown in mining soil containing 645.6 mg As kg(-1) for 14 weeks. Within this time, the plant biomass growth was 3.78 - 8.64 g d. wt. per plant and the removal amounted 6.3-18.4 mg As per plant. Translocation factor (ratio of As in fronds to roots) of the fern was 3.6 - 9.7, indicating its potential in phytoremediation of As contaminated soil. Influence of pH on As bioavailability was visible as the available As concentration was higher in acidic soil compared to alkaline soil. Furthermore, it was found that As accumulation by Pityrogramma calomelanos was optimum in the soil of pH 3.6. Nevertheless, the results of this study demonstrate that remediation of As-contaminated mining soils, by this fern, can be improved by changing the soil pH from 4.6 to 6.8.

Integrating Palliative Care Into Physiatric Care: Perspective of the Association of Academic Physiatrists Physiatry Palliative Care Task Force.

ABSTRACT: There are opportunities for physiatrists to apply a palliative care lens within clinical encounters across rehabilitation settings. The expanding population of patients with serious illness and injury cared for by physiatrists and the anticipated shortage of specialty palliative care clinicians make it important that physiatrists hone and apply basic palliative care skills as part of comprehensive physiatric care. In this article, four clinical vignettes highlight relevant palliative care communication skills and demonstrate the value of integrating these skills within physiatry encounters. Resources to support physiatrists in applying basic palliative skills are provided throughout.

Large branchial arch cyst excision using superficial and deep cervical plexus blocks in a patient with severe comorbidities.

Branchial arches are embryologic structures that develop between the fourth and seventh gestational week. Anomalies may form if these structures fail to develop. The majority of cases are diagnosed during childhood, with surgical excision recommended to prevent risk of infection, growth or malignancy. We report an unusual case of a 72-year-old man with severe cardiac comorbidities who presented with a large second branchial arch cyst extending into the oropharynx. General anaesthesia to facilitate surgical excision was deemed too risky. Therefore, we performed successful ultrasound-guided superficial and deep cervical plexus blocks as a sole mode of anaesthesia. This case highlights how regional anaesthesia can be utilised to facilitate surgery in high-risk patients, as well as presenting an alternative for general anaesthesia.

A comparison of the effects of clozapine and its metabolite norclozapine on metabolic dysregulation in rodent models.

RATIONALE: The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine. METHODS: Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance. RESULTS: In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance. ABSTRACT: While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Complete thrombospondin mRNA sequence includes potential regulatory sites in the 3' untranslated region.

The nucleotide sequence of human thrombospondin (TS) mRNA has been determined from human fibroblast and endothelial cDNAs. The sequence of 5802 bp begins 110 bp upstream from the initiator codon and includes the entire 3' untranslated region (UTR) of the mRNA. The coding region (3510 bp) specifies a protein of 1170 amino acids with all of the known features of the TS subunit (Frazier, W. A. 1987. J. Cell Biol. 105:625-632). The long 3' UTR of 2166 nucleotides is extremely A/T-rich, particularly in the latter half. It contains 37 TATT or ATTT(A) sequences that have been suggested as mediators of the stability of mRNAs for cytokines, lymphokines, and oncogenes (Shaw, G., and R. Kamen. 1986. Cell. 46:659-667). Another unusual feature of the 3' UTR of TS mRNA is a stretch of 42 nucleotides of which 40 are thymidines (uridine in the mRNA) including an uninterrupted sequence of 26 thymidines. This region is flanked by two sets of direct repeats suggesting that it may be an insertion element of retrotranscriptional origin. Comparison of the 3' untranslated region of TS mRNA with the GenBank data base indicates the greatest degree of similarity with an alpha-interferon gene which contains a number of the TATT/ATTT consensus sites. The degree of similarity between the TS and interferon sequences is the same in regions of the interferon gene corresponding to its coding and noncoding regions suggesting that most of the TS 3' UTR may be derived from an interferon gene or pseudogene. The features of the TS mRNA 3' UTR provide a potential explanation for the rapid regulation of TS message observed in cultured cells in response to PDGF and suggest that TS is a member of a group of proteins which are intimately involved in the control of cell growth and differentiation.

Tissue-specific changes in mRNA expression of Abc and Slc transporters in murine pulmonary tuberculosis.

A pulmonary tuberculosis mouse model was used to assess the pharmacodynamic and pharmacokinetic characteristics of tuberculosis therapeutics. While membrane transporters play important roles in drug disposition and physiological homeostasis, their expressional changes and contribution have never been analysed in a tuberculosis animal model. The mRNA expression level of 20 Abc family transporters and 32 Slc family transporters in tuberculosis-infected mice were compared with those in naïve uninfected mice using real-time polymerase chain reaction (PCR). Mycobacterium tuberculosis infection induced many dramatic expression changes of families of both Abc transporters and Slc transporters at 4 and 8 weeks, as observed in the livers, kidneys, and intestines of test mice--and in a different mode, in the lungs and spleens as well. These changes were dependent on the tuberculosis progression with the tissue-specific manner, that is, in the lungs, the number of transporters of which the expression level changed due to M. tuberculosis infection had increased, and the magnitude of change also greater at 8 weeks, while in the spleen, the transcription of most transporters except Mrps had not changed or had recovered back to the same level of naïve transcription at 8 weeks. Understanding the expression changes of transporters will assist in setting up rational preclinical dosing plans through the ability to predict the pharmacokinetics of new anti-tuberculosis chemotherapeutics and, furthermore, will assist in the design of safer and more efficient drug regimens.

Decreased urinary secretion of belotecan in folic acid-induced acute renal failure rats due to down-regulation of Oat1 and Bcrp.

The effects of folic acid-induced acute renal failure on the renal excretion of belotecan were investigated in rats after intravenous administration. Both glomeruli and renal tubules were seriously damaged by folic acid-induced acute renal failure. The renal excretion clearance, CLr, of belotecan was significantly decreased by folic acid-induced acute renal failure. Furthermore, glomerular filtration rate and secretion clearance of the drug were dramatically decreased by folic acid-induced acute renal failure. In vivo renal uptake of belotecan was inhibited by p-aminohippurate, whereas renal excretion was inhibited by GF120918, but not by verapamil and bromosulphalein. This indicates that Oat1/3 and Bcrp are involved in the renal uptake and urinary excretion of belotecan, respectively. Both mRNA and protein levels of Oat1, Oat3 and Bcrp were significantly decreased in folic acid-induced acute renal failure rats. Based on the finding that belotecan is a substrate of OAT1 but not of OAT3, the decrease in CLr of belotecan in folic acid-induced acute renal failure could, therefore, mainly be attributed to the down-regulation of Oat1 and Bcrp, in addition to the decrease in glomerular filtration rate.

A pilot randomized trial of adjuvanted influenza vaccine in adult allogeneic hematopoietic stem cell transplant recipients.

The annual influenza vaccine is recommended for hematopoietic stem cell transplant (HSCT) patients although studies have shown suboptimal immunogenicity. Influenza vaccine containing an oil-in-water emulsion adjuvant (MF59) may lead to greater immunogenicity in HSCT recipients. We randomized adult allogeneic HSCT patients to receive the 2015-2016 influenza vaccine with or without MF59 adjuvant. Preimmunization and 4-week post-immunization sera underwent strain-specific hemagglutination inhibition assay. We randomized 73 patients and 67 (35 adjuvanted; 32 non-adjuvanted) had paired samples available at follow-up. Median age was 54 years (range 22-74) and time from transplant was 380 days (range 85-8107). Concurrent graft-versus-host disease was seen in 42/73 (57.5%). Geometric mean titers increased significantly after vaccination in both groups. Seroconversion to at least one of three influenza antigens was present in 62.9% vs 53.1% in adjuvanted vs non-adjuvanted vaccine (P=0.42). Factors associated with lower seroconversion rates were use of calcineurin inhibitors (P<0.001) and shorter duration from transplantation (P=0.001). Seroconversion rates were greater in patients who got previous year influenza vaccination (82.6% vs 45.5%, P=0.03). Adjuvanted vaccine demonstrated similar immunogenicity to non-adjuvanted vaccine in the HSCT population and may be an option for some patients.

A multicenter trial of myeloablative clofarabine and busulfan conditioning for relapsed or primary induction failure AML not in remission at the time of allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.

The clonal origins of leukemic progression of myelodysplasia.

The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.

Stable bioavailability of cyclosporin A, regardless of food intake, from soft gelatin capsules containing a new self-nanoemulsifying formulation.

AIM: We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. VOLUNTEERS AND METHODS: A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. RESULTS: The differences in bioavailability parameters (i.e., AUC(0-24h), AUC(0-infinity) and C(max)) between the treatments were within the range of 80-125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. CONCLUSION: These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol.

Clonal dynamics in a single AML case tracked for 9 years reveals the complexity of leukemia progression.

Most types of cancers are made up of heterogeneous mixtures of genetically distinct subclones. In particular, acute myeloid leukemia (AML) has been shown to undergo substantial clonal evolution over the course of the disease. AML tends to harbor fewer mutations than solid tumors, making it challenging to infer clonal structure. Here, we present a 9-year, whole-exome sequencing study of a single case at 12 time points, from the initial diagnosis until a fourth relapse, including 6 remission samples in between. To the best of our knowledge, it covers the longest time span of any data set of its kind. We used these time series data to track the hierarchy and order of variant acquisition, and subsequently analyzed the evolution of somatic variants to infer clonal structure. From this, we postulate the development and extinction of subclones, as well as their anticorrelated expansion via varying drug responses. In particular, we show that new subclones started appearing after the first complete remission. The presence and absence of different subclones during remission and relapses implies differing drug responses among subclones. Our study shows that time series analysis contrasting remission and relapse periods provides a much more comprehensive view of clonal structure and evolution.

Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

Recurrence of papillary thyroid carcinoma presenting as a focal neurologic deficit.

Papillary-follicular thyroid carcinoma usually remains localized to the thyroid bed and, in cases of metastasis, almost always involves the lung, bone, or liver. The two patients described here presented with papillary carcinoma and neurologic dysfunction. Total body iodine 131 scans disclosed cerebral uptake, and cerebral masses were confirmed by computed tomographic scan. Both patients presented diagnostic and therapeutic dilemmas, and ultimately underwent craniotomy. One patient's cerebral metastasis recurred and was treated by a second craniotomy. The other patient received postoperative external cerebral radiotherapy and a novel intraoperative treatment: implantation of 22 iodine 125 seeds in the tumor bed, estimated to yield 16,000 rad (160 Gy) in one year. To date, cerebral metastases have not recurred in the latter patient, although tumor has reappeared in other sites. There is little reported in the medical literature concerning cerebral metastases of thyroid carcinoma, and the present report reviews this experience and discusses treatment alternatives.

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD.

Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n=180) and validation sets (n=88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P<0.0001) and donor genotypes of IL6 (rs1800797; P=6.2 × 10(-4)) and IFNG (rs2069727; P=4.4 × 10(-4)) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n=74) vs high risk (scores 1-3; n=106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P<0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P=0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

Patient age, remission status and HCT-CI in a combined score are prognostic for patients with AML undergoing allogeneic hematopoietic cell transplantation in CR1 and CR2.

For AML, older age, advanced disease and increased hematopoietic cell transplant comorbidity index (HCT-CI) are associated with worse prognosis following allogeneic hematopoietic cell transplantation (HCT). This single-center retrospective study investigated the influence of pre-transplant characteristics on outcomes of 387 patients undergoing allogeneic HCT for AML in CR1 and CR2. The multivariable analysis model for overall survival (OS) included age (hazard ratio (HR)=2.24 for ages 31-64 years and HR=3.23 for age ⩾65 years compared with age ⩽30 years, P=0.003), remission status (HR=1.49 for CR2 compared with CR1, P=0.005) and HCT-CI score (HR=1.47 for ⩾3 compared with <3, P=0.005). Transplant year was significantly associated with OS (P=0.001) but this did not influence the model. A weighted score was developed with age ⩽30, CR1 and HCT-CI score <3 receiving 0 points each, and CR2 and HCT-CI score ⩾3 receiving 1 point each. Ages 31-64 received 2 points, age ⩾65 received 3 points. Scores were grouped as follows: scores 0-1 (low risk, n=36), score 2 (intermediate-low risk, n=147), score 3 (intermediate-high risk, n=141) and scores 4-5 (high risk, n=63) with 3-year OS of 71%, 55%, 42% and 29% for scores 0-1, 2, 3 and 4-5, respectively (P<0.0001). The score predicted nonrelapse mortality (P=0.03) but not cumulative incidence of relapse (P=0.18). This model should be validated for the pre-HCT assessment of AML patients in CR1 and CR2.