Synergism of benflumetol and artemether in Plasmodium falciparum.

Using a continuous in vitro culture system, the sensitivity of Plasmodium falciparum to artemether and a new antimalarial drug, benflumetol (lumefantrine), alone and in combination, was investigated with a multiresistant strain (T-996) from Thailand and a chloroquine-resistant strain (LS-21) from India. Both strains showed similar 50% inhibitory concentration (IC50) levels with artemether alone or benflumetol alone, but the IC90 was higher in strain T-996 compared with strain LS-21: for artemether, 34.45 and 7.11 nmol/L (10.28 and 2.12 ng/ml of erythrocyte-medium mixture [EMM]), and for benflumetol, 293.03 and 95.61 nmol/L (154.69 and 50.47 ng/ml of EMM). When tested in association at artemether:benflumetol (mol: mol) ratios between 100:1 and 1:100, substantial synergism was seen in both strains, especially at the IC90 and IC99 levels. This phenomenon resembles the synergistic interaction of artemisinin derivatives and mefloquine, first observed in laboratory models and later confirmed in clinical experience.     

Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics

The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine‐sensitive (F32) strain of Plasmodium falciparum . A method of repetitive dosing and extending the culture observation period to 28–30 days was used to mimic the in vivo pharmacokinetic situation. Plasmodium falciparum was exposed to artemisinin from 10⁻⁸ to 10⁻⁵  m , mefloquine from 3×10⁻⁹ to 10⁻⁵  m and their combinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug‐dosing duration was 3 days.
Neither artemisinin nor mefloquine alone provided radical clearance of P. falciparum , even when maximum concentrations (10⁻⁵  m ) were applied. The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination. At concentrations normally reached in vivo , this effect was clearly synergistic ( P =0.016)
Our in vitro model of intermittent dosing of artemisinin and mefloquine combinations for 3 days provides significant evidence of positive interaction between the two compounds. Lower combination concentrations around the MIC‐values for the individual compounds showed synergistic effect, and high concentrations showed additive effect. This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single‐drug treatment.     

Filter-protected carotid stenting via a minimal cervical access with transitory aspirated reversed flow during initial passage of the target lesion.

PURPOSE: To evaluate the preliminary results of filter-protected carotid artery stenting (CAS) via a minimal cervical access, with temporary common carotid artery (CCA) occlusion and aspiration in selected high-risk candidates for carotid endarterectomy. METHODS: Since February 2002, 26 patients (17 men; mean age 73.7 years, range 54-98) at high surgical risk according to the SAPPHIRE eligibility criteria underwent 29 transcervical CAS procedures under filter protection. Under general anesthesia, a 6-F short introducer sheath was directly mounted in the CCA through a small (2-4 cm) laterocervical cutdown. The CCA was briefly clamped, and blood was aspirated while the filter device was positioned above the target lesion. With the filter in place and the clamp released, nitinol stents were deployed under filter protection. Hemostasis was achieved by direct suture. RESULTS: Twenty-eight (96%) interventions were technically successful; 1 complex lesion could not be crossed and was converted to surgery. Mean clamping time was 1.7 (range 1.0-3.5) minutes. Combined 30-day stroke/mortality was 0%. Ultrasound surveillance demonstrated a < 60% asymptomatic in-stent restenosis in 1 (4%) patient with radiation-induced arteritis after 28 months. During a mean follow-up of 11.6 months (range 3-38), 1 (4%) minor ipsilateral stroke was noted at 6 months in a patient whose antiplatelet therapy was transitorily interrupted. CONCLUSION: Our preliminary observations from this small early experience suggest that this variant CAS technique is feasible and probably diminishes the neuroembolic risk during initial navigation of the ICA target stenosis.     

2015/16 I‐MOVE/I‐MOVE+ multicentre case‐control study in Europe: Moderate vaccine effectiveness estimates against influenza A(H1N1)pdm09 and low estimates against lineage‐mismatched influenza B among children

Background

During the 2015/16 influenza season in Europe, the cocirculating influenza viruses were A(H1N1)pdm09 and B/Victoria, which was antigenically distinct from the B/Yamagata component in the trivalent influenza vaccine.

Methods

We used the test‐negative design in a multicentre case‐control study in twelve European countries to measure 2015/16 influenza vaccine effectiveness (VE) against medically attended influenza‐like illness (ILI) laboratory‐confirmed as influenza. General practitioners swabbed a systematic sample of consulting ILI patients and a random sample of influenza‐positive swabs was sequenced. We calculated adjusted VE against influenza A(H1N1)pdm09, A(H1N1)pdm09 genetic group 6B.1 and influenza B overall and by age group.

Results

We included 11 430 ILI patients, of which 2272 were influenza A(H1N1)pdm09 and 2901 were influenza B cases. Overall VE against influenza A(H1N1)pdm09 was 32.9% (95% CI: 15.5‐46.7). Among those aged 0‐14, 15‐64 and ≥65 years, VE against A(H1N1)pdm09 was 31.9% (95% CI: ? 32.3 to 65.0), 41.4% (95% CI: 20.5‐56.7) and 13.2% (95% CI: ? 38.0 to 45.3), respectively. Overall VE against influenza A(H1N1)pdm09 genetic group 6B.1 was 32.8% (95% CI: ? 4.1 to 56.7). Among those aged 0‐14, 15‐64 and ≥65 years, VE against influenza B was ? 47.6% (95% CI: ? 124.9 to 3.1), 27.3% (95% CI: ? 4.6 to 49.4) and 9.3% (95% CI: ? 44.1 to 42.9), respectively.

Conclusions

Vaccine effectiveness (VE) against influenza A(H1N1)pdm09 and its genetic group 6B.1 was moderate in children and adults, and low among individuals ≥65 years. Vaccine effectiveness (VE) against influenza B was low and heterogeneous among age groups. More information on effects of previous vaccination and previous infection is needed to understand the VE results against influenza B in the context of a mismatched vaccine.

     

Genome‐wide association study of shared liability to anxiety disorders in Army STARRS

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome‐wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM‐based ANX diagnoses. We factor‐analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta‐analyzed across ancestries (N_Total = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta‐analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome‐wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10^?11). Gene‐based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.     

A practical approach to acromegaly management in Latin America

The purpose of this study it was to evaluate the frequency of Multiple Endocrine Neoplasia type 1 (MEN1) in patients with pituitary adenoma and to perform genetic analysis and familial screening of those individuals afflicted with MEN1. 144 patients with pituitary adenoma at Botucatu Medical School, UNESP—Univ Estadual Paulista, were assessed retrospectively for MEN1 during the years of 2005–2011. The patients were evaluated for the presence of primary hyperparathyroidism (PHP) and enteropancreatic tumors. Genetic analysis was performed for the individuals with clinically diagnosed MEN1. Thirteen patients met the diagnostic criteria for MEN1, but three individuals belong to the same family and they were considered as a single MEN1 event, revealing 7.7 % frequency of MEN1 in this patient group. Genetic analysis showed MEN1 mutations in four index cases: IVS4+1 G>A, IVS3-6 C>T, c.1547insC and a new D180A mutation. One patient did not agree to participate in the genetic study and another one was referred for follow up in other hospital. Only polymorphisms were found in the other individuals, one of which was novel. We identified a high frequency of MEN1 in pituitary adenoma patients. Since PHP is one of the most common MEN1 tumor and patients are mostly asymptomatic, we suggest that all pituitary adenoma patients have their calcium profile analyzed.     

Modeling considerations for 11C-CUMI-101, an agonist radiotracer for imaging serotonin 1A receptor in vivo with PET.

Several lines of evidence demonstrate involvement of serotonin 1A receptors (5-HT1ARs) in the pathophysiology of neuropsychiatric disorders such as depression, suicidal behavior, schizophrenia, and Alzheimer's disease. We recently published the synthesis and initial evaluation of [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (11C-MMP), a 5-HT1AR agonist. Here we determine the optimal modeling parameters for 11C-MMP under its new name, 11C-CUMI-101, in Papio anubis. METHODS: PET scans were performed on 2 adult male P. anubis; 166.5 MBq +/- 43.0 (4.50 +/- 1.16 mCi) of 11C-CUMI-101 were injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 4 different models (1- and 2-tissue compartment iterative and noniterative kinetic models, basis pursuit, and likelihood estimation in graphical analysis [LEGA]), using binding potential (BPF = Bmax/Kd) (Bmax = maximum number of binding sites; Kd = dissociation constant) as the outcome measure. Arterial blood sampling and metabolite-corrected arterial input function were used for full quantification of BPF. To assess the performance of each model, we compared results using 6 different metrics (percentage difference, within-subject mean sum of squares [WSMSS] for reproducibility; variance across subjects, intraclass correlation coefficient [ICC] for reliability; identifiability based on bootstrap resampling of residuals; and time stability analysis to determine minimal required scanning time) at each of 6 different scanning durations. Models were also evaluated on scans acquired after injecting the 5-HT1A antagonist [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] [WAY100635] 0.5 mg/kg, intravenous) and the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin) [8-OH-DPAT] 2 mg/kg, intravenous). RESULTS: All metabolites are more polar than 11C-CUMI-101, and no significant change in metabolites was observed in the blocking studies. The free fraction is 59% +/- 3%. We determined that 100 min of scanning time is adequate and that for the region-of-interest (ROI)-level analysis, the LEGA model gives the best results. The median test-retest percentage difference for BPF is 11.15% +/- 4.82% across all regions, WSMSS = 2.66, variance = 6.07, ICC = 0.43, and bootstrap identifiability = 0.59. Preadministration of WAY100635 and 8-OH-DPAT resulted in 87% and 76% average reductions in BPF values, respectively, across ROIs. CONCLUSION: On the basis of the measurable free fraction, high affinity and selectivity, adequate blood-brain permeability, and favorable plasma and brain kinetics, 11C-CUMI-101 is an excellent candidate for imaging high-affinity 5-HT1ARs in humans.     

中药骨痹痛外敷治疗骨关节病112例报告

[目的]探索中药治疗骨关节病有效方法。[方法]治疗组62例采用中药骨痹痛治疗，对照组采用复方南星止痛膏。[结果]治疗组治愈30例（48．4％），好转25例（40．3％），无效7例（11．3%），总有效率88．70%；对照组治愈20例（40．0％），好转15例（30．0％），无效15例（30．0％），总有效率70．0％。[结论]中药骨痹痛对骨关节病有效好治疗作用。     

Graft Versus Host Disease in Intestinal Transplantation

Our aim was to analyze the clinical course and outcome of patients with graft vs. host disease (GVHD) after intestinal transplantation (ITx). All patients receiving ITx between May, 1990 and December, 2003 were retrospectively reviewed for evidence of GVHD. Two hundred and fifty patients underwent ITx during the study period. Graft vs. host disease was suspected clinically in 23 patients on the clinical basis of presentation such as skin rash, ulceration of oral mucosa, diarrhea, lymphadenopathy, or native liver dysfunction. Fourteen (eight children and six adults) patients (5.6% of total patient population) had GVHD confirmed by histopathological criteria including keratinocyte necrosis (n = 9), epithelial apoptosis of the native gastrointestinal tract (n = 4), and epithelial cell necrosis of oral mucosa (n = 1). Donor-cell tissue infiltration or extensive peripheral blood donor-cell chimerism was documented on seven occasions. The majority of cases of GVHD resolved with steroid administration and optimization of tacrolimus immunosuppression. The incidence of histologically proven GVHD after clinical intestinal transplantation is 6.5% (8/122) in children and 4.7% (6/128) in adults. Successful clinical management requires a high index of suspicion to minimize morbidity and mortality. Diagnostic and treatment strategies based on this experience are proposed.