Synthesis,characterization, and monoamine transporter activity of the new psychoactive substance 3′,4′‐methylenedioxy‐4‐methylaminorex (MDMAR)

The recent occurrence of deaths associated with the psychostimulant cis‐4,4′‐dimethylaminorex (4,4′‐DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4‐methylenedioxy‐4‐methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis‐ and trans‐MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis‐isomer (90%). Exposure of the cis‐isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans‐isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non‐selective monoamine releasing agent (+)‐3,4‐methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis‐ and trans‐4,4′‐DMAR, were assessed under identical conditions. cis‐MDMAR, trans‐MDMAR, cis‐4,4′‐DMAR and trans‐4,4′‐DMAR were more potent than MDMA in their ability to function as efficacious substrate‐type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis‐4,4′‐DMAR, cis‐MDMAR and trans‐MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans‐4,4′‐DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring‐substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side‐effects after high dose exposure. Copyright © 2014 John Wiley & Sons, Ltd.     

NICE’s Selective Application of Differential Discounting: Ambiguous,Inconsistent, and Unjustified

The National Institute for Health and Clinical Excellence (NICE) recently recommended differential discounting of costs and health effects in the economic appraisal of health care interventions in certain circumstances. The recommendation was published in an amendment to NICE’s Guide to the Methods of Technology Appraisal. The amendment states that differential discounting should be applied where “treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years).” Renewed interest in differential discounting from NICE is welcome; however, the recommendation’s selective application of differential discounting raises a number of concerns. The stated criteria for applying differential discounting are ambiguous. The rationale for the selective application of differential discounting has not been articulated by NICE and is questionable. The selective application of differential discounting leads to several inconsistencies, the most concerning of which is the lower valuation of health gains for those with less than 30 years remaining life expectancy, which can be interpreted as age discrimination. Furthermore, the discount rates chosen by NICE do not appear to be informed by recent advances in the theoretical understanding of differential discounting. NICE’s apparent motivation for recommending differential discounting was to ensure a favorable cost-effectiveness ratio for a pediatric oncology drug. While flexibility may be appropriate to allow some interventions that exceed conventional cost-effectiveness thresholds to be adopted, the selective adjustment of appraisal methods is problematic and without justification.     

Silica vesicles as nanocarriers and adjuvants for generating both antibody and T-cell mediated immune resposes to Bovine Viral Diarrhoea Virus E2 protein

Bovine Viral Diarrhoea Virus (BVDV) is widely distributed in cattle industries and causes significant economic losses worldwide annually. A limiting factor in the development of subunit vaccines for BVDV is the need to elicit both antibody and T-cell-mediated immunity as well as addressing the toxicity of adjuvants. In this study, we have prepared novel silica vesicles (SV) as the new generation antigen carriers and adjuvants. With small particle size of 50 nm, thin wall (∼6 nm), large cavity (∼40 nm) and large entrance size (5.9 nm for SV-100 and 16 nm for SV-140), the SV showed high loading capacity (∼ 250 μg/mg) and controlled release of codon-optimised E2 (oE2) protein, a major immunogenic determinant of BVDV. The in vivo functionality of the system was validated in mice immunisation trials comparing oE2 plus Quil A (50 μg of oE2 plus 10 μg of Quil A, a conventional adjuvant) to the oE2/SV-140 (50 μg of oE2 adsorbed to 250 μg of SV-140) or oE2/SV-140 together with 10 μg of Quil A. Compared to the oE2 plus Quil A, which generated BVDV specific antibody responses at a titre of 10⁴, the oE2/SV-140 group induced a 10 times higher antibody response. In addition, the cell-mediated response, which is essential to recognise and eliminate the invading pathogens, was also found to be higher [1954-2628 spot forming units (SFU)/million cells] in mice immunised with oE2/SV-140 in comparison to oE2 plus Quil A (512–1369 SFU/million cells). Our study has demonstrated that SV can be used as the next-generation nanocarriers and adjuvants for enhanced veterinary vaccine delivery.     

Preoperative two-dimensional echocardiographic prediction of prosthetic aortic and mitral valve size in children

Preoperative two-dimensional echocardiograms (2D-ECHOs) were done on 18 patients to determine the accuracy of assessing the mitral and aortic anulus diameter in children undergoing valve replacement. Fourteen patients underwent primary valve replacement and four underwent repeat valve replacement. The mean age was 11.5 years (range 2 to 17 years). The 2D-ECHO measured mitral or aortic valve anulus was compared with the external diameter of the largest prosthetic valve that could be inserted. There was a strong correlation (r = 0.99, p less than 0.001, SEE = 1.0 mm) between the 2D-ECHO measurements and the prosthetic valve size in patients undergoing primary valve replacement, but the correlation (r = 0.16, p = NS) was poor for those undergoing repeat valve replacement. In conclusion, 2D-ECHO prediction of prosthetic mitral and aortic valve size is accurate in children undergoing primary valve replacement but is poor in those undergoing repeat valve replacement.     

EAACI Biologicals Guidelines—dupilumab for children and adults with moderate-to-severe atopic dermatitis

Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based), its cost-effectiveness and long-term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.     

Fulminant limb and retroperitoneal necrotizing fasciitis in a 15-year-old girl with Fanconi anaemia

Necrotizing fasciitis (NF) is an uncommon soft-tissue infection in children that carries a high mortality rate. We present a 15-year-old girl with chronic pancytopenia secondary to Fanconi anaemia who developed extensive NF of the lower limb, which unfortunately resulted in a fatal outcome. Immunodeficiency is a known risk factor for the development of this condition. The findings in this case demonstrate that patients with Fanconi anaemia may be susceptible to NF and that the clinical course may be more aggressive due to underlying immunosuppression. Prompt diagnosis of NF is vital in order to initiate appropriate treatment and to optimize patient outcome. Radiological investigation demonstrated extensive soft-tissue gas and destruction affecting the entire lower limb, abdominal wall and retroperitoneum, which led to timely definitive diagnosis and management.     

A Review of Barriers to Utilization of the Medicare Hospice Benefits in Urban Populations and Strategies for Enhanced Access

Disparities in access to health care extend to end-of-life care. Lack of access to hospice mirrors lack of access to health maintenance and primary care. Patients who are served by hospice nationally are disproportionately white and likely to reside in economically stable communities. In many urban low-income communities, less than 5% of decedents receive hospice care in the last 6 months of life. This review focuses on barriers to palliative care and hospice in urban, predominantly low-income communities, including cultural and reimbursement factors and the paucity of hospice providers, outreach projects, and in-patient hospice beds in urban communities. This review will also address some strategies that are being implemented by hospices locally and nationally to overcome demographic barriers to hospice care.     

Inhibition of human sperm-zona pellucida tight binding in the presence of antisperm antibody positive polyclonal patient sera

Patient sera previously characterized as containing high levels of IgG and IgA antisperm antibodies that bound to the sperm surface, most specifically the head region, were evaluated for their effect on sperm-zona pellucida tight binding as assessed by the hemizona assay (HZA). Of the ten patient sera tested, 7 reduced zona binding by approximately half. Two of the most strongly inhibitory (greater than 70% inhibition) were examined for their effect on the prefertilization maturation of sperm. The patient sera did not affect sperm motion characteristics, or development of hyperactivated motility. However, in the presence of these sera some impedance was noted in calcium uptake after stimulation with human follicular fluid and in the acrosome reaction after calcium ionophore induction. Whether these two sera specifically affect sperm-zona pellucida binding or non-specifically affect the normal progression of capacitation remains to be eludicated.     

Femur length shortening in the detection of Down syndrome: is prenatal screening feasible?

The potential utility of screening for femur length shortening in prenatal detection of Down syndrome (trisomy 21) was evaluated by comparing 49 consecutive fetuses with Down syndrome with 572 chromosomally normal fetuses before genetic amniocentesis. Ratios of measured femur length/predicted femur length and biparietal diameter/femur length were calculated for each fetus. The predicted femur length was calculated from a regression equation relating the biparietal diameter and femur length derived from a sample control group. With this normal regression equation, 7 of 49 (14.3%) fetuses with Down syndrome had short femur lengths (measured femur length/predicted femur length ratio of less than or equal to 0.91) compared with 35 of 572 (6.1%) fetuses with a normal karyotype (p less than 0.05). However, the maximum positive predictive value for identification of Down syndrome based on short femur lengths was only 0.93% for a high-risk population (prevalence of Down syndrome, 1:250) and 0.33% for a low-risk population (prevalence of Down syndrome, 1:700). We conclude that ultrasonographic screening of short femur length is less effective for prenatal detection of Down syndrome than initially suggested.