Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m²) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465).     

Lyme-associated parkinsonism: a neuropathologic case study and review of the literature

Neurological complications of Lyme disease include meningitis, encephalitis, dementia, and, rarely, parkinsonism. We present a case of striatonigral degeneration, a form of multiple system atrophy, in Lyme-associated parkinsonism. A 63-year-old man presented with erythema migrans rash, joint pains, and tremors. Serum and cerebrospinal fluid antibodies and polymerase chain reaction for Borrelia burgdorferi were positive. Clinical parkinsonism was diagnosed by several neurologists. Despite treatment, the patient continued to decline, with progressive disability, cognitive dysfunction, rigidity, and pulmonary failure. At autopsy, the brain showed mild basal ganglia atrophy and substantia nigra depigmentation, with extensive striatal and substantia nigral neuronal loss and astrogliosis. No Lewy bodies were identified; however, ubiquitin-positive glial cytoplasmic inclusions were identified in striatal and nigral oligodendroglia. There were no perivascular or meningeal infiltrates, the classic findings of neuroborreliosis. To our knowledge, this is the first report of striatonigral degeneration in a patient with B burgdorferi infection of the central nervous system and clinical Lyme-associated parkinsonism.     

Blockade of the glycine modulatory site of NMDA receptors modifies dynorphin-induced behavioral effects

Intrathecal (i.t.) administration of the opioid dynorphin causes neurological dysfunction and tissue damage. It has been suggested that these effects of dynorphin may be mediated, in part, by N-methyl-D-aspartate (NMDA) receptors. In the present studies, recently developed compounds that block the glycine potentiation site of the NMDA receptor (Gly-NMDA site), including the competitive antagonist 5-fluoro-indole-2-carboxylic acid and the non-competitive antagonist 7-chlorokynurenic acid, prevented the neurologic deficits and mortality caused by i.t. dynorphin A(1-17). These findings are consistent with the hypothesis that dynorphin-induced neurological dysfunction involves activation of NMDA receptors. Moreover, blockade of the Gly-NMDA site may provide an alternative to blockade of the glutamate binding site or NMDA receptor ion channel as an in vivo pharmacological strategy to treat conditions previously associated with excitotoxin mediated tissue injury.     

Naringenin; a bioflavonoid,impairs the reproductive potential of male mice

Present study analyzed the effect of naringenin, a bioflavonoid, on male reproductive function in adult mouse, after intraperitoneal treatment with varying concentrations of naringenin (2, 8 and 20?mg/kg b.wt.) for two weeks. Naringenin increased the generation of reactive oxygen species and lipid peroxidation in the testis with concomitant decrease in sperm count and motility in a dose-dependent manner. Activities of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase and levels of reduced glutathione were found to be decreased in a dose-dependent manner. Also, the levels of oxidized glutathione were increased leading to a shift in redox ratio. Naringenin treatment also led to a dose-dependent increase in the mRNA expression of c-jun, c-fos and NF-κB. The testicular histomorphology was also altered dose dependently. Additionally, the number of apoptotic germ cells increased with increasing doses of naringenin as evident from acridine orange/ethidium bromide costaining and JC-1 staining. In conclusion, our study reveals that naringenin despite being a potent antioxidant with numerous important biological functions may also act as pro-oxidant, thus causing damaging effects in the testicular tissue.     

Effectiveness and implementation of a community-based prevention programme targeting anabolic androgenic steroid use in gyms: study protocol of a quasi-experimental control group study

Background

During the past decades, concerns about increased anabolic androgenic steroid (AAS) use among recreational sportspeople have been raised, yet there is a paucity of AAS prevention efforts targeting this group. Accordingly, doping prevention efforts aimed at gyms have been recommended. The overall objective of the present project is to examine a prevention programme named 100% Pure Hard Training (100% PHT), which targets AAS use among recreational sportspeople training in gyms. Specifically, the project aims to: 1) assess the prevalence of AAS, and its associations with alcohol, illicit drugs, and nutritional supplements use; 2) examine whether 100% PHT can decrease AAS use in gyms, and 3) provide insights into which factors facilitate and/or impede implementation of the programme.

Methods/design

The intervention group consists of 27 gyms, and 27 gyms serve as controls. Intervention gyms take part in 100% PHT, a community-based programme involving several components: (a) training of key stakeholders (i.e., gym staff, gym owners, local police, and municipal prevention coordinators) regarding AAS use; (b) developing an action plan for AAS prevention for each gym; (c) certification of gyms that follow 100% PHT; (d) cooperative relationship between stakeholders; (e) annual follow-up of gyms. The project consists of two studies: Study A will examine the prevalence of AAS use and the effectiveness of 100% PHT (aims 1 and 2), and data for Study A will be collected using questionnaires distributed to gym attendees at two assessment points: baseline (pre-intervention) and follow-up (post-intervention). Study B will evaluate the implementation of 100% PHT (aim 3), and semi-structured interviews with participating stakeholders will be carried out post-intervention.

Discussion

Knowledge gained from the present project can be used to develop community-based doping prevention efforts aimed at recreational sportspeople training in gyms. Furthermore, it can provide insights into which factors are important for successful implementation of AAS prevention programmes that target gyms. Results are also expected to yield information on the prevalence of AAS use as well as associations between the use of AAS and other licit and illicit substances, including nutritional supplements, among recreational sportspeople.

Trial registration

The study was registered retrospectively at isrctn.com (Identifier: ISRCTN11655041; Registration date: 3 November 2016;).

     

Enhanced oral delivery of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations: in-vitro and ex-vivo assessment

Context: The oral delivery of risperidone encounters a number of problems, such as pH dependent solubility and low bioavailability, due to its lipophilicity and aqueous insolubility.

Objective: To improve the solubility, dissolution and intestinal permeation thereby bioavailability of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations.

Materials and methods: Oleic acid, Tween^® 20, PEG 600 and Aerosil^® 200 were chosen as oil, surfactant, co-surfactant and carrier, respectively from solubility and emulsification studies. Ternary phase diagram was constructed to determine emulsifying region.

Results and discussion: The Z-average and polydispersity Index of developed formulation was 83.1?nm and 0.306, respectively. Ex vivo permeation studies on isolated rat intestine indicated that the amount of risperidone permeated from SNEP formulation was increased around 4- and 1.8-fold than that of pure drug and marketed formulation, respectively.

Conclusion: This developed SNEP formulations can be regarded as novel and commercially feasible alternative to the current risperidone formulations.     

Anti-oxidized low density lipoprotein antibody determination as a predictor of restenosis following percutaneous transluminal coronary angioplasty.

Recent data suggests that autoimmune factors play an important role in the pathogenesis of atherosclerosis. In this context several autoantigens have been shown to elicit an immune response that results in accelerated atherosclerotic plaque formation. In the present study, we investigated whether elevated titers of anti-oxidized low density lipoprotein (oxLDL), anticardiolipin and antibodies to beta2-glycoprotein I (beta2GPI) can predict subsequent restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). A total of 74 consecutive patients (52 males, 22 females) with coronary artery disease were enrolled in the study. All patients underwent successful PTCA prior to which blood was drawn for the antibody analysis. The PTCA was followed by a clinical evaluation. Patients with recurrent chest pains underwent a repeated angiography and 34 of the 74 patients (46%) experienced restenosis. Patients positive for the presence of anti-oxLDL antibodies were more likely to develop restenosis within 6 months when compared with patients with no subsequent restenosis (relative-risk of 1.87; P< 0.05). Presence of anti-oxLDL antibodies was associated with hyperlipidemia (r = 0.25; P < 0.05) but not with other risk factors for atherosclerosis. Positivity for anticardiolipin or anti-beta2GPI antibodies which associate with a prothrombotic state, was not effective in predicting lumen narrowing. Thus, the presence of elevated levels of anti-oxLDL antibodies is associated with a higher risk for coronary restenosis following PTCA.