FK506 vs. cyclosporin. Pathologic findings in 1067 endomyocardial biopsies.

INTRODUCTION: Whether FK506 or cyclosporin is better for chronic immunosuppression in heart transplant patients has been debated. We examined endomyocardial biopsies from patients treated with these two drugs to determine if there was a difference in frequency of histologic cellular rejection episodes and Quilty lesions. The Quilty lesion (AKA cyclosporin effect) may be an atypical form of rejection, and is thought to be related to the use of cyclosporin immunosuppression. METHODS: We reviewed 1067 endomyocardial biopsies from 65 patients who were assigned FK506 or cyclosporin after heart transplantation. RESULTS: The number of episodes of rejection (162 FK506 vs. 145 cyclosporin) was the same. However, when compared to cyclosporin treatment, FK506 was associated with significantly more Quilty A lesions and fewer Quilty B lesions. CONCLUSION: FK506 appears to prevent some Quilty A lesions from progressing to Quilty B lesions. Since Quilty B lesion is associated with myocyte injury and Quilty A is not, this effect of FK506 could be associated with improved long-term graft function.     

Research Priorities for Data Collection and Management Within Global Acute and Emergency Care Systems

Barriers to global emergency care development include a critical lack of data in several areas, including limited documentation of the acute disease burden, lack of agreement on essential components of acute care systems, and a lack of consensus on key analytic elements, such as diagnostic classification schemes and regionally appropriate metrics for impact evaluation. These data gaps obscure the profound health effects of lack of emergency care access in low‐ and middle‐income countries (LMICs). As part of the Academic Emergency Medicine consensus conference “Global Health and Emergency Care: A Research Agenda,” a breakout group sought to develop a priority research agenda for data collection and management within global emergency care systems.     

Clinical features,neurologic recovery,and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study

BackgroundPosterior fossa syndrome (PFS) is a known consequence of medulloblastoma resection. Our aim was to clinically define PFS, its evolution over time, and ascertain risk factors for its development and poor recovery.MethodsChildren with medulloblastoma treated at St Jude Children’s Research Hospital from 6/2013 to 7/2019 received standardized neurological examinations, before and periodically after radiation therapy. Most (98.3%) were enrolled on the ongoing multi-institutional protocol (SJMB12; {"type":"clinical-trial","attrs":{"text":"NCT 01878617","term_id":"NCT01878617"}}NCT 01878617).ResultsSixty (34%) of 178 evaluated children had PFS. Forty (23%) had complete mutism (PFS1) and 20 (11%) had diminished speech (PFS2). All children with PFS had severe ataxia and 42.5% of PFS1 had movement disorders. By multivariable analysis, younger age (P = .0005) and surgery in a low-volume surgery center (P = .0146) increased PFS risk, while Sonic Hedgehog tumors had reduced risk (P = .0025). Speech and gait returned in PFS1/PFS2 children at a median of 2.3/0.7 and 2.1/1.5 months, respectively, however, 12 (44.4%) of 27 PFS1 children with 12 months of follow-up were nonambulatory at 1 year. Movement disorder (P = .037) and high ataxia score (P < .0001) were associated with delayed speech recovery. Older age (P = .0147) and high ataxia score (P < .0001) were associated with delayed gait return. Symptoms improved in all children but no child with PFS had normal neurologic examination at a median of 23 months after surgery.ConclusionsCategorizing PFS into types 1 and 2 has prognostic relevance. Almost half of the children with PFS1 with 12-month follow-up were nonambulatory. Surgical experience was a major modifiable contributor to the development of PFS.     

Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension

Heterozygous germline defects in a gene encoding a type II receptor for bone morphogenetic proteins (BMPR-II) underlie the majority of inherited cases of the vascular disorder known as pulmonary arterial hypertension (PAH). However, the precise molecular consequences of PAH causing mutations on the function of the receptor complex remain unclear. We employed novel enzymatic and fluorescence activity based techniques to assess the impact of PAH mutations on pre-mRNA splicing, nonsense-mediated decay (NMD) and receptor complex interactions. We demonstrate that nonsense and frameshift mutations trigger NMD, providing further evidence that haplo-insufficiency is a major molecular consequence of disease-related BMPR2 mutations. We identified heterogeneous functional defects in BMPR-II activity, including impaired type I receptor phosphorylation, receptor interactions and altered receptor complex stoichiometry leading to perturbation of downstream signalling pathways. Importantly, these studies demonstrate that the intracellular domain of BMPR-II is both necessary and sufficient for receptor complex interaction. Finally and to address the potential for resolution of stoichiometric balance, we investigated an agent that promotes translational readthrough of a BMPR2 nonsense reporter construct without interfering with the NMD pathway. We propose that stoichiometric imbalance, due to either haplo-insufficiency or loss of optimal receptor-receptor interactions impairs BMPR-II mediated signalling in PAH. Taken together, these studies have identified an important target for early therapeutic intervention in familial PAH.     

Efficacy and safety of two polyherbal combinations: E-MA-H and E-MA-HP in male sexual dysfunction

Efficacy and safety of 2 herbal products--E-MA-H at 2 dose levels, low (HLD) and high (HHD), and E-MA-HP (HP) capsules--versus placebo (PL) was evaluated in subjects with male sexual dysfunction. Males aged 21-60 with erectile dysfunction, premature ejaculation, or other form of sexual dysfunction were studied in this triple-blind, randomized, placebo-controlled, parallel-groups trial. Subjects received any one of the following 4 interventions: E-MA-H 2 capsules at night (HLD) for 60 days; E-MA-H 2 capsules twice daily for 30 days, followed by 2 capsules at night for 30 days (HHD); E-MA-HP (HP) 2 capsules twice daily for 60 days; or placebo (PL) 2 capsules twice daily for 60 days. All dosage regimens were standardized to 2 capsules twice daily by using 2 matching placebo capsules as the morning dose for HLD and on days 31-60 for HHD. Efficacy outcome measures were the international index of erectile function; index for premature ejaculation; erectile dysfunction inventory of treatment satisfaction; subjects' and investigators' global assessment. Safety was assessed through adverse events; hematology; blood chemistry. Of 148 subjects enrolled, 1 was excluded from analysis; data on the intention-to-treat population of 147 (PL = 36, HLD = 38, HHD = 37, HP = 36) were analyzed. There was a significant (P < 0.01) increase in the total international index of erectile function score (mean ± SEM) in subjects receiving HLD (16.28 ± 1.39), HHD (15.40 ± 1.22), and HP (18.55 ± 1.36) compared with PL (6.83 ± 1.52). The same pattern was seen with increase in index for premature ejaculation scores: HLD (9.68 ± 1.17), HHD (10.27 ± 1.05), HP (11.36 ± 1.20) versus PL (3.77 ± 1.04). There was no significant difference in effect among the active treatment groups. The incidence of adverse events was similar in all the groups. Laboratory evaluations did not show any clinically significant abnormality in any of the groups. Treatment with HLD, HHD, and HP is well tolerated, and more effective than placebo (P < 0.01), in subjects with erectile dysfunction, premature ejaculation, and other forms of sexual dysfunction.