MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain

Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homologue, MrgX1, and is located specifically in small-diameter dorsal root ganglion neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the miniature excitatory postsynaptic currents frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn neurons of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain.     

High tacrolimus trough level variability is associated with rejections after heart transplant

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post‐HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post‐HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long‐term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post‐HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8‐fold increased risk for any rejection beyond the first year post‐HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.     

Reliability of the Catz-Itzkovich Spinal Cord Independence Measure assessment by interview and comparison with observation

OBJECTIVE: To examine the reliability of assessment with the Catz-Itzkovich Spinal Cord Independence Measure II (SCIM II) by interview and compare the findings with assessment by observation. DESIGN: In a cohort, comparative study, 28 inpatients with spinal cord lesions were assessed by two nurses using the Catz-Itzkovich SCIM II (interview) and by a multidisciplinary team (observation). RESULTS: Total agreement between interviewers ranged from 50% to 80% (Kappa coefficients 0.40-0.60). Pearson's coefficients of the correlation between scores obtained for the various SCIM subscales by interview or observation were 0.765-0.940 (P < 0.0001). The differences in mean scores obtained between the interview and observation methods were small and not statistically significant for most of the subscales. CONCLUSIONS: The results support the reliability of the Catz-Itzkovich SCIM assessment by interview and show it to be comparable with assessment by observation. The SCIM II interview may serve as an accurate measure of daily function in patients with spinal cord injury. However, with the sample of the study being relatively small, a larger scale examination is needed to generalize the results.     

An update on immunizations before and after transplantation in the pediatric solid organ transplant recipient

Vaccination offers a unique opportunity to decrease the burden of infectious complications following solid organ transplantation. In this paper we review the current guidelines for routine immunizations before and after solid organ transplantation, including the recent updates and changes to recommendations for certain vaccines. We also address the issue of waning immunity in solid organ transplant recipients and discuss the current data on vaccinating this patient population with live vaccines after transplantation.     

Topical treatment of tinea capitis in a neonate

Tinea capitis is the most common fungal skin infection in children. Given that this infection invades the hair shaft and the pilosebaceous unit, systemic antifungal therapy is the gold standard of treatment. Despite the neonate's increased susceptibility to infections, tinea capitis is rare in this population. We present the case of a 16-day-old infant with tinea capitis caused by Microsporum canis and effectively treated with topical bifonazole 1%.     

Progressive cerebello-cerebral atrophy and progressive encephalopathy with edema,hypsarrhythmia and optic atrophy may be allelic syndromes

In 2003, a new syndrome was described in the Sephardi Jewish population, named progressive cerebello-cerebral atrophy (PCCA) based on the typical neuroradiological findings. Following the identification of the causal genes in 2010 and 2014, two types were defined: PCCA type 1 due to SEPSECS mutations and PCCA type 2 due to VPS53 mutations.Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) was described in 1991 in Finland. The clinical and radiological phenotype resembles PCCA. The genetic background has been elusive for many years. Recently, mutations in multiple genes including SEPSECS have been described in patients with a PEHO-like syndrome.In 2007 two siblings of Moroccan-Jewish origin were diagnosed as having PEHO due to a severe developmental encephalopathy, limb and facial edema, intractable epilepsy, optic atrophy in one sibling and dysmorphic features. Six years ago an extensive workup, including whole exome sequencing, did not reveal the cause. Recently, a clinical reevaluation of the siblings suggested the possibility that they suffer from PCCA. A reanalysis of the exome data from 2014 revealed that the siblings indeed carried the two VPS53 mutations (exon 19 c.2084A>G p.(Gln695Arg) and c.1556 + 5G>A) and the parents were found to be carriers.The discovery that mutations in both VPS53 and SEPSECS can present with a PEHO-like phenotype, place PCCA and PEHO on the same clinical spectrum and suggest they may be allelic syndromes.     

Time to blood culture positivity as a marker for catheter-related candidemia

Candida spp. are important causes of nosocomial bloodstream infections. Around 80% of patients with candidemia have an indwelling central venous catheter (CVC). Determining whether the CVC is the source of candidemia has implications for patient management. We assessed whether the time to detection of Candida species in peripheral blood (time to positivity [TTP]) can serve as a marker for catheter-related candidemia. Prospective surveillance of Candida bloodstream infection was conducted in two medical centers. TTP was recorded by the BacT/Alert automated system. Sixty-four candidemia episodes were included. Fifty patients (78%) had an indwelling CVC. Thirteen patients (20.3%) had definite catheter-related candidemia. TTP was shorter for definite catheter-related candidemia (17.3 +/- 2 h) than that for candidemia from other sources (38.2 +/- 3 h; P < 0.001). A TTP cutoff of 30 h was 100% sensitive and 51.4% specific for catheter-related candidemia (area under the receiver-operator characteristic curve of 0.76). We conclude that TTP in peripheral blood is a sensitive but nonspecific marker for catheter-related candidemia and that a TTP of more than 30 h can help exclude an intravascular catheter as the possible source of candidemia.     

HNF1A variant,energy‐reduced diets and insulin resistance improvement during weight loss: The POUNDS Lost trial and DIRECT

Aim

To determine whether weight‐loss diets varying in macronutrients modulate the genetic effect of hepatocyte nuclear factor 1α (HNF1A) rs7957197 on weight loss and improvement of insulin resistance.

Materials and methods

We analysed the interaction between HNF1A rs7957197 and weight‐loss diets with regard to weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2‐year randomized weight‐loss trial, the POUNDS Lost trial. The findings were replicated in another independent 2‐year weight‐loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT), in 280 overweight/obese adults.

Results

In the POUNDS Lost trial, we found that a high‐fat diet significantly modified the genetic effect of HNF1A on weight loss and reduction in waist circumference (P for interaction = .006 and .005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction = .07 and .06, respectively) were observed. We replicated the results in DIRECT. Pooled results showed similar significant interactions with weight loss, waist circumference reduction, and improvement in fasting insulin and insulin resistance (P values for interaction = .001, .005, .02 and .03, respectively). Greater decreases in weight, waist circumference, fasting insulin level and insulin resistance were observed in participants with the T allele compared to those without the T allele in the high‐fat diet group (P = .04, .03 and .01, respectively).

Conclusions

Our replicable findings provide strong evidence that individuals with the HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing a hypocaloric and high‐fat diet.     

SMS messaging to improve ART adherence: perspectives of pregnant HIV-infected women in Kenya on HIV-related message content

There is growing evidence that mobile health (mHealth) approaches including short messaging service (SMS) can improve antiretroviral therapy (ART) adherence, but consensus is lacking regarding communication of HIV-related information. Most interventions to date have delivered SMS that do not overtly refer to HIV or ART in order to avoid risk of status disclosure. In formative work for an ongoing randomized controlled trial (RCT) evaluating one-way and two-way educational SMS for prevention of mother-to-child-transmission (PMTCT) adherence in Kenya, we conducted 10 focus group discussions (FGDs) with 87 HIV-infected peripartum women to determine desirability and preferred terminology of HIV-related content. SMS for the RCT were developed based on FGD findings. Roughly half of FGD participants supported receiving SMS containing overtly HIV-related terms, such as “HIV” and “medication”, citing desire for detailed educational messages about ART and PMTCT. Those opposed to overt content expressed concerns about confidentiality. Many participants argued that acceptability of HIV-related content depended on the recipient’s disclosure status and others’ access to her phone. Based on these findings, both covert and overt SMS were developed for the RCT and participants who owned their phone or had disclosed their HIV status to anyone with access to their phone were able to choose one of three options: (1) covert SMS only, (2) overt SMS only in response to HIV-related questions from the participant, (3) overt SMS routinely, initiated by the study. Of the 825 participants in the RCT, 94% were eligible to receive overt SMS. Of these, 66% opted to receive routine overt SMS and 10% to receive participant-initiated overt SMS. These findings show there may be interest in overt HIV-related information by SMS when risk of status disclosure is low, and support use of messaging strategies that allows participant choice in HIV-related content while protecting against undesired disclosure.