Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex wit

A novel mitragynine analog with low-efficacy mu opioid receptor agonism displays antinociception with attenuated adverse effects

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OC

Clinical presentation of simple and combined or syndromic arteriovenous malformations.

OBJECTIVES Arteriovenous malformations of the lower extremities (AVMLE) can present as simple or complex combined or syndromic forms (e.g. Parkes Weber Syndrome). We aimed to characterize the differences in clinical presentation and natural history of these potentially life and limb threatening congenital vascular malformations. METHODS We conducted a retrospective analysis of a consecutive series of patients with AVMLE, who presented to a tertiary referral center in Switzerland between 2008 and 2018. Clinical baseline characteristics, D-dimer level and course were summarized and differences between simple, non-syndromic and combined or syndromic AVMLE determined. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models. RESULTS Overall, 506 patients were prospectively enrolled in the Bernese Congenital Vascular Malformation Registry, 31 (6%) with AVMLE. There were 16 women and 15 men with a mean age of 18 years at first diagnosis (1 month - 72 years). Simple AVMLE was present in 22 (71%), combined or syndromic AVMLE with limb overgrowth in 9 patients (29%), respectively. Common symptoms and signs were pain 25 (81%), swelling 21 (68%) and soft tissue hypertrophy 13 (42%). Among combined or syndromic patients, 3 patients died from wound infection with sepsis or disseminated intravascular coagulation with bleeding complications (intracranial hemorrhage and bleeding from extensive leg ulcers). Combined or syndromic patients presented more often with bleeding (67% vs. 5%; p<0.001), malformation related infection (44% vs. 5%; p=0,017) and leg length difference (56% vs. 14%; p=0.049). D-dimer levels were elevated (mean 17256 μg/L, range 1557 μg/L to 80000 μg/L) and angiographic appearance showed complex, mixed type of AVMs, including interstitial type IV, in all patients with combined or syndromic AVMLE. CONCLUSION Patients with congenital simple AVMLE most often present with benign clinical features and rarely complications related to hemodynamic changes. Patients with combined or syndromic AVMLE often face serious outcomesdominated by complications other than direct high flow related heart failure

Molecular mechanism of biased signaling at the kappa opioid receptor

The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays. We determine a crystal structure of KOR bound to the G protein-biased agonist nalfurafine, the first approved KOR-targeting drug. We also identify an arrestin-biased KOR agonist, WMS-X600. Using MD simulations of KOR bound to nalfurafine, WMS-X600, and a balanced agonist U50,488, we identify three active-state receptor conformations, including one that appears to favor arrestin signaling over G protein signaling and another that appears to favor G protein signaling over arrestin signaling. These results, combined with mutagenesis validation, provide a molecular explanation of how agonists achieve biased signaling at KOR

A systematic review of the safety and efficacy of currently used treatment modalities in the treatment of patients with PIK3CA-related overgrowth spectrum.

BACKGROUND PIK3CA-related overgrowth syndromes (PROS) include a variety of clinical presentations that are associated with hypertrophy of different parts of the body. AIM Perform a systematic literature review to assess the current treatment options and their efficacy and safety in PROS. METHODS A literature search was performed in EMBASE, MEDLINE (Ovid), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Google Scholar to retrieve publications on the treatment for hypertrophy in PROS and randomized controlled trials, cohort studies or case series including ≥10 patients reporting were included in the review. Titles, abstracts and full texts were assessed by two reviewers independently. The Risk of Bias (RoB) was assessed using the Newcastle Ottawa Scale. RESULTS 16 articles for the treatment of hypertrophy in PROS patients were included, 13 (81.3%) from clinical retrospective studies and 3 (13.7%) from prospective cohort studies. The ROB grade was low for 2, medium for 12 and high for 2 studies. 13 articles reported surgical treatment, while 3 reported pharmacological treatment using PIK3/mTOR pathway inhibitors in PROS patients. In 3 studies, PROS was defined by a mutation in the PIK3CA gene, while the other studies relied on a clinical definition of PROS. Surgical therapy was beneficial for a specific subgroup of PROS (macrodactyly), but little was reported concerning surgery and potential benefits in other PROS entities. Reported side effects in surgical therapy were mostly prolonged wound healing or scarring. PIK3/mTOR pathway inhibition was beneficial in patients with PROS reducing hypertrophy as well as systemic symptoms. Adverse effects reported included infection, changes in blood count, liver enzymes and metabolic measures. CONCLUSION Surgery is a locally limited treatment option in specific types of PROS. A promising treatment option in PROS is the pharmacological PIK3CA inhibition. However, the level of evidence on treatment of overgrowth in PROS patients is limited

Improving nursing care in a children’s hospital in rural India

Background: Nursing care quality in developing countries is an ongoing challenge leading to poor patient outcomes. The objective of this study is to evaluate changes in nursing performance providing routine cares following a training program in children’s hospital in Mota Fofalia, Gujarat, India. Methods: The main outcome measure was the proportion of newborns with vital signs and weights obtained by nursing staff before and after a training program. The training program consisted of an in-service reinforced by hands-on management of patient care for 2 weeks. Following the training, the nurses were observed for 2 months. Results: Observation of 138 newborn encounters demonstrated a 29.7% improvement in vital sign monitoring and 88.4% in weight monitoring from the 0% baseline. Conclusion: We observed a moderate improvement in measuring vital signs and a substantial improvement in measuring weights in newborns with the training intervention. For further improvement, continued training, and follow-up is indicated

Parkes Weber Syndrome: Contribution of the Genotype to the Diagnosis

Objectives: Parkes Weber syndrome (PWS) is a rare disorder that combines overgrowth, capillary malformations, and arteriovenous malformations (AVM)/arteriovenous fistulas, for which underlying activating mutations in the ras/mitogen-activated protein kinase/extracellular-signal-regulated kinase signaling pathway have been described. The clinical overlap with Klippel-Trenauny syndrome, associated with mutations in PIK3CA, is significant. This case series aimed to elaborate on the phenotypic description of PWS, to underline its clinical overlap with Klippel-Trenauny syndrome and nonsyndromic AVM, and to evaluate the contribution of genotypic characterization to the diagnosis. Methods: All patients diagnosed with PWS upon enrollment in the Bernese VAScular COngenital Malformations (VASCOM) cohort were included. The diagnostic criteria of PWS were retrospectively reviewed. A next-generation sequencing (NGS) gene panel (TSO500, Illumina) was used on tissue biopsy samples. Results: Overall, 10/559 patients of the VAScular COngenital Malformations cohort were initially diagnosed with PWS. Three patients were reclassified as nonsyndromic AVM (Kristen Rat Sarcoma Viral oncogene homolog [KRAS], KRAS+tumor protein p53, and protein tyrosine phosphatase non-receptor type 11). Finally, 7 patients fulfilled all clinical diagnostic criteria of PWS. Genetic testing was available in 5 PWS patients. Only 1 patient had the classic RASA1 mutation; another patient had mutations in G protein subunit alpha q (GNAQ) and phosphatase and tensin homolog. In a third case, a PIK3CA mutation was detected. In 2 patients, no mutations were identified. Conclusion: Overgrowth syndromes with vascular malformations are rare and their clinical overlap hampers the classification of individual phenotypes under specific syndrome labels, sometimes even despite genetic testing. To provide optimal patient care, an accurate phenotypic description combined with the identification of molecular targets for precision medicine may be more meaningful than the syndrome classification itself

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

BACKGROUND: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). METHODS: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). RESULTS: HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers. CONCLUSION: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution

Circulating brain‐derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community

BACKGROUND: Brain‐derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). METHODS AND RESULTS: We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome‐Wide Replication And Meta‐Analysis) consortium (>22 000 coronary artery disease [CAD] cases, >60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow‐up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable‐adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1‐SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect). CONCLUSION: Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD