Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis

CD4陽性T細胞に発現するA20(tnfaip3) はTh2型アレルギー性気道炎症を抑制する

研究科: 千葉大学大学院医学薬学府（先端医学薬学専攻）学位記番号: 千大院医薬博甲第医1412号博士（医学）千葉大学 = Chiba Universit

Age makes a difference: Symptoms in pediatric supraventricular tachycardia

Background: Supraventricular tachycardia is a group of rhythm disturbances that affect 1 in 300-1200 Australian children annually. The differentiation of supraventricular tachycardia (SVT) symptoms and age of onset according to their subtype is not well understood in the pediatric population. Most studies rely on ECG criteria only to characterize the subtype of the SVT, which is not applicable to all subtypes. The purpose of this study was to identify the symptoms and ages of onset of SVT subtypes, and to analyze whether ethnicity or severity correlated with the SVT subtype confirmed in an invasive Electrophysiology (EP) study. Methods: A retrospective analysis and prospective survey evaluated 364 patients who underwent an EP study at The Royal Children's Hospital, Melbourne between 2009 and 2015. Age of onset, symptoms, and ethnicity were collected by phone survey or medical records in addition to EP study diagnostic data, medication status, and follow-up information about their symptom status following EP procedure. Patients were grouped according to their SVT subtype. Data analysis was performed using chi-squared, Fisher's exact, and ANOVA statistical tests to determine associations between SVT substrates. Results: Two hundred and thirty-three suitable cases of SVT were identified (131 men, 102 women) aged between 0 and 18 years. Atrioventricular Reentrant Tachycardia (AVRT) (n = 153) was the most common SVT subtype, followed by Atrioventricular Nodal Reentrant Tachycardia (AVNRT) (n = 55), Atrial Tachycardia (AT) (n = 17), and other SVT subtypes (n = 8) which included Atrial Fibrillation, Atrial Flutter, and Junctional Tachycardia. There was a male predominance in all subtypes, except for AVNRT. AVNRT patients had palpitations, dyspnoea, dizziness, and anxiety more than any other group, AVRT patients complained of vomiting most and patients with AT had the most fatigue. The mean age of symptom onset varied among groups, being earlier in AVRT, later in AVNRT with a significant difference between AVRT with unidirectional retrograde accessory pathway (URAP) and AVNRT subtypes (P < 0.01). Conclusion: Some specific symptoms were strong discriminators between different SVT subtypes. Ethnicity did not have strong correlations with SVT subtype incidence. This study was able to show clinical differences among children with SVT due to AVRT (URAP) compared to AVNRT, allowing the prognosis and intended management of pediatric SVT to be anticipated by less invasive means

Successful ablation of refractory neonatal atrial flutter

Atrial flutter is an uncommonly diagnosed arrhythmia in the neonatal period. The majority of cases can be successfully converted to sinus rhythm by electrical cardioversion or atrial overdrive pacing. Sinus rhythm usually is maintained without the need for ongoing arrhythmic medication.1 Ablation of atrial flutter in neonates for arrhythmia control has yet to be reported

50 Years of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) – Time to Explore the Dark Side of the Moon

Despite significant progress in understanding catecholaminergic polymorphic ventricular tachycardia (CPVT), there are still multiple uncertainties and gaps in our knowledge. Like the dark side of the moon, we cannot see them directly. Unfortunately, clinicians must make diagnostic and therapeutic decisions without solid evidence. Instead of summarising the current state of science and reiterating the guidelines, we review difficulties in understanding the disease mechanism, diagnosis and therapy. Highlighting these truths helps to avoid misconceptions, think clearly about our patients and direct future research efforts. It has become clear that CPVT encompasses more than just uniformly expressed ryanodine receptor mutations leading to bidirectional ventricular tachycardia, rather it is a disease caused by different genetic mutations, overlapping with other entities and possibly affecting not only the heart. Treatment in addition to beta blockers is often necessary: flecainide and left cardiac sympathetic denervation are therapies that come before consideration of defibrillator implantation and new treatment options are on the horizon

Ten-year experience in atenolol use and exercise evaluation in children with genetically proven long QT syndrome

Background: Due to its availability, atenolol is the primary beta-blocker used in Australia for children with long QT syndrome. There is limited data on long-term follow-up of its use. Methods: A single-tertiary-center, retrospective, observational study investigating all children and adolescents who had genetically proven long QT syndrome type 1 (LQT1) and type 2 (LQT2) was conducted. Their pretreatment exercise tests were evaluated for QTc intervals into the recovery phase of exercise. Results: Eighty six patients were identified (LQT1, 67, and LQT2, 19) from 2004 to 2014. The majority (86%) of patients were initially referred for family screening. Atenolol was administered at a mean dose of 1.58 ± 0.51 mg/kg/day. During the median follow-up period of 4.29 years, only one proband developed ventricular arrhythmia whilst taking atenolol, No patient had cardiac arrest or aborted cardiac arrest. With respect to side effects of atenolol, only two patients had intolerable side effects necessitating changes of medication. Evaluation of exercise tests (pretreatment) demonstrated that corrected QT (QTc) intervals at 2-3 min into the recovery phase of exercise were significantly prolonged for LQT1 patients. LQT1 patients with transmembrane mutation had longer QTc intervals than their C-terminus mutation counterparts, reaching statistical significance at 3 min into the recovery phase of exercise. Conclusions: Atenolol is an effective treatment for genetically proven LQT1 and LQT2 children and adolescents, with good tolerability. In LQT1 patients, QTc intervals at 2-3 min into the recovery phase of exercise were significantly prolonged, particularly in patients with transmembrane mutations

Built environments for inpatient stroke rehabilitation services and care : A systematic literature review

Objectives To identify, appraise and synthesise existing design evidence for inpatient stroke rehabilitation facilities; to identify impacts of these built environments on the outcomes and experiences of people recovering from stroke, their family/caregivers and staff. Design A convergent segregated review design was used to conduct a systematic review. Data sources Ovid MEDLINE, Scopus, Web of Science and Cumulative Index to Nursing and Allied Health Literature were searched for articles published between January 2000 and November 2020. Eligibility criteria for selecting studies Qualitative, quantitative and mixed-methods studies investigating the impact of the built environment of inpatient rehabilitation facilities on stroke survivors, their family/caregivers and/or staff. Data extraction and synthesis Two authors separately completed the title, abstract, full-text screening, data extraction and quality assessment. Extracted data were categorised according to the aspect of the built environment explored and the outcomes reported. These categories were used to structure a narrative synthesis of the results from all included studies. Results Twenty-four articles were included, most qualitative and exploratory. Half of the included articles investigated a particular aspect of the built environment, including environmental enrichment and communal areas (n=8), bedroom design (n=3) and therapy spaces (n=1), while the other half considered the environment in general. Findings related to one or more of the following outcome categories: (1) clinical outcomes, (2) patient activity, (3) patient well-being, (4) patient and/or staff safety and (5) clinical practice. Heterogeneous designs and variables of interest meant results could not be compared, but some repeated findings suggest that attractive and accessible communal areas are important for patient activity and well-being. Conclusions Stroke rehabilitation is a unique healthcare context where patient activity, practice and motivation are paramount. We found many evidence gaps that with more targeted research could better inform the design of rehabilitation spaces to optimise care. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ