Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the ...survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.
Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying ...spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.
The Joint Committee for Oceanography and Marine Meteorology (JCOMM), a joint technical commission of IOC of UNESCO and WMO, has devised a coordination mechanism for the fit-for-purpose delivery of an ...end-to-end system, from ocean observations to met-ocean operational services. This paper offers a complete overview of the activities carried out by JCOMM and the status of the achievements up to 2017. The JCOMM stakeholders are the WMO Members and the IOC Member States, their research and operational Institutions, which mandated JCOMM to devise an international strategy to advance toward the achievement of the United Nations Sustainable Development Goals. The three activity areas, namely the Observation Program Area-OPA, the Data Management Program Area-DMPA and the Services and Forecasting Services Program Area-SFSPA have established several expert teams to contribute to the international coordination. OPA is organized in observing networks connected with different observing technologies, DMPA organizes the overall near-real time and delayed mode data assembly and delivery methodology and architecture and the SFSPA coordinates the met-ocean services stemming out of observations and data management. The future developments should strengthen the coordination in the three program areas considering the inclusion of new and emergent observing technologies, the interoperability of met-ocean data assembly centers and the establishment of efficient research to operations protocols, as well as better fit-for-purpose customized services for the public and private sectors.
Abstract Objectives Identifying clinical prediction rules (CPRs) for primary care from electronic databases is difficult. This study aims to identify a search filter to optimize retrieval of these to ...establish a register of CPRs for the Cochrane Primary Health Care field. Study Design and Setting Thirty primary care journals were manually searched for CPRs. This was compared with electronic search filters using alternative methodologies: (1) textword searching; (2) proximity searching; (3) inclusion terms using specific phrases and truncation; (4) exclusion terms; and (5) combinations of methodologies. Results We manually searched 6,344 articles, revealing 41 CPRs. Across the 45 search filters, sensitivities ranged from 12% to 98%, whereas specificities ranged from 43% to 100%. There was generally a trade-off between the sensitivity and specificity of each filter (i.e., the number of CPRs and total number of articles retrieved). Combining textword searching with the inclusion terms (using specific phrases) resulted in the highest sensitivity (98%) but lower specificity (59%) than other methods. The associated precision (2%) and accuracy (60%) were also low. Conclusion The novel use of combining textword searching with inclusion terms was considered the most appropriate for updating a register of primary care CPRs where sensitivity has to be optimized.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective The discovery of local anesthesia revolutionized urologic surgery. We investigate the evolution of intraurethral anesthesia in urologic surgery beginning in 1884. Methods A review of the ...literature was performed, reviewing the history of local anesthesia for urologic surgery, with a specific emphasis on intraurethral anesthesia. Using the University of Rochester libraries catalog “Voyager,” a search was performed reviewing the primary literature published on intraurethral anesthesia beginning from 1884 through 2009. We also reviewed published literature in Ovid Med and PubMed for articles relevant to the topic of intraurethral anesthesia. The search terms were intraurethral, cocaine, lidocaine, and anesthesia. Results In the 1840s, it was demonstrated that ether, nitrous oxide, and chloroform could prevent the pain of surgery, resulting in a dramatic increase in surgery. At Massachusetts General Hospital between 1845 and 1847, surgeries increased 2.5-fold. Four decades later, it was demonstrated that cocaine allowed for adequate analgesia without the side effects of general anesthesia, resulting in a dramatic increase in urologic surgery. Cocaine was gradually replaced as an intraurethral anesthetic as safer local anesthetics, such as lidocaine, became introduced. Modern studies show conflicting results over the efficacy and ideal administration of intraurethral anesthetics. Conclusions Local anesthesia was rapidly accepted by urologists around the world and used in a wide variety of urologic surgeries, contributing to the acceptance of anesthesia and a revolution of the practice of surgery. To this day, intraurethral anesthesia continues to be a widely used and effective technique in urology, although the ideal method of use is largely left up to individual preference.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective: To compare whole brain and caudate volume on MRI in subjects with Parkinson’s disease without cognitive impairment (PD), Parkinson’s disease with dementia with Lewy bodies (PD + DLB), ...Alzheimer’s disease (AD) and normal control subjects. To examine the relationship between caudate volume and cognitive impairment, depression and movement disorder. Method: Whole brain and caudate volumes were segmented from volumetric 1.5-tesla magnetic resonance imaging (MRI) scans of older subjects with PD (n = 28; mean age 75.5 years), PD + DLB (n = 20; 73.0 years), AD (n = 27; 77.5 years) and normal controls (n = 35; 74.9 years). Results: Subjects with AD had significantly reduced whole brain and caudate volume compared to controls and those with PD. Caudate atrophy in AD was proportionate to whole brain atrophy. There were no significant differences in whole brain or caudate volume between controls, PD and PD + DLB. There were no significant correlations between caudate volume and either global cognitive function, executive performance or processing speed. Conclusions: Caudate atrophy occurs in AD but not PD without dementia. Caudate atrophy is not regionally specific but part of generalised brain volume loss. Structural changes in the caudate, as assessed by in vivo MRI, do not appear to contribute to the cognitive impairment observed amongst patients with PD, PD + DLB or AD. Results indicate that the executive and attentional dysfunctions associated with PD and DLB are unlikely to be a direct and specific consequence of caudate atrophy as assessed on MRI.
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