Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154673/1/ana25681_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154673/2/ana25681.pd

Negative Online Ratings of Joint Replacement Surgeons: An Analysis of 6,402 Reviews

Background: With the expanding accessibility of online health-care information, patients frequently report visiting physician rating websites before choosing a surgeon. As such, it is important to analyze patients’ perception of arthroplasty surgeons as reflected on physician rating websites. Methods: A total of 6402 online reviews of arthroplasty surgeons were extracted for analysis. Each review rated less than 5 on a 5-point scale was deemed a “negative” review and was subsequently assigned to an appropriate category. Reviews were stratified by practice type, years in practice, gender, and low ( 3) ratings. Results: A total of 6402 reviews comprising 315 physicians were included in the analysis. The average rating for all surgeons was 4.35. The average rating for physicians in private practice was 4.3, compared to 4.5 for those in an academic setting. The average rating for physicians in practice for 1-10 years was 4.46, compared to 4.03 for those with >10 years of experience (P < .001). The most common factors contributing to negative reviews were bedside manner, wait time, poor outcome, and surgeon proficiency. Surgeon-dependent factors were more commonly associated with lower rated reviews (P < .001). Conclusions: Arthroplasty surgeons typically receive high online ratings, with a mean of 4.35 on a 5-point scale. Physicians in academic practice received higher ratings than those in private practice, and physicians who have been in practice for 1-10 years received higher ratings than those with more than 10 years in practice. The most common factors contributing to negative reviews are surgeon-dependent, including bedside manner, poor outcome, and surgeon proficiency

Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies