The charlotte large artery occlusion endovascular therapy outcome score compares favorably to the critical area perfusion score for prognostication before basilar thrombectomy.

INTRODUCTION: The Critical Area Perfusion Score (CAPS) predicts functional outcomes in vertebrobasilar thrombectomy patients based on computed tomography perfusion (CTP) hypoperfusion. We compared CAPS to the clinical-radiographic Charlotte Large artery occlusion Endovascular therapy Outcome Score (CLEOS). METHODS: Acute basilar thrombosis patients from January 2017-December 2021 were included in this retrospective analysis from a health system's stroke registry. Inter-rater reliability was assessed for 6 CAPS raters. A logistic regression with CAPS and CLEOS as predictors was performed to predict 90-day modified Rankin Scale (mRS) score 4-6. Area under the curve (AUC) analyses were performed to evaluate prognostic ability. RESULTS: 55 patients, mean age 65.8 (± 13.1) years and median NIHSS score 15.55-24, were included. Light's kappa among 6 raters for favorable versus unfavorable CAPS was 0.633 (95% CI 0.497-0.785). Increased CLEOS was associated with elevated odds of a poor outcome (odds ratio (OR) 1.0010, 95% CI 1.0007-1.0014, p<0.01), though CAPS was not (OR 1.0028, 95% CI 0.9420-1.0676, p=0.93). An overall favorable trend was observed for CLEOS (AUC 0.69, 95% CI 0.54-0.84) versus CAPS (AUC 0.49, 95% CI 0.34-0.64; p=0.051). Among 85.5% of patients with endovascular reperfusion, CLEOS had a statistically higher sensitivity than CAPS at identifying poor 90-day outcomes (71% versus 21%, p=0.003). CONCLUSIONS: CLEOS demonstrated better predictive ability than CAPS for poor outcomes overall and in patients achieving reperfusion after basilar thrombectomy.

Transcriptomic analysis of the development of skeletal muscle atrophy in cancer-cachexia in tumor-bearing mice.

Cancer-cachexia (CC) is a wasting condition directly responsible for 20-40% of cancer-related deaths. The mechanisms controlling development of CC-induced muscle wasting are not fully elucidated. Most investigations focus on the postcachectic state and do not examine progression of the condition. We recently demonstrated mitochondrial degenerations precede muscle wasting in time course progression of CC. However, the extent of muscle perturbations before wasting in CC is unknown. Therefore, we performed global gene expression analysis in CC-induced muscle wasting to enhance understanding of intramuscular perturbations across the development of CC. Lewis lung carcinoma (LLC) was injected into the hind-flank of C57BL6/J mice at 8 wk of age with tumor allowed to develop for 1, 2, 3, or 4 wk and compared with PBS-injected control. Muscle wasting was evident at 4 wk LLC. RNA sequencing of gastrocnemius muscle samples showed widespread alterations in LLC compared with PBS animals with largest differences seen in 4 wk LLC, suggesting extensive transcriptomic alterations concurrent to muscle wasting. Commonly altered pathways included: mitochondrial dysfunction and protein ubiquitination, along with other less studied processes in this condition regulating transcription/translation and cytoskeletal structure. Current findings present novel evidence of transcriptomic shifts and altered cellular pathways in CC-induced muscle wasting.

Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size.

Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia.

Autophagy activation, not peroxisome proliferator-activated receptor γ coactivator 1α, may mediate exercise-induced improvements in glucose handling during diet-induced obesity.

NEW FINDINGS: What is the central question of this study? What are the individual and combined effects of muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) overexpression and physical activity during high-fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle-specific PGC-1α overexpression provides no protection against lipid-overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC-1α content, protects against high-fat diet-induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise-induced protection from lipid overload. The prevalence of glucose intolerance is alarmingly high. Efforts to promote mitochondrial biogenesis through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition. The aim of this study was to determine the combined effects of muscle-specific overexpression of PGC-1α and physical activity on glucose handling during diet-induced obesity. Wild-type (WT, ∼20) and PGC-1α muscle transgenic (MCK-PGC-1α, ∼20) mice were given a Western diet (WD) at 8 weeks age and allowed to consume food ab libitum throughout the study. At 12 weeks of age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11 and 15 weeks of age, animals underwent glucose tolerance tests (GTT) and graded exercise tests (GXT). At 16 weeks of age, tissues were collected. At 11 weeks, the MCK-PGC-1α animals had 50% greater glucose tolerance integrated area under the curve compared with WT. However, at 15 weeks, SED animals also had greater GTT integrated area under the curve compared with VWR, regardless of genotype; furthermore, SED animals demonstrated reduced exercise capacity compared with earlier time points, which was not seen in VWR animals. Voluntary distance run per day was correlated with GTT in VWR-WT, but not VWR-MCK-PGC-1α mice. Voluntary wheel running and genotype independently resulted in a greater LC3II/LC3I ratio, suggesting enhanced autophagosome formation, which was correlated with exercise-induced improvements in GTT. In conclusion, artificially increasing mitochondrial content does not protect from lipid-induced pathologies nor does it augment exercise adaptations. Physical activity ameliorates the effects of lipid overload-induced glucose intolerance, an effect that appears to be related to enhanced activation of autophagy.

Skeletal Muscle Insulin Resistance as a Precursor to Diabetes: Beyond Glucoregulation.

BACKGROUND: Prevalence of Type 2 Diabetes Mellitus (T2DM) has reached pandemic levels in the Western societies. T2DM begins with the development of peripheral insulin resistance which prior research suggests may commonly originate within the skeletal muscle. A number of mechanisms have been proposed for the development of muscle insulin resistance including those of classical glucose handling, and also other cellular derangements observed in this disease which include mitochondrial degeneration, alterations in muscle protein turnover and early evidences for dysregulation of the microRNAs. The purpose of the current review is to examine the current findings on these latter aspects of mitochondrial maintenance, protein turnover and microRNA dysregulation along with the potential implications for these derangements in the development of insulin resistance and hence T2DM. We summarize multiple evidences for the degeneration of mitochondria and known elements of the processes regulating mitochondrial quality. Subsequently, we examine current findings of the alterations in muscle protein synthesis and autophagic protein degradation in T2DM and potential feedback of these systems onto canonical insulin signaling. Finally, evidences have emerged for the dysregulation of microRNAs in muscle insulin resistance. Of note early data point to several microRNAs altered by the insulin resistant state which exhibit relations to classic insulin signaling and the other processes discussed here. CONCLUSION: Considering that T2DM may be initiated with muscle insulin resistance, improved understanding of the dysregulation of these metabolic parameters of skeletal muscle in the pathogenesis of T2DM may be key to developing efficacious therapeutic modalities to prevent and treat this condition.

Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice.

BACKGROUND: Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20-40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice. METHODS: First, weight-stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student-Newman-Kuels post hoc test. RESULTS: MinStable mice displayed ~50% lower Pgc-1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1-3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting. CONCLUSIONS: Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia.

A new model for accreditation of residency programs in internal medicine.

A renewed emphasis on clinical competence and its assessment has grown out of public concerns about the safety, efficacy, and accountability of health care in the United States. Medical schools and residency training programs are paying increased attention to teaching and evaluating basic clinical skills, stimulated in part by these concerns and the responding initiatives of accrediting, certifying, and licensing bodies. This paper, from the Residency Review Committee for Internal Medicine of the Accreditation Council for Graduate Medical Education, proposes a new outcomes-based accreditation strategy for residency training programs in internal medicine. It shifts residency program accreditation from external audit of educational process to continuous assessment and improvement of trainee clinical competence.

Problem-based learning in a managed care seminar for all new residents at an academic medical center.

One of the most important challenges in resident education is to train residents how to function in relation to managed care companies and systems so as to enhance the quality, accessibility, and efficiency of health care. Since 1996, The University of Texas Medical Branch in Galveston has presented an annual half-day seminar on managed care to new residents. The format involves training sessions and didactic presentations aimed at small groups (led by faculty physicians and nonphysicians from throughout the medical and managed care establishments). Problem-based learning sessions conducted in these groups focus on topics such as the organization of managed care systems, access, network, admit versus observation, inpatient status, denials, avoidable hospital days, concurrent reviews, gatekeepers, referrals, behavioral health, disease management programs, and financial considerations. Pretests and posttests are given to those participating to gauge the effectiveness of the program. In addition, participants complete evaluation forms that can be used by program coordinators to assess resident satisfaction with the learning format and to determine what improvements can be made in the process. For the 1999 and 2000 seminars, posttest results were significantly higher than pretest results for the new residents who participated in the seminar. Each year, seminar evaluations show that the small-group format is well received. We conclude that the small-group learning format is effective and enjoyable for the residents and their leaders. The format necessitates the training of 30 group leaders to increase their knowledge of managed care systems.

Emergency preparedness for residency/fellowship programs: lessons learned during Hurricane Katrina and applied during Hurricane Ike.

When it struck the US Gulf Coast in 2005, Hurricane Katrina severely disrupted many graduate medical education residency/fellowship programs in the region and the training of hundreds of residents/fellows. Despite the work of the Accreditation Council for Graduate Medical Education in responding to this natural disaster and facilitating communication and transfer of residents/fellows to other unaffected training programs, the storm exposed the gaps in the existing system. Subsequently, the Accreditation Council for Graduate Medical Education, with the aid of its member organizations, including the American Medical Association, developed a new disaster recovery plan to allow for a more rapid, effective response to future catastrophic events. These policies were instrumental in the rapid relocation of 597 residents/fellows from the University of Texas Medical Branch at Galveston after the landfall of Hurricane Ike in September 2008. As a further accommodation to affected trainees, medical certification boards should be as flexible as possible in waiving continuity requirements in the event of a disaster that affects residency/fellowship programs.

Craniofacial hyperhidrosis successfully treated with topical glycopyrrolate.

Treatment of craniofacial hyperhidrosis currently consists of thoracic sympathectomy, which is not widely available. Oral anticholinergic agents and beta-blockers may be effective but also carry significant side effects. We describe a healthy, active 27-year-old male resident physician who had excessive facial sweating with minimal exertion or stress. The sweating was especially pronounced on the forehead, nose, and upper lip. Daily topical application of a 0.5% glycopyrrolate solution to the face and forehead was offered. After the first treatment, facial sweating was significantly reduced and was well controlled under stressful situations, without any discomfort to the skin. No loss of efficacy was seen after multiple face washings. Facial hyperhidrosis recurred after withdrawal of the glycopyrrolate for 2 days, confirming its therapeutic effect. Two years later, he continues to use glycopyrrolate as needed. We conclude that topical glycopyrrolate is effective in treating craniofacial hyperhidrosis and is associated with few adverse effects.