Multimodal prerehabilitation for elderly patients with sarcopenia in colorectal surgery.

Sarcopenia, which is characterized by progressive and generalized loss of skeletal muscle mass and strength, has been well described to be associated with numerous poor postoperative outcomes, such as increased perioperative mortality, postoperative sepsis, prolonged length of stay, increased cost of care, decreased functional outcome, and poorer oncological outcomes in cancer surgery. Multimodal prehabilitation, as a concept that involves boosting and optimizing the preoperative condition of a patient prior to the upcoming stressors of a surgical procedure, has the purported benefits of reversing the effects of sarcopenia, shortening hospitalization, improving the rate of return to bowel activity, reducing the costs of hospitalization, and improving quality of life. This review aims to present the current literature surrounding the concept of sarcopenia, its implications pertaining to colorectal cancer and surgery, a summary of studied multimodal prehabilitation interventions, and potential future advances in the management of sarcopenia.

Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study.

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 .

Additive risk of surgical site infection from more than one risk factor following craniotomy for tumor.

PURPOSE: This study seeks to expound upon risk factor etiologies for surgical site infection (SSI) and investigate their combinatorial effects on infection rate following craniotomy for neuro-oncologic pathology. METHODS: Patients who underwent neuro-oncologic craniotomy between 2006 and 2020 were included. Medical records were reviewed to identify the occurrence of wound infection at ≤ 3 months postoperatively. Potential risk factors for infection included tumor pathology, location, anesthesia type, indication, ventricular entry, foreign body, brachytherapy, lumbar drain, prior operation, prior cranial radiation, prior infection, bevacizumab, and medical comorbidities (hypertension, obesity, diabetes, hyperlipidemia, other cancer, cirrhosis). Logistic regression was implemented to determine risk factors for SSI. Chi-square tests were used to assess whether the number of risk factors (e.g., 0, ≥ 1, ≥2, ≥ 3, ≥4) increases the risk of SSI compared to patients with fewer risk factors. The relative increase with each additional risk factor was also evaluated. RESULTS: A total of 1209 patients were included. SSI occurred in 42 patients (3.5%) by 90 days after surgery. Significant risk factors on multivariate logistic regression were bevacizumab (OR 40.84; p < 0.001), cirrhosis (OR 14.20, p = 0.03), foreign body placement (OR 4.06; P < 0.0001), prior radiation (OR 2.20; p = 0.03), and prior operation (OR 1.92; p = 0.04). Infection rates in the combinatorial analysis were as follows: ≥1 risk factor = 5.9% (OR 2.74; p = 0.001), ≥ 2 = 6.7% (OR 2.28; p = 0.01), ≥ 3 = 19.0% (OR 6.5; p < 0.0001), ≥ 4 = 100% (OR 30.2; p < 0.0001). CONCLUSIONS: Risk factors in aggregate incrementally increase the risk of postoperative SSI after craniotomy for tumor.

Context and priorities for health systems strengthening for pain and disability in low- and middle-income countries: a secondary qualitative study and content analysis of health policies.

Musculoskeletal (MSK) health impairments contribute substantially to the pain and disability burden in low- and middle-income countries (LMICs), yet health systems strengthening (HSS) responses are nascent in these settings. We aimed to explore the contemporary context, framed as challenges and opportunities, for improving population-level prevention and management of MSK health in LMICs using secondary qualitative data from a previous study exploring HSS priorities for MSK health globally and (2) to contextualize these findings through a primary analysis of health policies for integrated management of non-communicable diseases (NCDs) in select LMICs. Part 1: 12 transcripts of interviews with LMIC-based key informants (KIs) were inductively analysed. Part 2: systematic content analysis of health policies for integrated care of NCDs where KIs were resident (Argentina, Bangladesh, Brazil, Ethiopia, India, Kenya, Malaysia, Philippines and South Africa). A thematic framework of LMIC-relevant challenges and opportunities was empirically derived and organized around five meta-themes: (1) MSK health is a low priority; (2) social determinants adversely affect MSK health; (3) healthcare system issues de-prioritize MSK health; (4) economic constraints restrict system capacity to direct and mobilize resources to MSK health; and (5) build research capacity. Twelve policy documents were included, describing explicit foci on cardiovascular disease (100%), diabetes (100%), respiratory conditions (100%) and cancer (89%); none explicitly focused on MSK health. Policy strategies were coded into three categories: (1) general principles for people-centred NCD care, (2) service delivery and (3) system strengthening. Four policies described strategies to address MSK health in some way, mostly related to injury care. Priorities and opportunities for HSS for MSK health identified by KIs aligned with broader strategies targeting NCDs identified in the policies. MSK health is not currently prioritized in NCD health policies among selected LMICs. However, opportunities to address the MSK-attributed disability burden exist through integrating MSK-specific HSS initiatives with initiatives targeting NCDs generally and injury and trauma care.

Characteristics of procalcitonin in hospitalized COVID-19 patients and clinical outcomes of antibiotic use stratified by procalcitonin levels.

We examined the characteristics of pro-calcitonin (PCT) in hospitalized COVID-19 patients (cohort 1) and clinical outcomes of antibiotic use stratified by PCT in non-critically ill patients without bacterial co-infection (cohort 2). Retrospective reviews were performed in adult, hospitalized COVID-19 patients during March-May 2020. For cohort 1, we excluded hospital transfers, renal disease and extra-pulmonary infection without isolated pathogen(s). For cohort 2, we further excluded microbiologically confirmed infection, 'do not resuscitate ± do not intubate' status, and intensive care unit (ICU). For cohort 1, PCT was compared between absent/low-suspicion and proven bacterial co-infections. Factors associated with elevated PCT and sensitivity/specificity/PPV/NPV of PCT cutoffs for identifying bacterial co-infections were explored. For cohort 2, clinical outcomes including mechanical ventilation within 5 days (MV5) were compared between the antibiotic and non-antibiotic groups stratified by PCT ≥ 0.25 µg/L. Nine hundred and twenty four non-ICU and 103 ICU patients were included (cohort 1). The median PCT was higher in proven vs. absent/low-suspicion of bacterial co-infection. Elevated PCT was significantly associated with proven bacterial co-infection, ICU status and oxygen requirement. For PCT ≥ 0.25 µg/L, sensitivity/specificity/PPV/NPV were 69/65/6.5/98% (non-ICU) and 75/33/8.6/94% (ICU). For cohort 2, 756/1305 (58%) patients were included. Baseline characteristics were balanced between the antibiotic and non-antibiotic groups except PCT ≥ 0.25 µg/L (antibiotic:non-antibiotic = 59%:24%) and tocilizumab use (antibiotic:non-antibiotic = 5%:2%). 23% (PCT < 0.25 µg/L) and 58% (PCT ≥ 0.25 µg/L) received antibiotics. Antibiotic group had significantly higher rates of MV5. COVID-19 severity inferred from ICU status and oxygen requirement as well as the presence of bacterial co-infections were associated with elevated PCT. PCT showed poor PPV and high NPV for proven bacterial co-infections. The use of antibiotics did not show improved clinical outcomes in COVID-19 patients with PCT ≥ 0.25 µg/L outside of ICU when bacterial co-infections are of low suspicion.

Combined use of vancomycin powder and betadine irrigation lowers the incidence of postcraniotomy wound infection in low-risk cases: a single-center risk-stratified cohort analysis.

PURPOSE: Postoperative surgical site infections (SSIs) constitute a significant source of morbidity for neurosurgical patients. Protocols that minimize postoperative wound infections are integral to improving outcomes and curtailing expenditures. The present study seeks to identify risk factors for infection and assess the efficacy of prophylactic betadine irrigation and vancomycin powder in addition to standard antibiotic irrigation. METHODS: We reviewed craniotomies performed by THS at Weill Cornell/New York Presbyterian Hospital to treat neuro-oncologic pathology. Patients were divided into three groups: group 1 - antibiotic irrigation, group 2 - antibiotic irrigation and betadine irrigation, group 3 - antibiotic irrigation, betadine irrigation, and vancomycin powder. SSI was confirmed with bacterial culture. Risk factor identification and assessment of treatment paradigms was performed using chi-square tests and univariate logistic regression. RESULTS: Among 1209 total patients, the 30- and 90-day SSI rates were 1.7% and 3.5%, respectively. Significant predictors of SSI included preoperative use of bevacizumab (OR 40.84; p < 0.0001), foreign body (OR 4.06; p < 0.0001), prior radiation (OR 2.20; p = 0.03), and prior operation/biopsy (OR 1.92; p = 0.04). Risk of infection was 2.1% in low-risk cases and 6.9% in high-risk cases. A significant, incremental decrement in SSIs was identified between the prophylaxis groups, although only among low-risk cases: group 1: 4.53%, group 2: 1.39%, group 3: 0.42% (p = 0.02). Neither vancomycin powder nor betadine significantly reduced the risk of SSI in patients with one or more risk factors. CONCLUSION: Vancomycin powder with betadine irrigation decreased SSI rates following neuro-oncologic cranial procedures in patients at low risk of infection (i.e., no preoperative risk factors).

Structured presurgery prehabilitation for aged patients undergoing elective surgery significantly improves surgical outcomes and reduces cost: A nonrandomized sequential comparative prospective cohort study.

BACKGROUND: With increasing global life expectancy, the number of major surgeries performed on aged adults invariably increases. This study aimed to examine the effectiveness of a structured prehabilitative program for aged colorectal cancer patients in improving short-term surgical outcomes. METHODS: A prospective philanthropically sponsored Programme for Enhanced Elderly Recovery at Sengkang General Hospital (PEERS) was initiated in February 2017 for patients ≥70-years-old who were due to undergo elective colectomies. These patients were put through a 2- to 4-week-long program before surgery, which included geriatric assessment, nutrition supplementation, and resistance training. They were compared with patients from a similar age group before PEERS was introduced (non-PEERS). RESULTS: Fifty-eight patients, with a median age of 78.5 (70-93) years, were recruited from a single institution to undergo PEERS. Baseline characteristics between the groups were similar. There was no significant improvement of anthropometric and functional characteristics before and after PEERS. Duration of hospitalization was shorter in the PEERS group (9 vs 11 days, P = 0.01). Both groups had similar 30-days' morbidity rates (8.6% vs 17.4%, P = 0.26). The PEERS group had significant improvement in their median EuroQol-5 Dimension score (0.70 presurgery to 0.80 6-months' postsurgery, P = 0.01). After multivariate analysis, the average duration of hospitalization in the PEERS group was 6.8 days shorter (P = 0.018; CI, 1.2-12.4) after adjusting for modality of surgery and complications. This represented a cost saving of USD$11,838.80. CONCLUSION: A standardized prehabilitation program for aged adults reduced the duration of hospitalization, improved the quality of life after surgery, and reduced costs.

Paradigm shift in gastrointestinal surgery - combating sarcopenia with prehabilitation: Multimodal review of clinical and scientific data.

A growing body of evidence has demonstrated the prognostic significance of sarcopenia in surgical patients as an independent predictor of postoperative complications and outcomes. These included an increased risk of total complications, major complications, re-admissions, infections, severe infections, 30 d mortality, longer hospital stay and increased hospitalization expenditures. A program to enhance recovery after surgery was meant to address these complications; however, compliance to the program since its introduction has been less than ideal. Over the last decade, the concept of prehabilitation, or "pre-surgery rehabilitation", has been discussed. The presurgical period represents a window of opportunity to boost and optimize the health of an individual, providing a compensatory "buffer" for the imminent reduction in physiological reserve post-surgery. Initial results have been promising. We review the literature to critically review the utility of prehabilitation, not just in the clinical realm, but also in the scientific realm, with a resource management point-of-view.

Development of a specific live-cell assay for native autophagic flux.

Autophagy is an evolutionarily conserved pathway mediating the breakdown of cellular proteins and organelles. Emphasizing its pivotal nature, autophagy dysfunction contributes to many diseases; nevertheless, development of effective autophagy modulating drugs is hampered by fundamental deficiencies in available methods for measuring autophagic activity or flux. To overcome these limitations, we introduced the photoconvertible protein Dendra2 into the MAP1LC3B locus of human cells via CRISPR/Cas9 genome editing, enabling accurate and sensitive assessments of autophagy in living cells by optical pulse labeling. We used this assay to perform high-throughput drug screens of four chemical libraries comprising over 30,000 diverse compounds, identifying several clinically relevant drugs and novel autophagy modulators. A select series of candidate compounds also modulated autophagy flux in human motor neurons modified by CRISPR/Cas9 to express GFP-labeled LC3. Using automated microscopy, we tested the therapeutic potential of autophagy induction in several distinct neuronal models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In doing so, we found that autophagy induction exhibited discordant effects, improving survival in disease models involving the RNA binding protein TDP-43, while exacerbating toxicity in neurons expressing mutant forms of UBQLN2 and C9ORF72 associated with familial ALS/FTD. These studies confirm the utility of the Dendra2-LC3 assay, while illustrating the contradictory effects of autophagy induction in different ALS/FTD subtypes.

Evidence-Based Practice: Temozolomide Beyond Glioblastoma.

PURPOSE OF REVIEW: Temozolomide is a first-line treatment for newly diagnosed glioblastoma. In this review, we will examine the use of temozolomide in other contexts for treating gliomas, including recurrent glioblastoma, glioblastoma in the elderly, diffuse low- and high-grade gliomas, non-diffuse gliomas, diffuse intrinsic pontine glioma (DIPG), ependymoma, pilocytic astrocytoma, and pleomorphic xanthoastrocytoma. RECENT FINDINGS: Temozolomide improved survival in older patients with glioblastoma, anaplastic gliomas regardless of 1p/19q deletion status, and progressive ependymomas. Temozolomide afforded less toxicity and comparable efficacy to radiation in high-risk low-grade gliomas and to platinum-based chemotherapy in pediatric high-grade gliomas. The success of temozolomide in promoting survival has expanded beyond glioblastoma to benefit patients with non-glioblastoma tumors. Identifying practical biomarkers for predicting temozolomide susceptibility, and establishing complementary agents for chemosensitizing tumors to temozolomide, will be key next steps for future success.

Psychosocial Support Following Maxillofacial Trauma and its Impact on Trauma Recurrence.

BACKGROUND: Injuries sustained to the maxillofacial region can result in significant physical trauma and long lasting psychosocial impairment. Maxillofacial trauma has been reported in literature to be a potentially recurrent disease. Patients who suffer maxillofacial trauma can benefit from psychological support. AIM: This study aims to identify maxillofacial trauma patient characteristics, investigate maxillofacial re-injury rate after provision of psychological support and report incidence of post traumatic stress disorder symptoms after maxillofacial trauma. METHOD: A total of 100 patients were identified from the departmental trauma database over two time periods at Royal Darwin Hospital; 50 patients did not have psychosocial intervention and 50 patients received intervention. Data on demographics, trauma pattern and aetiology were collected. A brief counselling session was conducted on second patient group by a trained mental health nurse and a survey using Trauma Screening Questionnaire was completed one month following injury. RESULTS: The most common cause of injuries was assault in both groups followed by falls and the most common site of injuries was in the mandible in both groups. Almost half of all patients were in the15-24 and 25-34 age groups. 17 % of patients in pre-intervention period and 4 % of patients in intervention period had injury recurrence at 3 year follow up. Patient groups at risk of developing post traumatic symptoms included male, non-indigenous population, employed group with no alcohol involvement. CONCLUSION: Maxillofacial trauma can cause considerable psychological morbidity and expose the patient to high risk of post traumatic disorder symptoms. This type of injury was found to affect particular groups of population and is associated with high rate of recurrence. Psychological support should be provided to these patients as a routine part of trauma aftercare.

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing.

Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO), a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations.

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA.

Hydrogen sulfide protects testicular germ cells against heat-induced injury.

OBJECTIVE: The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. RESULTS: It was found that all three H2S generating enzymes, cystathionine ß-synthase (CBS), cystathionine γ-lysase (CSE), and 3-mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 °C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 °C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production. CONCLUSIONS: Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity.

Anesthetic management of the patient with low ejection fraction.

The number of patients with heart failure presenting for surgery continues to rise, and anesthesiologists are increasingly being called upon to provide quality, safe care in the operating room for patients with low ejection fraction (EF). Perioperative goals in the management of these patients include maintaining forward flow, promoting inotropy without inducing or exacerbating ischemia, and returning patients to their preoperative level of function after surgery. Oftentimes, these goals can be met with pharmacologic support, including the use of calcium channel blockers, phosphodiesterase inhibitors, and novel agents, such as nesiritide and levosimendan. Many patients with diminished EF have implantable cardioverter-defibrillators (ICDs) in place. These devices can be complex to manage, and concern often arises regarding electromagnetic interference from monopolar cautery. Although simply placing a magnet on the device will often disable the antitachycardia interventions of an ICD, this is not always the case. The safest way to manage an ICD in the perioperative period is to interrogate and reprogram the device before and after surgery. Another helpful device in dealing with patients with low EF, particularly those in acute cardiogenic shock, is the intra-aortic balloon pump. These devices can serve a critical role in managing patients who have inadequate responses to pharmacologic therapy or in whom vasopressor and inotropic support are suboptimal because of concerns for increasing myocardial work. With full understanding of available pharmacologic agents, and an appreciation of the capabilities of ICDs and intra-aortic balloon pumps, anesthesiologists will be better equipped to meet the perioperative needs of the patient with low EF.

Antiandrogen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in exon 1 of the androgen receptor (AR) gene. SBMA demonstrates androgen-dependent toxicity due to unfolding and aggregation of the mutant protein. There are currently no disease-modifying therapies, but of increasing interest for therapeutic targeting is autophagy, a highly conserved cellular process mediating protein quality control. We have previously shown that genetic manipulations inhibiting autophagy diminish skeletal muscle atrophy and extend the lifespan of AR113Q knock-in mice. In contrast, manipulations inducing autophagy worsen muscle atrophy, suggesting that chronic, aberrant upregulation of autophagy contributes to pathogenesis. Since the degree to which autophagy is altered in SBMA and the mechanisms responsible for such alterations are incompletely defined, we sought to delineate autophagic status in SBMA using both cellular and mouse models. Here, we confirm that autophagy is induced in cellular and knock-in mouse models of SBMA and show that the transcription factors transcription factor EB (TFEB) and ZKSCAN3 operate in opposing roles to underlie these changes. We demonstrate upregulation of TFEB target genes in skeletal muscle from AR113Q male mice and SBMA patients. Furthermore, we observe a greater response in AR113Q mice to physiological stimulation of autophagy by both nutrient starvation and exercise. Taken together, our results indicate that transcriptional signaling contributes to autophagic dysregulation and provides a mechanistic framework for the pathologic increase of autophagic responsiveness in SBMA.

Anesthetic considerations for thoracoscopic sympathetic ganglionectomy to treat ventricular tachycardia storm: a single-center experience.

OBJECTIVE: The aim of this study was to determine the pertinent anesthetic considerations for patients undergoing surgical sympathectomy for electrical storm (incessant ventricular tachycardia (VT) refractory to traditional therapies). DESIGN: This is a retrospective review of a prospective database. SETTING: This single-center study took place in a university hospital setting. PARTICIPANTS: Twenty-six patients were enrolled. INTERVENTIONS: Fifteen patients underwent left-sided sympathectomy, whereas 11 patients underwent bilateral sympathectomy. MEASUREMENTS AND MAIN RESULTS: Anesthetic management of these patients was quite complex, requiring invasive monitoring, transesophageal echocardiography, one-lung ventilation, programming of cardiac rhythm management devices, and titration of vasoactive medications. Paired t test of hemodynamic data before, during, and after surgery showed no significant difference between preoperative and postoperative blood pressure values, regardless of whether the patient underwent unilateral or bilateral sympathectomy. Eight patients remained free of VT, three patients responded well to titration of oral medications, and one patient required 2 radiofrequency ablations after sympathectomy to control his VT. Three patients continued to have VT episodes, although reduced in frequency compared with before the procedure. Four patients were lost to followup. Overall, five patients within the cohort died within 30 days of the procedure. No patients developed any anesthetic complications or Horner's syndrome. The overall perioperative mortality (within the first 7 days of the procedure) was 2 of 26, or 7.7%. CONCLUSIONS: The anesthetic management of patients undergoing surgical sympathectomy for electrical storm can be quite complex, because these patients often present in a moribund and emergent state and cannot be optimized using current ACC/AHA guidelines. Expertise in invasive monitoring, transesophageal echocardiography, one-lung ventilation, cardiac rhythm device management, and pressor management is crucial for optimal anesthetic care.

Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation.

We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.

Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons.

The impact of endocrine disrupting chemical (EDC) exposure on human health is receiving increasingly focused attention. The prototypical EDC bisphenol A (BPA) is an estrogenic high-production chemical used primarily as a monomer for the production of polycarbonate and epoxy resins. It is now well established that there is ubiquitous human exposure to BPA. In the general population, exposure to BPA occurs mainly by consumption of contaminated foods and beverages that have contacted epoxy resins or polycarbonate plastics. To test the hypothesis that bioactive BPA was released from polycarbonate bottles used for consumption of water and other beverages, we evaluated whether BPA migrated into water stored in new or used high-quality polycarbonate bottles used by consumers. Using a sensitive and quantitative competitive enzyme-linked immunosorbent assay, BPA was found to migrate from polycarbonate water bottles at rates ranging from 0.20 ng/h to 0.79 ng/h. At room temperature the migration of BPA was independent of whether or not the bottle had been previously used. Exposure to boiling water (100 degrees C) increased the rate of BPA migration by up to 55-fold. The estrogenic bioactivity of the BPA-like immunoreactivity released into the water samples was confirmed using an in vitro assay of rapid estrogen signaling and neurotoxicity in developing cerebellar neurons. The amounts of BPA found to migrate from polycarbonate drinking bottles should be considered as a contributing source to the total "EDC-burden" to which some individuals are exposed.