Brain Research and Neuroethics

In the past year neuroethics has begun to command the attention of neuroscientists, ethicists and journalists. Ethical questions associated with new knowledge of the human brain have received extensive coverage in the popular press with cover stories in The Economist and The New Scientist. There has also been a burst of discussion in the scientific literature (Farah, 2002; Wolpe, 2003), and a number of professional conferences have recently focused attention on the field. The current capability of neuroscience to monitor and alter brain function has profound ethical implications, which scientists and the public have only begun to examine

The Cdc37 protein kinase–binding domain is sufficient for protein kinase activity and cell viability

Cdc37 is a molecular chaperone required for folding of protein kinases. It functions in association with Hsp90, although little is known of its mechanism of action or where it fits into a folding pathway involving other Hsp90 cochaperones. Using a genetic approach with Saccharomyces cerevisiae, we show that CDC37 overexpression suppressed a defect in v-Src folding in yeast deleted for STI1, which recruits Hsp90 to misfolded clients. Expression of CDC37 truncation mutants that were deleted for the Hsp90-binding site stabilized v-Src and led to some folding in both sti1Δ and hsc82Δ strains. The protein kinase–binding domain of Cdc37 was sufficient for yeast cell viability and permitted efficient signaling through the yeast MAP kinase–signaling pathway. We propose a model in which Cdc37 can function independently of Hsp90, although its ability to do so is restricted by its normally low expression levels. This may be a form of regulation by which cells restrict access to Cdc37 until it has passed through a triage involving other chaperones such as Hsp70 and Hsp90

Waste Not or Want Not? A Contingent Ranking Analysis of Curbside Waste Disposal Options

Recent growth in the municipal solid waste (MSW) stream nationwide has prompted considerable research into alternative waste management programs that would divert a portion of the MSW stream from landfills. Using a sample of 350 individuals from a random digit-dialed telephone survey, a discrete choice contingent ranking approach is used to estimate household’s willingness-to-pay for various curbside trash-separation services in Ogden, Utah. Results indicate that Ogden residents are willing to pay approximately 3.7–4.6¢ per gallon of waste diverted for a curbside service that enables separation of green waste and recyclable material from other solid waste. Relative to costly waste diversion experiments conducted by other municipalities, the Ogden experience suggests contingent ranking is a cost-effective means for municipalities to evaluate waste disposal options

Trunk muscle activation during movement with a new exercise device for lumbo‐pelvic reconditioning

Gravitational unloading leads to adaptations of the human body, including the spine and its adjacent structures, making it more vulnerable to injury and pain. The Functional Re‐adaptive Exercise Device (FRED) has been developed to activate the deep spinal muscles, lumbar multifidus (LM) and transversus abdominis (TrA), that provide inter‐segmental control and spinal protection. The FRED provides an unstable base of support and combines weight bearing in up‐right posture with side alternating, elliptical leg movements, without any resistance to movement. The present study investigated the activation of LM, TrA, obliquus externus (OE), obliquus internus (OI), abdominis, and erector spinae (ES) during FRED exercise using intramuscular fine‐wire and surface EMG. Nine healthy male volunteers (27 ± 5 years) have been recruited for the study. FRED exercise was compared with treadmill walking. It was confirmed that LM and TrA were continually active during FRED exercise. Compared with walking, FRED exercise resulted in similar mean activation of LM and TrA, less activation of OE, OI, ES, and greater variability of lumbo‐pelvic muscle activation patterns between individual FRED/gait cycles. These data suggest that FRED continuously engages LM and TrA, and therefore, has the potential as a stationary exercise device to train these muscles

MSCs: delivery routes and engraftment, cell-targeting strategies, and immunemodulation,”

Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the "first-pass" accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose

Short-Term Impact of Bracing in Multi-Level Posterior Lumbar Spinal Fusion

Background: Clinical practice in postoperative bracing after posterior lumbar spine fusion (PLF) is inconsistent between providers. This paper attempts to assess the effect of bracing on short-term outcomes related to safety, quality of care, and direct costs. Methods: Retrospective cohort analysis of consecutive patients undergoing multilevel PLF with or without bracing (2013-2017) was undertaken (n = 980). Patient demographics and comorbidities were analyzed. Outcomes assessed included length of stay (LOS), discharge disposition, quality-adjusted life years (QALY), surgical-site infection (SSI), total cost, readmission within 30 days, and emergency department (ED) evaluation within 30 days. Results: Amongst the study population, 936 were braced and 44 were not braced. There was no difference between the braced and unbraced cohorts regarding LOS (P = .106), discharge disposition (P = .898), 30-day readmission (P = .434), and 30-day ED evaluation (P = 1.000). There was also no difference in total cost (P = .230) or QALY gain (P = .740). The results indicate a significantly lower likelihood of SSI in the braced population (1.50% versus 6.82%, odds ratio = 0.208, 95% confidence interval = 0.057-0.751, P = .037). There was no difference in relevant comorbidities (P = .259-1.000), although the braced cohort was older than the unbraced cohort (63 versus 56 y, P = .003). Conclusion: Bracing following multilevel posterior lumbar fixation does not alter short-term postoperative course or reduce the risk for early adverse events. Cost analysis show no difference in direct costs between the 2 treatment approaches. Short-term data suggest that removal of bracing from the postoperative regimen for PLF will not result in increased adverse outcomes

The Type I Hsp40 Zinc Finger-like Region Is Required for Hsp70 to Capture Non-native Polypeptides from Ydj1

The cytosolic yeast Hsp40 Ydj1 contains a conserved zinc finger-like region (ZFLR), which has two zinc-binding domains (ZBD), that helps regulate and specify Hsp70 function. To investigate the mechanism for Ydj1 ZFLR action, ZBDI and ZBDII mutants were constructed and characterized. ZBDII mutants exhibited temperature-sensitive growth defects, but yeast tolerated mutation of ZBDI. However, ZBDI and ZBDII mutants were defective at facilitating androgen receptor (AR) folding. Defective AR folding was associated with the accumulation of complexes between AR and Ydj1 ZFLR mutants and a reduction in Hsp70.AR complex formation. Purified Ydj1 ZBDI and ZBDII mutants could bind non-native polypeptides but could not deliver luciferase to Hsp70 and were defective at luciferase refolding. Interestingly, the ability of Ydj1 to synergize with Hsp70 to suppress thermally induced protein aggregation was blocked by mutation of ZBDII, but not ZBDI. Hence, ZBDII is required for yeast to survive heat stress because it is essential for Ydj1 to cooperate with Hsp70 to suppress protein aggregation. On the other hand, protein folding is dependent upon the action of both ZBDI and ZBDII because each is required for Hsp70 to capture non-native polypeptides from Ydj1

Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation

Cdc37 is a molecular chaperone that functions with Hsp90 to promote protein kinase folding. Analysis of 65 Saccharomyces cerevisiae protein kinases (∼50% of the kinome) in a cdc37 mutant strain showed that 51 had decreased abundance compared with levels in the wild-type strain. Several lipid kinases also accumulated in reduced amounts in the cdc37 mutant strain. Results from our pulse-labeling studies showed that Cdc37 protects nascent kinase chains from rapid degradation shortly after synthesis. This degradation phenotype was suppressed when cdc37 mutant cells were grown at reduced temperatures, although this did not lead to a full restoration of kinase activity. We propose that Cdc37 functions at distinct steps in kinase biogenesis that involves protecting nascent chains from rapid degradation followed by its folding function in association with Hsp90. Our studies demonstrate that Cdc37 has a general role in kinome biogenesis

Use of an electronic administrative database to identify older community dwelling adults at high-risk for hospitalization or emergency department visits: The elders risk assessment index

<p>Abstract</p> <p>Background</p> <p>The prevention of recurrent hospitalizations in the frail elderly requires the implementation of high-intensity interventions such as case management. In order to be practically and financially sustainable, these programs require a method of identifying those patients most at risk for hospitalization, and therefore most likely to benefit from an intervention. The goal of this study is to demonstrate the use of an electronic medical record to create an administrative index which is able to risk-stratify this heterogeneous population.</p> <p>Methods</p> <p>We conducted a retrospective cohort study at a single tertiary care facility in Rochester, Minnesota. Patients included all 12,650 community-dwelling adults age 60 and older assigned to a primary care internal medicine provider on January 1, 2005. Patient risk factors over the previous two years, including demographic characteristics, comorbid diseases, and hospitalizations, were evaluated for significance in a logistic regression model. The primary outcome was the total number of emergency room visits and hospitalizations in the subsequent two years. Risk factors were assigned a score based on their regression coefficient estimate and a total risk score created. This score was evaluated for sensitivity and specificity.</p> <p>Results</p> <p>The final model had an AUC of 0.678 for the primary outcome. Patients in the highest 10% of the risk group had a relative risk of 9.5 for either hospitalization or emergency room visits, and a relative risk of 13.3 for hospitalization in the subsequent two year period.</p> <p>Conclusions</p> <p>It is possible to create a screening tool which identifies an elderly population at high risk for hospital and emergency room admission using clinical and administrative data readily available within an electronic medical record.</p