KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.

INTRODUCTION: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS: This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N = 122) and non-carriers (KL-VSNC; N = 332). RESULTS: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. DISCUSSION: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. HIGHLIGHTS: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.

The Influence of Education on the Nutritional Knowledge of Certified Fitness Professionals.

The American Fitness Industry has seen progressive success with recent increases in facility memberships and annual revenues of fitness centers. The number of fitness trainers and instructors in the United States has persisted this growth and is projected to grow over the next decade. However, only a few known studies have investigated the nutritional education of fitness professionals. This preliminary study explores the education and knowledge among certified fitness professions (CFPs) in the United States. A cross-sectional, descriptive survey design was utilized with a convenience sample of 120 female participants from the United States who were associated with a major fitness newsletter. The average age of the participants was 48.51 years (SD 12), and they had 14.85 years of experience (SD 10.16) and worked an average of 22.04 hours per week (SD 16.78). Most of the participants had some kind of college degree (96.2%) and held a group fitness certification (76.6%) or personal training certification (47.5%). Those with a nutrition certification were found to have significantly higher nutrition knowledge test scores on the 21 question test (18.2 ± 2.0 correct to 17.1 ± 1.9, p=0.04). Additionally, it is revealed that CFPs use the internet as a primary source for nutritional information and was the most frequently used source of nutrition information accessed. This pilot study suggests a more in-depth study would be beneficial to solidify the current results and could allow for more investigation into whether or not completion of nutrition coursework within formal earned degrees by CFPs positively influences their nutritional knowledge.

Squamous Papilloma Causing Airway Obstruction During Conscious Sedation.

Monitoring for respiratory depression is essential during conscious sedation. We report a case of a squamous papilloma as an unusual cause of intermittent partial airway obstruction in a 43-year-old man undergoing intravenous conscious sedation with midazolam. The Integrated Pulmonary Index (IPI) is an algorithm included in some commercially available monitors that constitutes a representation of 4 parameters: end-tidal carbon dioxide, respiratory rate, oxygen saturation, and pulse rate. We discuss the potential of the IPI as a monitoring tool during sedation.

Allosteric inhibition of antiapoptotic MCL-1.

MCL-1 is an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Although drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small-molecule covalent modification of C286 at a new interaction site distant from the BH3-binding groove. Our structure-function analyses revealed that the BH3 binding capacity of MCL-1 and its suppression of BAX are impaired by molecular engagement, a phenomenon recapitulated by C286W mutagenic mimicry in vitro and in mouse cells. Thus, we characterize an allosteric mechanism for disrupting the antiapoptotic BH3 binding activity of MCL-1, informing a new strategy for disarming MCL-1 in cancer.

Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer's Disease.

Higher occupational attainment has previously been associated with increased Alzheimer's disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.

Neuropsychological effects of bilateral deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

OBJECTIVE: Although a relatively new technique, bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of advanced cases of Parkinson's disease (PD) shows considerable promise. While the benefits of the STN stimulation for the treatment of motor symptoms of PD are well established, some studies have reported negative neuropsychological outcomes, especially in elderly patients. The objective of the present study was to investigate the neuropsychological effects of bilateral STN-DBS in a small sample of elderly patients with PD. METHODS: Six patients with PD (mean age 73.0 +/- 10.45 years) were assessed both before and approximately 6 months after DBS surgery in six neuropsychological domains. These domains included orientation, estimated IQ, attention/working memory, language, memory, and visual-spatial functioning. Additionally, depressive symptoms were assessed using the Geriatric Depression Scale. Daily doses of antiparkinsonian medications, in levodopa equivalents, were also compared pre- and postoperatively. RESULTS: Antiparkinsonian medications were reduced postoperatively by a mean of 65%, from a mean levodopa equivalent dosage of 987 mg/day to 346 mg/day. Category fluency, a word generation task within the language domain, was the only test in which participants demonstrated a statistically significant decline in performance. Participants demonstrated a mean score decrease of 41% (p < 0.05) in category fluency. CONCLUSIONS: The pathophysiology of the observed deficit remains ill defined. However, despite a small sample size, the study provides further evidence that bilateral STN-DBS in PD patients can be associated with negative neuropsychological outcome in word fluency, especially in elderly patients. Implications regarding patient selection for bilateral STN-DBS and recommendations for future research are further discussed.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

OBJECTIVE: To evaluate the clinical effects of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease within the first 12 months after surgery. METHODS: We performed a prospective study in 8 patients with Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus bilaterally. We compared levodopa-equivalents and the scores of the Unified Parkinson's Disease Rating Scale pre- and post-operatively. The post-operative evaluation was done between 3 and 12 months after surgery. RESULTS: Antiparkinsonian medications were reduced post-operatively by a mean of 61.5% (P < 0.01) from a levodopa-equivalent dosage of 1144.9 +/- 572.5 mg/day to 440.9 +/- 172.1 mg/day. Motor scores improved 44.4% (P < 0.01) and activities of daily living scores 38.2% (P < 0.01). Adverse events included a subcutaneous hematoma in 1 patient after internal pulse generator implantation necessitating evacuation. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus is associated with significant improvement in motor function and reduction of antiparkinsonian medications in patients with Parkinson's disease in the first 12 months after surgery. On-state dyskinesias were greatly reduced, probably due to the reduction of total antiparkinsonian medications. The procedure is well tolerated.

The association between suicide screening practices and attempts requiring emergency care in juvenile justice facilities.

OBJECTIVE: To provide a national description of suicide screening practices in juvenile residential facilities and to examine their association with whether facilities experience a suicide attempt. METHOD: Multivariate modeling with data from the 2000 Juvenile Residential Facility Census (n = 3690 facilities). RESULTS: Controlling for facility characteristics, screening the entire facility population within the first 24 hours after arrival is significantly linked to lower odds of serious suicide attempts (odds ratio 0.23-0.65). Facilities screening just some of their population in a 2- to 7-day window after arrival exhibited significantly higher odds of serious suicide attempts (odds ratio 1.30-4.73). CONCLUSIONS: Results suggest that facility-level risks of serious suicide attempts may be reduced by screening every child and adolescent entering a juvenile justice facility within the 24-hour window directly following arrival, regardless of the facility size and whether the youths came directly from another facility within the system.

Friedreich's ataxia associated with mitochondrial myopathy: clinicopathologic report.

A 13-year-old boy with clinical and electrophysiologic findings of Friedreich's ataxia developed unusually prominent myopathy. Skeletal muscle biopsy showed mitochondrial proliferation and structural abnormalities. No mutation was found in skeletal muscle mitochondrial DNA to explain this finding. Molecular genetic and pathologic studies confirmed a diagnosis of Friedreich's ataxia in the proband and affected relatives. Although the Friedreich's ataxia phenotype results from decreased expression of a mitochondrially targeted protein, frataxin, mitochondrial myopathy has not been described as a feature of the disease. The association between the frataxin gene mutation and mitochondrial myopathy in this case suggests that severe or cumulative insults to mitochondrial function may produce myopathic changes in some cases of Friedreich's ataxia. The patient also responded clinically to carnitine supplementation, suggesting a potential palliative therapy for the disease.