Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD. METHODS: We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1-12 months). RESULTS: Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7-8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (P < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (P < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, P < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, P < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5-6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3-4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 µm2 versus PS19's 1208 ± 94 µm2, and WT males at 1731 ± 185 µm2 versus PS19's 1227 ± 116 µm2. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 µm2 versus PS19's 858 ± 62 µm2, and WT males at 1257 ± 43 µm2 versus PS19's 1030 ± 55 µm2. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline. CONCLUSIONS: Progressive and accelerated neurogenic sarcopenia may precede and potentially predict cognitive deficits observed in AD.

Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform.

Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10-15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p < 0.05 compared to controls. From October 2020 to November 2022, 17 tumors from 7 patients were biofabricated into organoids, with 16/17 (94.1%) sites undergoing comparative 37° and 42° treatments with cisplatin and mitomycin C (MMC). Hyperthermic cisplatin and MMC enhanced cytotoxicity which reduced treatment viability by 25% and 22%, respectively, compared to normothermia. Heated cisplatin displayed the greatest cytotoxicity, with efficacy in 12/16 (75%) tumors and an average viability of 38% (5-68%). Heated MMC demonstrated efficacy in 7/16 (43.8%) tumors with an average treatment viability of 51% (17-92.3%). PTOs fabricated from distinct anatomic sites exhibited site-specific variability in treatment responses. PM PTOs exhibit patient and anatomic location treatment responses suggestive of underlying disease clonality. In PM organoids cisplatin is superior to MMC in HIPEC.

Association Among Opioid Use, Treatment Preferences, and Perceptions of Physician Treatment Recommendations in Patients With Neck and Back Pain.

OBJECTIVE: The purpose of this study was to explore the relationship between self-reported use of opioids by patients with neck and back pain and their demographics, pain characteristics, treatment preferences, and recollections of their physicians' opinions regarding treatment options. METHODS: We analyzed 2017 Gallup Poll survey data from 1680 US adults who had substantial spine pain in the past year and used logistic regression to explore the aforementioned relationships. RESULTS: Our multiple regression analysis indicated that adults with neck or back pain severe enough to have sought health care within the last year were more likely to have used opioids in the last year if they (in descending order of marginal impact) had pain that had lasted 1 year or less (adjusted odds ratio [OR] = 34.35, 90% confidence interval [CI] 17.56-74.32); concurrently used benzodiazepines (OR = 6.02, 90% CI 2.95-12.33); had Medicaid as an insurance source (OR = 3.29, 90% CI 1.40-7.48); indicated that they preferred to use pain medications prescribed by a doctor to treat physical pain (OR = 3.24, 90% CI 1.88-5.60); or were not college educated (OR = 1.83, 90% CI 1.05-3.25). Compared with patients aged 65 years and older, those aged 18 to 34 years were less likely to have used opioids in the past year (OR = 0.09, 90% CI 0.01-0.40, 0.50 for 95% CI). Respondents' perceptions of medical doctors' positive or negative opinions regarding a variety of neck and back pain treatment options were not significantly associated with opioid use. CONCLUSIONS: Patients with neck and back pain who use opioids differ from those who do not use opioids in that they are more likely to have pain that is of shorter duration, to use benzodiazepines, to have Medicaid as an insurance source, and to prefer to use pain medications. Those characteristics should be considered when developing opioid use prevention strategies.

Glucocorticoids suppress growth in neonatal cardiomyocytes co-expressing AT(2) and AT(1) angiotensin receptors.

BACKGROUND: Perinatal glucocorticoid treatment is associated with hypertrophic cardiomyopathy, but the cellular mechanism is controversial. An underlying interaction between glucocorticoids and the renin-angiotensin system may be important, but whether glucocorticoids modulate angiotensin II (AngII)-dependent cardiomyocyte growth responses in the neonate has not been investigated. OBJECTIVES: The major aim of this investigation was to determine whether glucocorticoids modulate the neonatal cardiomyocyte growth response to AngII. In particular we sought evidence to determine whether angiotensin II type 2 (AT(2)) receptor co-expression with angiotensin II type 1 (AT(1)) receptor is of specific importance in this modulatory function. METHODS: In this study, we used AT(1) and AT(2) receptor-expressing adenoviruses (Ad-AT(1) and Ad-AT(2)) in a well-defined in vitro neonatal cardiomyocyte culture model to assess whether glucocorticoids affect cardiomyocyte growth responses (i.e. total protein content). RESULTS: Following addition of AngII (0.1 micromol/l) to neonatal cardiomyocytes infected with Ad-AT(1) alone, a significant growth response was measured (133.2 +/- 4.8%). Expression of Ad-AT(2) alone induced a approximately 20% increase in total cellular protein content, which was unaffected by addition of AngII. Neither corticosterone (1 micromol/l) nor dexamethasone (1 micromol/l) had any significant effect on the AT(1)- or AT(2)-mediated growth responses. In contrast, the growth response to AngII was augmented following co-expression of AT(2) and AT(1) receptors (149.2 +/- 4.2%), which was reduced by approximately 20% in the presence of either corticosterone or dexamethasone (p < 0.05). CONCLUSIONS: The present study provides novel evidence that glucocorticoids suppress neonatal cardiomyocyte growth responsiveness when AT(2 )and AT(1) receptor subtypes are co-expressed.

A randomized controlled trial comparing 2 types of spinal manipulation and minimal conservative medical care for adults 55 years and older with subacute or chronic low back pain.

OBJECTIVE: Chiropractic care is used by many older patients for low back pain (LBP), but there are no published results of randomized trials examining spinal manipulation (SM) for older adults. The purpose of this study was to compare the effects of 2 biomechanically distinct forms of SM and minimal conservative medical care (MCMC) for participants at least 55 years old with subacute or chronic nonradicular LBP. METHODS: Randomized controlled trial. The primary outcome variable was low back-related disability assessed with the 24-item Roland Morris Disability questionnaire at 3, 6, 12, and 24 weeks. Participants were randomly allocated to 6 weeks of care including 12 visits of either high-velocity, low-amplitude (HVLA)-SM, low-velocity, variable-amplitude (LVVA)-SM, or 3 visits of MCMC. RESULTS: Two hundred forty participants (105 women and 135 men) ages 63.1 +/- 6.7 years without significant comorbidities. Adjusted mean Roland Morris Disability change scores (95% confidence intervals) from baseline to the end of active care were 2.9 (2.2, 3.6) and 2.7 (2.0, 3.3) in the LVVA-SM and HVLA-SM groups, respectively, and 1.6 (0.5, 2.8) in the MCMC group. There were no significant differences between LVVA-SM and HVLA-SM at any of the end points. The LVVA-SM group had significant improvements in mean functional status ranging from 1.3 to 2.2 points over the MCMC group. There were no serious adverse events associated with any of the interventions. CONCLUSIONS: Biomechanically distinct forms of SM did not lead to different outcomes in older LBP patients and both SM procedures were associated with small yet clinically important changes in functional status by the end of treatment for this relatively healthy older population. Participants who received either form of SM had improvements on average in functional status ranging from 1 to 2.2 over those who received MCMC. From an evidence-based care perspective, patient preference and clinical experience should drive how clinicians and patients make the SM procedure decision for this patient population.