Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed

Efficacy of intramuscular treatment of beef cows with oxytetracycline to reduce mastitis and to increase calf growth

Spring-calving multiparous Angus x Hereford cows were used to determine the efficacy of intramuscular treatment with oxytetracycline to reduce the incidence of mastitis-causing bacteria, decrease milk somatic cell counts (SCC), and increase calf growth. During 2 yr, milk samples were collected from each quarter from a total of 319 cows at 8 to 14 d after calving and at weaning, to determine the presence of bacteria and SCC. A California mastitis test (CMT) was performed on milk from each quarter of each cow at the initial sample collection. Cows with a CMT score of 1, 2, or 3 in at least one quarter, were randomly assigned to receive either an intramuscular injection of oxytetracycline (n = 63) or the control vehicle (n = 60), and cows with a CMT score of 0 or trace in all four quarters were not treated (n = 196). Calf weights were determined at birth, early lactation, and weaning. The number of somatic cells in milk and the percentage of quarters that were infected increased as CMT score increased (P 0.10) the percentage of cows or quarters infected with mastitis-causing bacteria or SCC of cows or quarters at weaning. Average SCC per cow was negatively correlated (P 0.10) calf weights at early lactation or at weaning. Cows with one or more dry quarters after calving had calves that weighed less at early lactation and weaning than cows with four functional quarters (P < 0.01). Intramuscular oxytetracycline treatment of beef cows that had CMT scores of 1 or greater after calving did not reduce intramammary infection rates or increase calf weights at weaning

Do Cultures Obtained During Primary THA Predict the Likelihood of Revision?

BackgroundThere can be unexpectedly positive culture results during elective hip arthroplasty, but the degree to which these are associated with an increased risk of subsequent premature revision is not known.Question/purposeAre unexpectedly positive culture results obtained during elective THA associated with an increased likelihood of revision within 5 years of the procedure?MethodsBetween March 2007 and March 2011, the hip unit at our institution performed elective primary THA in 829 patients. We systematically collected three samples in 52% (428 of 829) of the interventions. Of those, 26 patients were excluded because of sampling errors; 94% (402 of 428) had samples that were collected systematically and were eligible for the study. We only considered one hip randomly in bilateral procedures (4% [15 of 428]); patients presenting with acute (< 3 months) periprosthetic joint infection undergoing open debridement (4% [16 of 402]) and patients who died before 5 years of follow-up (2% [seven of 402]) were excluded from the study, leaving 91% (364 of 402) eligible for analysis in this retrospective study of a previous prospective trial. No patient included in the final analysis was lost to follow-up within 5 years from the index surgery. The patient group consisted of 52% (188 of 364) women, with a mean ± SD age of 64.8 ± 13.9 years.ResultsPositives culture results were associated with a higher risk of revision within 5 years of the index surgery. The proportion of revision surgery was higher in the group with positive culture results than in those with negative results (10% [eight of 77] versus 2% [seven of 290]; p = 0.01). The difference was mainly attributable to a higher proportion of aseptic loosening in those with positive culture results than in those with negative results (8% [six of 74] versus 1% [four of 290]; p = 0.01). After a multivariable analysis, the only independent variable associated with 5-year revision surgery was the presence of positive results during THA (odds ratio 4.9 [95% confidence interval 1.72 to 13.99]).ConclusionOur findings suggest that bacterial contamination during THA is associated with an increased likelihood of early revision. This higher risk of revision is mainly because of presumed aseptic loosening; thus, efforts should focus on the need to rule out infection. These results not only open new questions that should be answered in new prospective and well-designed studies, but also may help to better select patients to obtain a more favorable outcome after THA.Level of EvidenceLevel III, therapeutic study. Copyright © 2022 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited