Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

BACKGROUND: Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage

Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice

BACKGROUND: The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. RESULTS: We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ. CONCLUSIONS: The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression

Validation and preliminary data from a health-related quality of life questionnaire for owners of dogs with cardiac disease

BACKGROUND: Cardiac disease in dogs impacts the quality of life (QoL) of their owners, but owners\u27 QoL has not been comprehensively assessed in this population. OBJECTIVES: To develop, validate, and provide preliminary data from a health-related QoL (hrQoL) questionnaire for owners of dogs with cardiac disease. SUBJECTS: A total of 141 owners of dogs with cardiac disease were studied. METHODS: An owner hrQoL (O-hrQoL) questionnaire containing 20 items related to areas of a person\u27s life that could be impacted by caring for a dog with cardiac disease was developed and administered to owners of dogs with cardiac disease. The highest possible total score was 100, with higher scores indicating a worse hrQoL. Readability, internal consistency, face and construct validity, and item-total correlations were assessed. RESULTS: Median O-hrQoL score was 35 (range, 0-87). The questionnaire had good internal consistency (Cronbach\u27s alpha = 0.933), construct validity (Spearman\u27s r = 0.38-0.53; Kendall\u27s tau = 0.30-0.43; P \u3c .001), and item-total correlation (Spearman\u27s r = 0.44-0.79; Kendall\u27s tau = 0.34-0.66; all P \u3c .001). Fifty percent of owners indicated a negative effect of dogs\u27 cardiac disease on their own QoL, but all owners responded that caring for their dogs either had strengthened (n = 76; 53.9%) or had no effect on their relationship with their dog (n = 65; 46.1%). CONCLUSIONS AND CLINICAL IMPORTANCE: The O-hrQoL questionnaire had good validity, and results suggest that owners\u27 QoL is significantly impacted by caring for dogs with cardiac disease. Additional research on effective approaches to minimizing the negative effects of a dog\u27s cardiac disease on the owner is warranted

Applicant perception of virtual interviews in cardiothoracic surgery: A Thoracic Education Cooperative Group Study

OBJECTIVES: Cardiothoracic programs used virtual interviews exclusively this year. As programs consider using virtual interviews permanently, our goal was to evaluate the experience of applicants with virtual interviews. METHODS: All 2020-2021 traditional cardiothoracic fellowship applicants received an anonymous electronic survey after the Match process ended. The survey assessed the number of interviews, strengths, and inadequacies of virtual interviews and factors that affected rank decision. RESULTS: Forty-three percent of applicants responded (60/139). The average number of interviews was 16.0. Eighty percent (48/60) of respondents successfully matched. Eighty-seven percent (52/60) of respondents had a favorable experience with virtual interviews, and 97% (58/60) found them to be convenient. However, only 50% (30/60) were able to evaluate a program fully. Respondents who matched were more likely to have a favorable experience (P = .02), but not more likely to be able to evaluate a program fully (P = .35). The most valued aspect was the informal meet and greet session with fellows (4.2 of 5). The least valued aspect was the program\u27s social media site (2.0 of 5). The factors most frequently used to decide ranking were case numbers by 92% (55/60) and culture/personality by 82% (49/60). CONCLUSIONS: Virtual interviews were perceived more favorably compared with last year, but half of applicants were still unable to evaluate a program fully. Fellow interactions were the most popular aspect of virtual interviews. As programs consider using virtual interviews permanently, more exposure to current trainees and a more robust social media/online presence will improve favorability

The Assessment of Bipolar Disorder in Children and Adolescents

The overarching goal of this review is to examine the current best evidence for assessing bipolar disorder in children and adolescents and provide a comprehensive, evidence-based approach to diagnosis. Evidence-based assessment strategies are organized around the “3 Ps” of clinical assessment: Predict important criteria or developmental trajectories, Prescribe a change in treatment choice, and inform Process of treating the youth and his/her family. The review characterizes bipolar disorder in youths - specifically addressing bipolar diagnoses and clinical subtypes; then provides an actuarial approach to assessment - using prevalence of disorder, risk factors, and questionnaires; discusses treatment thresholds; and identifies practical measures of process and outcomes. The clinical tools and risk factors selected for inclusion in this review represent the best empirical evidence in the literature. By the end of the review, clinicians will have a framework and set of clinically useful tools with which to effectively make evidence-based decisions regarding the diagnosis of bipolar disorder in children and adolescents

High expression of Cathepsin E in tissues but not blood of patients with Barrett’s esophagus and adenocarcinoma

Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues

Physiological consequences of rising water salinity for a declining freshwater turtle.

Sea-level rise, drought and water diversion can all lead to rapid salinization of freshwater habitats, especially in coastal areas. Increased water salinities can in turn alter the geographic distribution and ecology of freshwater species including turtles. The physiological consequences of salinization for freshwater turtles, however, are poorly known. Here, we compared the osmoregulatory response of two geographically separate populations of the freshwater Western Pond Turtle (Actinemys marmorata)-a species declining across its range in western North America-to three constant salinities: 0.4 ppt, 10 ppt and 15 ppt over 2 weeks. We found that turtles from a coastal estuarine marsh population regulated their plasma osmolality at lower levels than their conspecifics from an inland freshwater creek population 45 km away. Plasma osmolalities were consistently lower in estuarine marsh turtles than the freshwater creek turtles over the entire 2-week exposure to 10 ppt and 15 ppt water. Furthermore, estuarine marsh turtles maintained plasma osmolalities within 1 SD of their mean field osmolalities over the 2-week exposure, whereas freshwater creek turtles exceeded their field values within the first few days after exposure to elevated salinities. However, individuals from both populations exhibited body mass loss in 15 ppt water, with significantly greater loss in estuarine turtles. We speculate that the greater ability to osmoregulate by the estuarine marsh turtles may be explained by their reduced feeding and drinking in elevated salinities that was not exhibited by the freshwater creek population. However, due to mass loss in both populations, physiological and behavioural responses exhibited by estuarine marsh turtles may only be effective adaptations for short-term exposures to elevated salinities, such as those from tides and when traversing saline habitats, and are unlikely to be effective for long-term exposure to elevated salinity as is expected under sea-level rise

Bovine tuberculosis epidemiology in Cameroon, Central Africa, based on the interferon gamma assay

Despite sub-Saharan Africa (SSA) accounting for ~20% of the global cattle population, prevalence estimates and related risk factors of bovine tuberculosis (bTB) are still poorly described. The increased sensitivity of the IFN-γ assay and its practical benefits suggest the test could be useful to investigate bTB epidemiology in SSA. This study used a population-based sample to estimate bTB prevalence, identify risk factors and estimate the effective reproductive rate in Cameroonian cattle populations. A cross-sectional study was conducted in the North West Region (NWR) and the Vina Division (VIN) of Cameroon in 2013. A regional stratified sampling frame of pastoral cattle herds produced a sample of 1,448 cattle from 100 herds. In addition, a smaller cross-sectional study sampled 60 dairy cattle from 46 small-holder co-operative dairy farmers in the NWR. Collected blood samples were stimulated with bovine and avian purified protein derivatives, with extracted plasma screened using the IFN-γ enzyme-linked immunosorbent assay (Prionics Bovigam®). Design-adjusted population prevalences were estimated, and multivariable mixed-effects logistic regression models using Bayesian inference techniques identified the risk factors for IFN-γ positivity. Using the IFN-γ assay, the prevalence of bTB in the dairy cattle was 21.7% (95% CI: 11.2–32.2). The design-adjusted prevalence of bTB in cattle kept by pastoralists was 11.4% (95% CI: 7.6–17.0) in the NWR and 8.0% (95% CI: 4.7–13.0) in the VIN. A within-herd prevalence estimate for pastoralist cattle also supported that the NWR had higher prevalence herds than the VIN. Additionally, the estimates of the effective reproductive rate Rt were 1.12 for the NWR and 1.06 for the VIN, suggesting different transmission rates within regional cattle populations in Cameroon. For pastoral cattle, an increased risk of IFN-γ assay positivity was associated with being male (OR = 1.89; 95% CI:1.15–3.09), increasing herd size (OR = 1.02; 95% CI:1.01–1.03), exposure to the bovine leucosis virus (OR = 2.45; 95% CI: 1.19–4.84) and paratuberculosis (OR = 9.01; 95% CI: 4.17–20.08). Decreased odds were associated with contacts at grazing, buffalo (OR = 0.20; 95% CI: 0.03–0.97) and increased contact with other herds [1–5 herds: OR = 0.16 (95% CI: 0.04–0.55); 6+ herds: OR = 0.18 (95% CI: 0.05–0.64)]. Few studies have used the IFN-γ assay to describe bTB epidemiology in SSA. This study highlights the endemic situation of bTB in Cameroon and potential public health risks from dairy herds. Further work is needed to understand the IFN-γ assay performance, particularly in the presence of co-infections, and how this information can be used to develop control strategies in the SSA contexts

Platelet Factor 4 Activity against P. falciparum and Its Translation to Nonpeptidic Mimics as Antimalarials

SummaryPlasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential