Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.     

Effect of Concussion on Reaction Time and Neurocognitive Factors: Implications for Subsequent Lower Extremity Injury

BackgroundRecent evidence has demonstrated that athletes are at greater risk for a lower extremity injury following a return-to-sport (RTS) after sport-related concussion (SRC). The reason for this is not completely clear, but it has been hypothesized that persistent deficits in neurocognitive factors may be a contributing factor.Hypothesis/PurposeThis study assessed simple reaction time, processing speed, attention, and concentration in a group of athletes, post-concussion upon clearance for RTS for potential deficits that may result in slower reaction time, processing speed, attention, and concentration. The researchers hypothesized that the concussion group would demonstrate worse scores on both assessments compared to a sex-, age-, and sport-matched cohort.Study DesignCase-controlled studyMethodsTwelve participants who had suffered a SRC and eight healthy individuals who were matched to the concussed group by age, sex, and sport were evaluated. Those with a concussion had been cleared for RTS by a licensed healthcare provider. Each participant underwent neurocognitive tests that included a simple reaction time test (SRT) and the King-Devick Test (K-D). Independent t-tests were performed to compare the groups with significance set a priori at p<0.05.ResultsThere was a significant difference (p =0.024) between groups for SRT with the concussed group demonstrating a better SRT than the control group. There were no significant differences (p =0.939) between the groups for the K-D.ConclusionWith no significant differences between groups in the K-D assessment and, surprisingly, the concussed group having a better SRT compared to the healthy group, our hypothesis was not supported.Clinical RelevanceThese specific measures, compounded with extensive post-concussion time lapse until RTS clearance, may have limited capacity in revealing potential persistent deficits in relevant neurocognitive characteristics.Level of EvidenceLevel of Evidence 3     

Polymorphic Forms of Human Cytomegalovirus Glycoprotein O Protect against Neutralization of Fibroblast Entry by Antibodies Targeting Epitopes Defined by Glycoproteins H and L

Human cytomegalovirus (CMV) utilizes different glycoproteins to enter into fibroblast and epithelial cells. A trimer of glycoproteins H, L, and O (gH/gL/gO) is required for entry into all cells, whereas a pentamer of gH/gL/UL128/UL130/UL131A is selectively required for infection of epithelial, endothelial, and some myeloid-lineage cells, but not of fibroblasts. Both complexes are of considerable interest for vaccine and immunotherapeutic development but present a conundrum: gH/gL-specific antibodies have moderate potency yet neutralize CMV entry into all cell types, whereas pentamer-specific antibodies are more potent but do not block fibroblast infection. Which cell types and neutralizing activities are important for protective efficacy in vivo remain unclear. Here, we present evidence that certain CMV strains have evolved polymorphisms in gO to evade trimer-specific neutralizing antibodies. Using luciferase-tagged variants of strain TB40/E in which the native gO is replaced by gOs from other strains, we tested the effects of gO polymorphisms on neutralization by monoclonal antibodies (mAbs) targeting four independent epitopes in gH/gL that are common to both trimer and pentamer. Neutralization of fibroblast entry by three mAbs displayed a range of potencies that depended on the gO type, a fourth mAb failed to neutralize fibroblast entry regardless of the gO type, while neutralization of epithelial cell entry by all four mAbs was potent and independent of the gO type. Thus, specific polymorphisms in gO protect the virus from mAb neutralization in the context of fibroblast but not epithelial cell entry. No influence of gO type was observed for protection against CMV hyperimmune globulin or CMV-seropositive human sera, suggesting that antibodies targeting protected gH/gL epitopes represent a minority of the polyclonal neutralizing repertoire induced by natural infection.     

Baixa Concordância entre a Classificação da NYHA e as Variáveis do Teste de Exercício Cardiopulmonar em Pacientes com Insuficiência Cardíaca e Fração de Ejeção Reduzida

BackgroundThe New York Heart Association (NYHA) functional classification is the most commonly used classification system for heart failure (HF), whereas cardiopulmonary exercise testing (CPET) is the gold standard for functional status evaluation in HF.ObjectiveThis study aimed to analyze correlation and concordance between NYHA classes and CPET variables.MethodsHF patients with clinical indication for CPET and ejection fraction (EF) < 50% were selected. Correlation (Spearman coefficient) and concordance (kappa) between NYHA classification and CPET-based classifications were analyzed. A p < 0.05 was accepted as significant.ResultsIn total, 244 patients were included. Mean age was 56 ± 14 years, and mean EF was 35.5% ± 10%. Distribution of patients according to NYHA classification was 31.2%% class I, 48.3% class II, 19.2% class III, and 1.3% class IV. Correlation (r) between NYHA and Weber classes was 0.489 (p < 0.001), and concordance was 0.231 (p < 0.001). Correlation (r) between NYHA and ventilatory classes (minute ventilation/carbon dioxide production [VE/VCO₂] slope) was 0.218 (p < 0.001), and concordance was 0.002 (p = 0.959). Spearman correlation between NYHA and CPET score classes was 0.223 (p = 0.004), and kappa concordance was 0.027 (p = 0.606).ConclusionThere was a moderate association between NYHA and Weber classes, although concordance was low. Ventilatory (VE/VCO₂slope) and CPET score classes had a weak association and a low concordance with NYHA classes.     

Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia

European Archives of Psychiatry and Clinical Neuroscience - Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the...     

Polarization-based smoke removal method for surgical images

Smoke generated during surgery affects tissue visibility and degrades image quality, affecting surgical decisions and limiting further image processing and analysis. Polarization is a fundamental property of light and polarization-resolved imaging has been studied and applied to general visibility restoration scenarios such as for smog or mist removal or in underwater environments. However, there is no related research or application for surgical smoke removal. Due to differences between surgical smoke and general haze scenarios, we propose an alternative imaging degradation model by redefining the form of the transmission parameters. The analysis of the propagation of polarized light interacting with the mixed medium of smoke and tissue is proposed to realize polarization-based smoke removal (visibility restoration). Theoretical analysis and observation of experimental data shows that the cross-polarized channel data generated by multiple scattering is less affected by smoke compared to the co-polarized channel. The polarization difference calculation for different color channels can estimate the model transmission parameters and reconstruct the image with restored visibility. Qualitative and quantitative comparison with alternative methods show that the polarization-based image smoke-removal method can effectively reduce the degradation of biomedical images caused by surgical smoke and partially restore the original degree of polarization of the samples.     

Intra-articular lipoma with osteochondroid metaplasia in the knee joint

We describe a case of lipoma with osteochondroid metaplasia in the knee joint. Although the location of the lesion and radiographic findings were unusual, computed tomography and magnetic resonance imaging were useful in characterizing adipose, cartilaginous and osseous tissue components within the lesion. Received: 12 October 2000 Revision requested: 3 November 2000 Revision received: 23 December 2000 Accepted: 28 December 2000     

Assessment of regional systolic and diastolic dysfunction in familial hypertrophic cardiomyopathy using MR tagging.

Diastolic and systolic left ventricular (LV) dysfunction often significantly contribute to disabling symptoms in familial hypertrophic cardiomyopathy (FHC). This study compares regional LV function (midwall circumferential strain) during systole and diastole in eight FHC patients and six normal volunteers (NVs) using MR tagging. A prospectively-gated fast gradient-echo sequence with an echo-train readout was modified to support complementary spatial modulation of magnetization (CSPAMM) tagging and full cardiac cycle data acquisition using the cardiac phase to order reconstruction (CAPTOR), thus providing tag persistence and data acquisition during the entire cardiac cycle. Total systolic strains in FHC patients were significantly reduced in septal and inferior regions (both P < 0.01). Early-diastolic strain rates were reduced in all regions of the FHC group (all P < 0.03). The combination of CSPAMM and CAPTOR allows regional indices of myocardial function to be quantified throughout the cardiac cycle. This technique reveals regional differences in systolic and diastolic impairment in FHC patients.