Habitat complexity influences neuron number in six species of Puerto Rican Anolis.

Elucidating the selective forces shaping the diversity of vertebrate brains continues to be a major area of inquiry, particularly as it relates to cognition. Historically brain evolution was interpreted through the lens of relative brain size; however, recent evidence has challenged this approach. Investigating neuroanatomy at a finer scale, such as neuron number, can provide new insights into the forces shaping brain evolution in the context of information processing capacity. Ecological factors, such as the complexity of a species' habitat, place demands on cognition that could shape neuroanatomy. In this study, we investigate the relationship between neuron number and habitat complexity in three brain regions across six closely related anole species from Puerto Rico. After controlling for brain mass, we found that the number of neurons increased with habitat complexity across species in the telencephalon and 'rest of the brain,' but not in the cerebellum. Our results demonstrate that habitat complexity has shaped neuroanatomy in the Puerto Rican anole radiation and provide further evidence of the role of habitat complexity in vertebrate brain evolution.

Quantitative proteomics study of carnosine effect in an animal model of Western diet-induced nonalcoholic fatty liver disease.

The nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver.

Pharmacokinetics of intraarticular liposomal amphotericin B in goats (Capra aegagrus hircus).

Lameness is a significant welfare concern in goats. Amphotericin B is used via intraarticular (IA) administration in models to study experimentally induced lameness in large animals. The main objective of this study was to estimate plasma pharmacokinetic (PK) parameters for amphotericin B in goats after a single IA administration. Liposomal amphotericin B was administered to ten Kiko-cross goats at a dose of 10 mg total (range: 0.34-0.51 mg/kg) via IA administration into the right hind lateral distal interphalangeal joint. Plasma samples were collected over 96 h. Amphotericin B concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive PK parameters. Following single IA administration, maximum plasma concentration was estimated at 54.6 ± 16.5 ng/mL, and time to maximum concentration ranged from 6 to 12 h. Elimination half-life was estimated at 30.9 ± 16.5 h, and mean residence time was 45.1 ± 10.4 h. The volume of distribution after IA administration was 13.3 ± 9.4 L/kg. The area under the curve was 1481 ± 761 h*ng/mL. The achieved maximum concentration was less than the observed concentrations for other species and routes of administration. Further research is needed into the pharmacodynamics of IA liposomal amphotericin B in goats to determine specific research strategies.

Pharmacokinetics of nalbuphine administered intravenously and subcutaneously in goats (Capra aegagrus hircus).

The purpose of this study was to evaluate the pharmacokinetics (PK) of intravenously (IV) and subcutaneously (SC) administered nalbuphine in domestic goats. Nalbuphine hydrochloride was administered at 0.8 mg/kg for both IV and SC routes in six goats with a minimum of 10-day washout period between sample collection phases. Eighteen plasma samples were collected over a 36-hour period, analyzed using reverse phase high-performance liquid chromatography (HPLC). Plasma data were analyzed using compartmental and noncompartmental approaches. Following IV nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), concentration at time zero (C0), and total body clearance were 120.4 ± 39.1 (min-1 ± SD), 17311.01 ± 7227.32 (min·ng·mL-1 ± SD), 675.6 ± 337.13 (ng·mL-1 ± SD), and 44.5 ± 13.8 (mL·min-1·kg-1 ± SD), respectively. After SC nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), and maximum plasma drug concentration were 129 ± 52.9 (min-1 ± SD), 20826.5 ± 14376.2 (min·ng·mL-1), and 368.03 ± 503.78 (ng·mL-1). Calculated bioavailability for the SC route was 138 ± 126 (% ± SD). Nalbuphine in goats is characterized by rapid elimination and high subcutaneous bioavailability and may be a safe analgesic opioid option in goats in the future.

The Metabolic Features of Osteoblasts: Implications for Multiple Myeloma (MM) Bone Disease.

The study of osteoblast (OB) metabolism has recently received increased attention due to the considerable amount of energy used during the bone remodeling process. In addition to glucose, the main nutrient for the osteoblast lineages, recent data highlight the importance of amino acid and fatty acid metabolism in providing the fuel necessary for the proper functioning of OBs. Among the amino acids, it has been reported that OBs are largely dependent on glutamine (Gln) for their differentiation and activity. In this review, we describe the main metabolic pathways governing OBs' fate and functions, both in physiological and pathological malignant conditions. In particular, we focus on multiple myeloma (MM) bone disease, which is characterized by a severe imbalance in OB differentiation due to the presence of malignant plasma cells into the bone microenvironment. Here, we describe the most important metabolic alterations involved in the inhibition of OB formation and activity in MM patients.

The Amoebicidal Activity of Diferrocenyl Derivatives: A Significant Dependence on the Electronic Environment.

Amoebiasis is the second leading cause of death worldwide associated with parasitic disease and is becoming a critical health problem in low-income countries, urging new treatment alternatives. One of the most promising strategies is enhancing the redox imbalance within these susceptible parasites related to their limited antioxidant defense system. Metal-based drugs represent a perfect option due to their extraordinary capacity to stabilize different oxidation states and adopt diverse geometries, allowing their interaction with several molecular targets. This work describes the amoebicidal activity of five 2-(Z-2,3-diferrocenylvinyl)-4X-4,5-dihydrooxazole derivatives (X = H (3a), Me (3b), iPr (3c), Ph (3d), and benzyl (3e)) on Entamoeba histolytica trophozoites and the physicochemical, experimental, and theoretical properties that can be used to describe the antiproliferative activity. The growth inhibition capacity of these organometallic compounds is strongly related to a fine balance between the compounds' redox potential and hydrophilic character. The antiproliferative activity of diferrocenyl derivatives studied herein could be described either with the redox potential, the energy of electronic transitions, logP, or the calculated HOMO-LUMO values. Compound 3d presents the highest antiproliferative activity of the series with an IC50 of 23 µM. However, the results of this work provide a pipeline to improve the amoebicidal activity of these compounds through the directed modification of their electronic environment.

Clinical presentation, diagnostics, treatment, and outcome of goats diagnosed with presumptive cerebrospinal nematodiasis at a veterinary teaching hospital.

This retrospective study describes clinical presentation, diagnostic approach, treatment, and outcome for goats with presumptive cerebrospinal nematodiasis. A presumptive diagnosis was made based on neurologic signs, results of cerebrospinal fluid analysis, and response to treatment. Six goats were identified that met inclusion criteria. Cerebrospinal fluid analysis revealed eosinophilic pleocytosis (total nucleated cell count: 12 to 430/µL, 33 to 89% eosinophils). All 6 goats were treated with fenbendazole and anti-inflammatory drugs (NSAIDs ± corticosteroids) and 4 received physical rehabilitation therapy. At discharge or follow-up, all 6 goats were ambulatory and had minimal neurologic deficits. Key clinical message: In goats, cerebrospinal nematodiasis caused by Parelaphostrongylus tenuis is often a presumptive diagnosis based on neurologic signs, shared habitat with white-tailed deer, eosinophilic pleocytosis, and response to anthelmintic therapy. Presumptive cases in goats have many similarities to confirmed cases in camelids. Further study is indicated to characterize the clinical signs and optimize the diagnosis and treatment of goats infected with P. tenuis.

Présentation clinique, diagnostic, traitement et devenir des chèvres diagnostiquées avec une nématodose cérébro-spinale présumée dans un hôpital d'enseignement vétérinaire. Cette étude rétrospective décrit la présentation clinique, l'approche diagnostique, le traitement et les résultats pour des chèvres atteintes de nématodose cérébro-spinale présumée. Un diagnostic présomptif a été posé sur la base des signes neurologiques, des résultats de l'analyse du liquide céphalo-rachidien et de la réponse au traitement. Six chèvres ont été identifiées qui répondaient aux critères d'inclusion. L'analyse du liquide céphalo-rachidien a révélé une pléocytose éosinophile (nombre total de cellules nucléées : 12 à 430/µL, 33 à 89 % d'éosinophiles). Les six chèvres ont été traitées avec du fenbendazole et des anti-inflammatoires (AINS ± corticostéroïdes) et quatre ont reçu une thérapie de réadaptation physique. À la sortie ou au suivi, les six chèvres étaient ambulatoires et présentaient des déficits neurologiques minimes.Message clinique clé :Chez les chèvres, la nématodose cérébro-spinale causée par Parelaphostrongylus tenuis est souvent un diagnostic présomptif basé sur des signes neurologiques, un habitat partagé avec des cerfs de Virginie, une pléocytose éosinophile et une réponse à un traitement anthelminthique. Les cas présumés chez les chèvres présentent de nombreuses similitudes avec les cas confirmés chez les camélidés. Une étude plus approfondie est indiquée pour caractériser les signes cliniques et optimiser le diagnostic et le traitement des chèvres infectées par P. tenuis.(Traduit par Dr Serge Messier).

Circular Upcycling of Bottlebrush Thermosets.

The inability to re-process thermosets hinders their utility and sustainability. An ideal material should combine closed-loop recycling and upcycling capabilities. This trait is realized in polydimethylsiloxane bottlebrush networks using thermoreversible Diels-Alder cycloadditions to enable both reversible disassembly into a polymer melt and on-demand reconfiguration to an elastomer of either lower or higher stiffness. The crosslink density was tuned by loading the functionalized networks with a controlled fraction of dormant crosslinkers and crosslinker scavengers, such as furan-capped bis-maleimide and anthracene, respectively. The resulting modulus variations precisely followed the stoichiometry of activated furan and maleimide moieties, demonstrating the lack of side reactions during reprocessing. The presented circularity concept is independent from the backbone or side chain chemistry, making it potentially applicable to a wide range of brush-like polymers.

Rice (Oryza sativa L.) bran preserves cardiac function by modulating pro-inflammatory cytokines and redox state in the myocardium from obese rats.

PURPOSE: This study aimed to evaluate the effect of rice bran (RB) supplementation to a high-sugar fat (HSF) diet on cardiac dysfunction in an experimental obesity model. METHODS: Male Wistar rats were distributed into three groups: control, high-sugar fat, and high-sugar fat supplemented with 11% RB for 20 weeks. RESULTS: HSF diet promoted obesity and metabolic complications. Obese rats showed cardiac structural and functional impairment associated with high levels of interleukin-6, tumoral necrosis factor alpha, and malondialdehyde, and decreased activity of superoxide dismutase and catalase in the myocardium. RB supplementation was able to mitigate obesity and its metabolic alterations in HSF diet-fed animals. Moreover, the RB also prevented structural and functional damage, inflammation, and redox imbalance in the heart of these animals. CONCLUSION: This study suggests that RB supplementation prevents cardiac dysfunction in rats fed on HSF by modulating systemic metabolic complications and inflammation and oxidative stress in the myocardium, representing potential alternative therapy.

Prevalence and predictors of bacteremia in dairy calves with diarrhea.

Gastrointestinal disease is the most common cause of mortality in dairy calves. Septicemia is an important sequela of diarrhea, and the possibility of bacteremia is the primary justification for empirical antimicrobial therapy. Prior reports estimate that approximately one-third of diarrheic calves are bacteremic; however, those estimates may not be representative of routine cases in heifer calves on commercial dairy operations early in the course of disease. We hypothesized that the prevalence of bacteremia in calves with diarrhea and systemic signs of illness is less than prior estimates (∼31%), and that clinical signs or hematological values would be associated with the presence or absence of bacteremia. Female calves less than 21 d of age with and without diarrhea were enrolled from 2 commercial dairy farms over a 10-wk period. Diarrheic calves were enrolled if they were newly diagnosed, had loose to watery stool, had either dehydration (assessed by skin tent and eye position) or depression (assessed by suckle reflex and standing ability), and had no prior antimicrobial treatments. Complete health assessments were conducted at 0, 7, and 14 d following enrollment. An aseptic jugular venous sample was collected and cultured using aerobic and anaerobic methods, and bacterial species were identified using mass spectrometry. Poisson regression models were used to identify associations with bacteremia and compute adjusted prevalence ratios. The prevalence of bacteremia in diarrheic and healthy calves was 9.26% (10/108, 95% confidence interval: 4.5-16%) and 14.8% (4/27, 95% confidence interval: 1.4-28.2%), respectively. Among calves with diarrhea, those with a fever (>39.7°C) or depression were 4.8 and 6.5 times more likely, respectively, to have bacteremia. Only 1 of 47 calves (2%) without signs of depression was bacteremic. The prevalence of bacteremia in diarrheic calves with signs of systemic illness (depression or dehydration) was significantly lower than previous estimates, and bacteremia was rare among calves without observed depression. Antimicrobial therapy targeting bacteremia is not currently justified in routine cases of diarrhea in preweaning calves without signs of depression. These results suggest a substantial opportunity for more targeted antimicrobial therapy to improve antimicrobial stewardship.

A Wireless Autonomous Real-Time Underwater Acoustic Positioning System.

Recent acoustic telemetry positioning systems are able to reconstruct the positions and trajectories of organisms at a scale of a few centimeters to a few meters. However, they present several logistical constraints including receiver maintenance, calibration procedures and limited access to real-time data. We present here a novel, easy-to-deploy, energy self-sufficient underwater positioning system based on the time difference of arrival (TDOA) algorithm and the Global System for Mobile (GSM) communication technology, capable of locating tagged marine organisms in real time. We provide an illustration of the application of this system with empirical examples using continuous and coded tags in fish and benthic invertebrates. In situ experimental tests of the operational system demonstrated similar performances to currently available acoustic positioning systems, with a global positioning error of 7.13 ± 5.80 m (mean ± SD) and one-third of the pings can be localized within 278 m of the farthest buoy. Despite some required improvements, this prototype is designed to be autonomous and can be deployed from the surface in various environments (rivers, lakes, and oceans). It was proven to be useful to monitor a wide variety of species (benthic and pelagic) in real time. Its real-time property can be used to rapidly detect system failure, optimize deployment design, or for ecological or conservation applications.

Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma.

Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.

Ontogeny of swimming performance of hatchery-reared post-larvae and juvenile fish: a case of two threatened Mediterranean species.

Swimming performance is a well-established key physiological parameter of fish that is highly linked to their fitness in the wild. In the context of fish restocking purposes, it therefore appears crucial to study this specific behaviour. Here, the authors investigated intra and interspecies differences in the swimming performance of hatchery-reared post-larvae and juveniles belonging to two Mediterranean candidate threatened species, the common dentex, Dentex dentex (Sparidae), and the brown meagre, Sciaena umbra (Sciaenidae), with body sizes ranging from 8 to 37 mm total length (TL, from 24 to 58 days post-hatch). The swimming abilities were estimated through the calculation of their critical swimming speed (Ucrit ), their relative Ucrit and their Reynolds number (Re ). Two different patterns were observed between D. dentex and S. umbra, showing a different effect of ontogeny on the performance of both species. The relative Ucrit of S. umbra decreased linearly through ontogeny, whereas the relative Ucrit and Ucrit of D. dentex increased linearly through the range of sizes tested. The ontogenetic change in Ucrit of S. umbra occurred in two stages: a first stage of sharp improvement and a second stage of a slow decrease in performance. Both stages were separated by a breakpoint that coincided with the appearance of a refusal to swim behaviour that occurred shortly after the end of metamorphosis and can potentially be associated with the establishment of this species sedentary behaviour. The swimming performance of both species showed ontogenetic differences. Sciaena umbra had the highest relative performance when its body sizes were the smallest, whereas D. dentex showed the highest relative performance when its body sizes were the largest. These results will be linked to future research on both of these species concerning their escape, exploratory and predatory behaviours, and for restocking purposes to draw a more realistic overview of hatchery-reared juvenile performance. Knowledge of both species' behavioural and swimming performance through ontogeny is important to consider when using hatchery-reared fish juveniles for restocking, as size-at-release can have a large impact on fish survival and thus on restocking success.

Protein Profiling of a Cellular Model of NAFLD by Advanced Bioanalytical Approaches.

Advanced quantitative bioanalytical approaches in combination with network analyses allow us to answer complex biological questions, such as the description of changes in protein profiles under disease conditions or upon treatment with drugs. In the present work, three quantitative proteomic approaches-either based on labelling or not-in combination with network analyses were applied to a new in vitro cellular model of nonalcoholic fatty liver disease (NAFLD) for the first time. This disease is characterized by the accumulation of lipids, inflammation, fibrosis, and insulin resistance. Hepatic G2 cells were used as model, and NAFLD was induced by a complex of oleic acid and bovine albumin. The development of the disease was verified by lipid vesicle staining and by the increase in the expression of perilipin-2-a protein constitutively present in the vesicles during NAFLD. The nLC-MS/MS analyses of peptide samples obtained from three different proteomic approaches resulted in accurate and reproducible quantitative data of protein fold-change expressed in NAFLD versus control cells. The differentially regulated proteins were used to evaluate the involved and statistically enriched pathways. Network analyses highlighted several functional and disease modules affected by NAFLD, such as inflammation, oxidative stress defense, cell proliferation, and ferroptosis. Each quantitative approach allowed the identification of similar modulated pathways. The combination of the three approaches improved the power of statistical network analyses by increasing the number of involved proteins and their fold-change. In conclusion, the application of advanced bioanalytical approaches in combination with pathway analyses allows the in-depth and accurate description of the protein profile of an in vitro cellular model of NAFLD by using high-resolution quantitative mass spectrometry data. This model could be extremely useful in the discovery of new drugs to modulate the equilibrium NAFLD health state.

ctDNA in Neuroendocrine Carcinoma of Gastroenteropancreatic Origin or of Unknown Primary: The CIRCAN-NEC Pilot Study.

INTRODUCTION: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterized by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. METHODS: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first- or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA was sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction. RESULTS: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post-first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n = 21), RB1 (n = 2), KRAS (n = 4), and BRAF (n = 3). Ten (42%) had an "adenocarcinoma-like" profile. Five of 6 patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA mutation/immunohistochemistry profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups, patients with KRAS (HR = 3.60, 95% CI [1.06-12.04]) and BRAF (HR = 4.25, 95% CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the 2 patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR = 0.37, 95% CI [0.15; 0.91]). CONCLUSION: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).

Evaluation of angiogenic signaling molecules associated with reactive thrombocytosis in an iron-deficient rat model.

BACKGROUND: Iron deficiency anemia (IDA)-induced reactive thrombocytosis can occur in children and adults. The underlying mechanism for this phenomenon is indeterminate. Traditional cytokines such as thrombopoietin (TPO), interleukin-6 (IL-6), and IL-11 involved in megakaryopoiesis have not been shown to be the cause. Recent studies suggest that growth factors and signaling molecules involved with angiogenesis influence the proliferation and differentiation of megakaryocytes. METHODS: We investigated the possible association between angiogenic cytokines with reactive thrombocytosis due to IDA in an iron-deficient (ID) rat model. Complete blood count, iron panels, and TPO levels were measured at baseline and 5 weeks later in both control (C) and ID rats. Angiogenic cytokines were evaluated in the bone marrow in all rats. RESULTS: We successfully induced IDA in our rats by phlebotomy and reduced iron diet. We did not find an increase of TPO in ID rats. A review of the bone marrow showed an increase in the number of megakaryocytes, vascular structures, as well as increased intensity of stain for vascular endothelial growth factor (VEGF), and CXC chemokine receptor 4 (CXCR4) in rats with IDA compared to controls. CONCLUSIONS: Our results of histological bone marrow data suggest an important role for angiogenesis in the development of IDA-induced thrombocytosis. IMPACT: Thrombocytosis is common with IDA in both children and adults, but the mechanism is unclear. We confirmed that TPO is not the major driver of iron deficiency-associated thrombocytosis. We confirmed the increase in the number of megakaryocytes in the bone marrow despite stable TPO levels. We provided evidence supporting an important role of angiogenesis in megakaryocytopoiesis/thrombopoiesis with increased vascular structures and angiogenic cytokines in the bone marrow of iron-deficient rats. The demonstration that angiogenesis may play an important role in secondary thrombocytosis could lead to a new approach in treating symptomatic reactive thrombocytosis by targeting angiogenesis.

Intrusion Errors and Progression of Cognitive Deficits in Older Adults with Mild Cognitive Impairment and PreMCI States.

INTRODUCTION: Among persons with amnestic mild cognitive impairment (aMCI), intrusion errors on subscales that measure proactive semantic interference (PSI) may be among the earliest behavioral markers of elevated Alzheimer's disease brain pathology. While there has been considerable cross-sectional work in the area, it is presently unknown whether semantic intrusion errors are predictive of progression of cognitive impairment in aMCI or PreMCI (not cognitively normal but not meeting full criteria for MCI). METHODS: This study examined the extent to which the percentage of semantic intrusion errors (PIE) based on total responses on a novel cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), could predict clinical/cognitive outcomes over an average 26-month period in older adults initially diagnosed with aMCI, PreMCI, and normal cognition. RESULTS: On the LASSI-L subscale sensitive to PSI, a PIE cut point of 44% intrusion errors distinguished between those at-risk individuals with PreMCI who progressed to MCI over time compared to individuals with PreMCI who reverted to normal on longitudinal follow-up. Importantly, PIE was able to accurately predict 83.3% of aMCI individuals who later progressed to dementia. DISCUSSION: These preliminary findings indicate that PIE on LASSI-L subscales that measure PSI may be a useful predictor of clinical progression overtime in at-risk older adults.

Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab.

Emicizumab is a recombinant, humanized, and a bispecific monoclonal antibody that bridges activated factor (F) IX and FX in place of FVIII to restore hemostasis in persons with hemophilia A (PHA). Data on the efficacy and safety of emicizumab in young children is limited. Immunologic naivety, physiologically decreased production of vitamin K dependent proteins, specifically FIX, and enhanced clearance of emicizumab in infants may support decreased emicizumab effectiveness. We report on the facilitation of care rendered by using emicizumab in young PHA with inhibitors and extend data on the efficacy and safety in PHA < 3 years.

Concomitant Primary Hyperparathyroidism in Patients with Multiple Myeloma: A Possible Link?

Hypercalcemia is a significant feature of patients with active multiple myeloma (MM) with extensive bone disease. Among the causes of non-neoplastic hypercalcemia, primary hyperparathyroidism (PHPT) is one of the most common, leading to osteoporosis and bone fractures. Interestingly, some preclinical data indicate that high secretion of parathyroid hormone (PTH) may have a negative impact on bone disease and MM progression. However, concomitant diagnosis of MM and PHPT has rarely been described. Here, we present 4 cases of patients with active MM and hypercalcemia with high or inappropriately normal PTH levels. Interestingly, CD138+ cells from these 4 MM patients lack PTH receptor 1 and PTH-related peptide expressions, indicating that PTH could have a paracrine rather than a direct pro-tumoral effect. Moreover, these cases suggest that the concomitant diagnosis of MM and PHTP may not be so rare and should be considered for the clinical management of MM patients with hypercalcemia.

Differentially expressed proteins obtained by label-free quantitative proteomic analysis reveal affected biological processes and functions in Western diet-induced steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a pathological manifestation with a progressive incidence in response to the epidemic of hepatic steatosis caused primarily by excessive energy intake. The present study unravels affected biological processes and functions by the presence of NASH in rats using a label-free quantitative proteomic strategy. NASH was induced by a Western high-sugar and high-fat diet for 20 weeks. The liver tissue was collected for histology and for a mass spectrometry-based proteomic protocol. The NASH group showed severe lipidosis, hepatocyte ballooning, and the presence of collagen deposition. Among upregulated proteins in NASH perilipin-2 (Plin-2; F6QBA3; difference [diff]: 2.29), ferritin heavy (Fth1; Q66HI5; diff: 2.19) and light (Ftl1; P02793; diff: 1.75) chains, macrophage migration inhibitory factor 1 (Mif; P30904; diff: 1.69), and fibronectin (Fn1; F1LST1; diff: 0.35) were observed, whereas among downregulated proteins, plectin (Q6S399; diff: -3.34), some Cyp2 family proteins of the cytochrome P450 complex, glutathione S-transferases, flavin-containing monooxygenase 1 (Fmo1; P36365; diff: -2.08), acetyl-CoA acetyltransferase 2 (Acat2; Q5XI22; diff: -2.25), acyl-CoA oxidase 2 (Acox2; F1LNW3; diff: -1.59), and acyl-CoA oxidase 3 (Acox3; F1M9A7; diff: -2.41) were observed. Also, biological processes and functions such as LPS/IL-1 inhibition of RXR, fatty acid metabolism, Nrf2-mediated oxidative stress response, xenobiotic metabolism, and PXR/RXR and CAR/RXR activations were predicted to be affected. In conclusion, the liver of rats with NASH induced by Western diet shows a decreased capacity of metabolizing lipids, fatty acids, and xenobiotic compounds that predispose fibrosis development.