IL-10 indirectly modulates functional activity of CD4+CD28null T-lymphocytes through LFA-3 and HLA class II inhibition.

Expansion of CD4+CD28null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4+CD28null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4+CD28null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4+CD28null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T-lymphocytes.

Risk Factors for Therapeutic Failure and One-Year Mortality in Patients with Intramedullary Nail-Associated Infection after Trochanteric and Subtrochanteric Hip Fracture Repair.

Despite the implications of trochanteric and subtrochanteric intramedullary (IM) nail infection for patients with hip fracture, little is known about risk factors for therapeutic failure and mortality in this population. We performed a retrospective observational analysis including patients diagnosed with trochanteric and subtrochanteric IM nail infection at a Spanish academic hospital during a 10-year period, with a minimum follow-up of 22 months. Of 4044 trochanteric and subtrochanteric IM nail implants, we identified 35 cases of infection during the study period (0.87%), 17 of which were chronic infections. Patients with therapeutic failure (n = 10) presented a higher average Charlson Comorbidity Index (CCI) (5.40 vs. 4.21, p 0.015, CI 0.26-2.13) and higher rates of polymicrobial (OR 5.70, p 0.033, CI 1.14-28.33) and multidrug-resistant (OR 7.00, p 0.027, CI 1.24-39.57) infections. Upon multivariate analysis, polymicrobial infection and the presence of multidrug-resistant pathogens were identified as independent risk factors for therapeutic failure. Implant retention was associated with an increased risk of failure in chronic infection and was found to be an independent risk factor for overall one-year mortality in the multivariate analysis. Our study highlights the importance of broad-spectrum empirical antibiotics as initial treatment of trochanteric and subtrochanteric IM nail-associated infection while awaiting microbiological results. It also provides initial evidence for the importance of implant removal in chronic IM-nail infection.

Involvement of ArlI, ArlJ, and CirA in archaeal type IV pilin-mediated motility regulation.

Many prokaryotes use swimming motility to move toward favorable conditions and escape adverse surroundings. Regulatory mechanisms governing bacterial flagella-driven motility are well-established; however, little is yet known about the regulation underlying swimming motility propelled by the archaeal cell surface structure, the archaella. Previous research showed that the deletion of the adhesion pilins (PilA1-6), subunits of the type IV pili cell surface structure, renders the model archaeon Haloferax volcanii non-motile. In this study, we used ethyl methanesulfonate mutagenesis and a motility assay to identify motile suppressors of the ∆pilA[1-6] strain. Of the eight suppressors identified, six contain missense mutations in archaella biosynthesis genes, arlI and arlJ. In trans expression of arlI and arlJ mutant constructs in the respective multi-deletion strains ∆pilA[1-6]∆arlI and ∆pilA[1-6]∆arlJ confirmed their role in suppressing the ∆pilA[1-6] motility defect. Additionally, three suppressors harbor co-occurring disruptive missense and nonsense mutations in cirA, a gene encoding a proposed regulatory protein. A deletion of cirA resulted in hypermotility, while cirA expression in trans in wild-type cells led to decreased motility. Moreover, quantitative real-time PCR analysis revealed that in wild-type cells, higher expression levels of arlI, arlJ, and the archaellin gene arlA1 were observed in motile early-log phase rod-shaped cells compared to non-motile mid-log phase disk-shaped cells. Conversely, ∆cirA cells, which form rods during both early- and mid-log phases, exhibited similar expression levels of arl genes in both growth phases. Our findings contribute to a deeper understanding of the mechanisms governing archaeal motility, highlighting the involvement of ArlI, ArlJ, and CirA in pilin-mediated motility regulation.IMPORTANCEArchaea are close relatives of eukaryotes and play crucial ecological roles. Certain behaviors, such as swimming motility, are thought to be important for archaeal environmental adaptation. Archaella, the archaeal motility appendages, are evolutionarily distinct from bacterial flagella, and the regulatory mechanisms driving archaeal motility are largely unknown. Previous research has linked the loss of type IV pili subunits to archaeal motility suppression. This study reveals three Haloferax volcanii proteins involved in pilin-mediated motility regulation, offering a deeper understanding of motility regulation in this understudied domain while also paving the way for uncovering novel mechanisms that govern archaeal motility. Understanding archaeal cellular processes will help elucidate the ecological roles of archaea as well as the evolution of these processes across domains.

Involvement of ArlI, ArlJ, and CirA in Archaeal Type-IV Pilin-Mediated Motility Regulation.

Many prokaryotes use swimming motility to move toward favorable conditions and escape adverse surroundings. Regulatory mechanisms governing bacterial flagella-driven motility are well-established, however, little is yet known about the regulation underlying swimming motility propelled by the archaeal cell surface structure, the archaella. Previous research showed that deletion of the adhesion pilins (PilA1-6), subunits of the type IV pili cell surface structure, renders the model archaeon Haloferax volcanii non-motile. In this study, we used EMS mutagenesis and a motility assay to identify motile suppressors of the ΔpilA[1-6] strain. Of the eight suppressors identified, six contain missense mutations in archaella biosynthesis genes, arlI and arlJ. Overexpression of these arlI and arlJ mutant constructs in the respective multi-deletion strains ΔpilA[1-6]ΔarlI and ΔpilA[1-6]ΔarlJ confirmed their role in suppressing the ΔpilA[1-6] motility defect. Additionally, three suppressors harbor co-occurring disruptive missense and nonsense mutations in cirA, a gene encoding a proposed regulatory protein. A deletion of cirA resulted in hypermotility, while cirA overexpression in wild-type cells led to decreased motility. Moreover, qRT-PCR analysis revealed that in wild-type cells, higher expression levels of arlI, arlJ, and the archaellin gene arlA1 were observed in motile early-log phase rod-shaped cells compared to non-motile mid-log phase disk-shaped cells. Conversely, ΔcirA cells, which form rods during both early and mid-log phases, exhibited similar expression levels of arl genes in both growth phases. Our findings contribute to a deeper understanding of the mechanisms governing archaeal motility, highlighting the involvement of ArlI, ArlJ, and CirA in pilin-mediated motility regulation.

Review and analysis of the results of kidney transplantation programs in Mexico.

OBJECTIVE: To know, analyze and compare kidney transplant programs; considering the survival of recipients at 1 and 5 years, from hospitals in Mexico. METHOD: A systematic review was carried out whose search focused on the survival of kidney transplant recipients. All publications found in PubMed and Google from 1963 to 2021 were included. The expectation-maximization algorithm was applied, proposing a mixture of normals, and hierarchical grouping to establish if there is any type of pattern and determine if there is a difference between the percentages. of survival at 1 and 5 years between the groups formed. RESULTS: Eight hospitals that published the survival of kidney transplant recipients were found. Survival rates ranged, at 1 year, from 94.7% to 100%, and at 5 years, from 85% to 96.2%. The methods used for their comparison indicated that there is a difference between survival at 1 and 5 years. CONCLUSIONS: In Mexico there is little information on the results of kidney transplant programs, and the information found shows great heterogeneity in said programs. Some strategies and actions are proposed to improve survival underreporting.

OBJETIVO: Conocer, analizar y comparar los programas de trasplante renal, considerando la supervivencia de los receptores a 1 y 5 años, en los hospitales en México. MÉTODO: Se realizó una revisión sistemática cuya búsqueda se centró en la supervivencia de los receptores de trasplante renal. Se incluyeron todas las publicaciones encontradas en PubMed y Google de 1963 a 2021. Se aplicó el algoritmo de expectation-maximization, proponiendo una mezcla de normales, y agrupamiento jerárquico para establecer si hay algún tipo de patrón y determinar si hay diferencia entre los porcentajes de supervivencia a 1 y 5 años entre los grupos formados. RESULTADOS: Se encontraron ocho hospitales que publicaron la supervivencia de los receptores de trasplante renal. Los rangos de las tasas de supervivencia fueron, a 1 año, del 94.7% al 100%, y a los 5 años, del 85% al 96.2%. Los métodos empleados para su comparación indican que hay diferencia entre la supervivencia a 1 y 5 años. CONCLUSIONES: En México se tiene poca información sobre los resultados de los programas de trasplante renal, y la información encontrada muestra gran heterogeneidad en dichos programas. Se proponen algunas estrategias y acciones para mejorar el subregistro de supervivencia.

Zn-doped MnOx nanowires displaying plentiful crystalline defects and tunable small cross-sections for an optimized volcano-type performance towards supercapacitors.

MnOx-based nanomaterials are promising large-scale electrochemical energy storage devices due to their high specific capacity, low toxicity, and low cost. However, their slow diffusion kinetics is still challenging, restricting practical applications. Here, a one-pot and straightforward method was reported to produce Zn-doped MnOx nanowires with abundant defects and tunable small cross-sections, exhibiting an outstanding specific capacitance. More specifically, based on a facile hydrothermal strategy, zinc sites could be uniformly dispersed in the α-MnOx nanowires structure as a function of composition (0.3, 2.1, 4.3, and 7.6 wt.% Zn). Such a process avoided the formation of different crystalline phases during the synthesis. The reproducible method afforded uniform nanowires, in which the size of cross-sections decreased with the increase of Zn composition. Surprisingly, we found a volcano-type relationship between the storage performance and the Zn loading. In this case, we demonstrated that the highest performance material could be achieved by incorporating 2.1 wt.% Zn, exhibiting a remarkable specific capacitance of 1082.2 F.g-1 at a charge/discharge current density of 1.0 A g-1 in a 2.0 mol L-1 KOH electrolyte. The optimized material also afforded improved results for hybrid supercapacitors. Thus, the results presented herein shed new insights into preparing defective and controlled nanomaterials by a simple one-step method for energy storage applications.

Boosting Mitochondrial Biogenesis Diminishes Foam Cell Formation in the Post-Stroke Brain.

Following ischemic stroke, the degradation of myelin and other cellular membranes surpasses the lipid-processing capabilities of resident microglia and infiltrating macrophages. This imbalance leads to foam cell formation in the infarct and areas of secondary neurodegeneration, instigating sustained inflammation and furthering neurological damage. Given that mitochondria are the primary sites of fatty acid metabolism, augmenting mitochondrial biogenesis (MB) may enhance lipid processing, curtailing foam cell formation and post-stroke chronic inflammation. Previous studies have shown that the pharmacological activation of the ß2-adrenergic receptor (ß2-AR) stimulates MB. Consequently, our study sought to discern the effects of intensified ß2-AR signaling on MB, the processing of brain lipid debris, and neurological outcome using a mouse stroke model. To achieve this goal, aged mice were treated with formoterol, a long-acting ß2-AR agonist, daily for two and eight weeks following stroke. Formoterol increased MB in the infarct region, modified fatty acid metabolism, and reduced foam cell formation. However, it did not reduce markers of post-stroke neurodegeneration or improve recovery. Although our findings indicate that enhancing MB in myeloid cells can aid in the processing of brain lipid debris after stroke, it is important to note that boosting MB alone may not be sufficient to significantly impact stroke recovery.

Sustainable Cellulose Nanofibers-Mediated Synthesis of Uniform Spinel Zn-Ferrites Nanocorals for High Performances in Supercapacitors.

Spinel ferrites are versatile, low-cost, and abundant metal oxides with remarkable electronic and magnetic properties, which find several applications. Among them, they have been considered part of the next generation of electrochemical energy storage materials due to their variable oxidation states, low environmental toxicity, and possible synthesis through simple green chemical processing. However, most traditional procedures lead to the formation of poorly controlled materials (in terms of size, shape, composition, and/or crystalline structure). Thus, we report herein a cellulose nanofibers-mediated green procedure to prepare controlled highly porous nanocorals comprised of spinel Zn-ferrites. Then, they presented remarkable applications as electrodes in supercapacitors, which were thoroughly and critically discussed. The spinel Zn-ferrites nanocorals supercapacitor showed a much higher maximum specific capacitance (2031.81 F g-1 at a current density of 1 A g-1) than Fe2O3 and ZnO counterparts prepared by a similar approach (189.74 and 24.39 F g-1 at a current density of 1 A g-1). Its cyclic stability was also scrutinized via galvanostatic charging/discharging and electrochemical impedance spectroscopy, indicating excellent long-term stability. In addition, we manufactured an asymmetric supercapacitor device, which offered a high energy density value of 18.1 Wh kg-1 at a power density of 2609.2 W kg-1 (at 1 A g-1 in 2.0 mol L-1 KOH electrolyte). Based on our findings, we believe that higher performances observed for spinel Zn-ferrites nanocorals could be explained by their unique crystal structure and electronic configuration based on crystal field stabilization energy, which provides an electrostatic repulsion between the d electrons and the p orbitals of the surrounding oxygen anions, creating a level of energy that determines their final supercapacitance then evidenced, which is a very interesting property that could be explored for the production of clean energy storage devices.

Facile Gram-Scale Synthesis of NiO Nanoflowers for Highly Selective and Sensitive Electrocatalytic Detection of Hydrazine.

The design and development of efficient and electrocatalytic sensitive nickel oxide nanomaterials have attracted attention as they are considered cost-effective, stable, and abundant electrocatalytic sensors. However, although innumerable electrocatalysts have been reported, their large-scale production with the same activity and sensitivity remains challenging. In this study, we report a simple protocol for the gram-scale synthesis of uniform NiO nanoflowers (approximately 1.75 g) via a hydrothermal method for highly selective and sensitive electrocatalytic detection of hydrazine. The resultant material was characterized by scanning electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. For the production of the modified electrode, NiO nanoflowers were dispersed in Nafion and drop-cast onto the surface of a glassy carbon electrode (NiO NF/GCE). By cyclic voltammetry, it was possible to observe the excellent performance of the modified electrode toward hydrazine oxidation in alkaline media, providing an oxidation overpotential of only +0.08 V vs Ag/AgCl. In these conditions, the peak current response increased linearly with hydrazine concentration ranging from 0.99 to 98.13 µmol L-1. The electrocatalytic sensor showed a high sensitivity value of 0.10866 µA L µmol-1. The limits of detection and quantification were 0.026 and 0.0898 µmol L-1, respectively. Considering these results, NiO nanoflowers can be regarded as promising surfaces for the electrochemical determination of hydrazine, providing interesting features to explore in the electrocatalytic sensor field.

Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke.

The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naïve and sham mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid ß-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naïve controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. Spatial transcriptomics and RNA in situ hybridization localized these alterations to microglia within the area of axonal degeneration. These results indicate that chronic metabolic differences exist between stroked and control brains, including alterations in fatty acid metabolism and glycolysis within microglia in areas of degenerating white matter for at least 12 weeks after stroke.

MnO2-Ir Nanowires: Combining Ultrasmall Nanoparticle Sizes, O-Vacancies, and Low Noble-Metal Loading with Improved Activities towards the Oxygen Reduction Reaction.

Although clean energy generation utilizing the Oxygen Reduction Reaction (ORR) can be considered a promising strategy, this approach remains challenging by the dependence on high loadings of noble metals, mainly Platinum (Pt). Therefore, efforts have been directed to develop new and efficient electrocatalysts that could decrease the Pt content (e.g., by nanotechnology tools or alloying) or replace them completely in these systems. The present investigation shows that high catalytic activity can be reached towards the ORR by employing 1.8 ± 0.7 nm Ir nanoparticles (NPs) deposited onto MnO2 nanowires surface under low Ir loadings (1.2 wt.%). Interestingly, we observed that the MnO2-Ir nanohybrid presented high catalytic activity for the ORR close to commercial Pt/C (20.0 wt.% of Pt), indicating that it could obtain efficient performance using a simple synthetic procedure. The MnO2-Ir electrocatalyst also showed improved stability relative to commercial Pt/C, in which only a slight activity loss was observed after 50 reaction cycles. Considering our findings, the superior performance delivered by the MnO2-Ir nanohybrid may be related to (i) the significant concentration of reduced Mn3+ species, leading to increased concentration of oxygen vacancies at its surface; (ii) the presence of strong metal-support interactions (SMSI), in which the electronic effect between MnOx and Ir may enhance the ORR process; and (iii) the unique structure comprised by Ir ultrasmall sizes at the nanowire surface that enable the exposure of high energy surface/facets, high surface-to-volume ratios, and their uniform dispersion.

TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype.

Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3-26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset.

Forearm and Hand Muscles Exhibit High Coactivation and Overlapping of Cortical Motor Representations.

Most of the motor mapping procedures using navigated transcranial magnetic stimulation (nTMS) follow the conventional somatotopic organization of the primary motor cortex (M1) by assessing the representation of a particular target muscle, disregarding the possible coactivation of synergistic muscles. In turn, multiple reports describe a functional organization of the M1 with an overlapping among motor representations acting together to execute movements. In this context, the overlap degree among cortical representations of synergistic hand and forearm muscles remains an open question. This study aimed to evaluate the muscle coactivation and representation overlapping common to the grasping movement and its dependence on the stimulation parameters. The nTMS motor maps were obtained from one carpal muscle and two intrinsic hand muscles during rest. We quantified the overlapping motor maps in size (area and volume overlap degree) and topography (similarity and centroid Euclidean distance) parameters. We demonstrated that these muscle representations are highly overlapped and similar in shape. The overlap degrees involving the forearm muscle were significantly higher than only among the intrinsic hand muscles. Moreover, the stimulation intensity had a stronger effect on the size compared to the topography parameters. Our study contributes to a more detailed cortical motor representation towards a synergistic, functional arrangement of M1. Understanding the muscle group coactivation may provide more accurate motor maps when delineating the eloquent brain tissue during pre-surgical planning.

Repeated Administration of 2-Hydroxypropyl-ß-Cyclodextrin (HPßCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke.

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPßCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPßCD 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HPßCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPßCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPßCD also preserved NeuN immunoreactivity in the striatum and thalamus and c-Fos immunoreactivity in hippocampal regions. Additionally, HPßCD improved recovery through the protection of hippocampal-dependent spatial working memory and reduction of impulsivity. These results indicate that systemic HPßCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents poststroke cognitive decline.SIGNIFICANCE STATEMENT Dementia is a common and debilitating sequela of stroke. Currently, there are no available treatments for poststroke dementia. Our study shows that lipid metabolism is disrupted in chronic stroke infarcts, which causes an accumulation of uncleared lipid debris and correlates with a chronic inflammatory response. To our knowledge, these substantial changes in lipid homeostasis have not been previously recognized or investigated in the context of ischemic stroke. We also provide a proof of principle that solubilizing and entrapping lipophilic substances using HPßCD could be an effective strategy for treating chronic inflammation after stroke and other CNS injuries. We propose that using HPßCD for the prevention of poststroke dementia could improve recovery and increase long-term quality of life in stroke sufferers.

Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery.

The aim of this study was to test whether poststroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle-treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke-induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks after stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31-treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31-treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75NTR for preserving neuronal health and function during stroke recovery. SIGNIFICANCE STATEMENT: The findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer's disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

Cytomegalovirus in Haematological Tumours.

The exquisite coupling between herpesvirus and human beings is the result of millions of years of relationship, coexistence, adaptation, and divergence. It is probably based on the ability to generate a latency that keeps viral activity at a very low level, thereby apparently minimising harm to its host. However, this evolutionary success disappears in immunosuppressed patients, especially in haematological patients. The relevance of infection and reactivation in haematological patients has been a matter of interest, although one fundamentally focused on reactivation in the post-allogeneic stem cell transplant (SCT) patient cohort. Newer transplant modalities have been progressively introduced in clinical settings, with successively more drugs being used to manipulate graft composition and functionality. In addition, new antiviral drugs are available to treat CMV infection. We review the immunological architecture that is key to a favourable outcome in this subset of patients. Less is known about the effects of herpesvirus in terms of mortality or disease progression in patients with other malignant haematological diseases who are treated with immuno-chemotherapy or new molecules, or in patients who receive autologous SCT. The absence of serious consequences in these groups has probably limited the motivation to deepen our knowledge of this aspect. However, the introduction of new therapeutic agents for haematological malignancies has led to a better understanding of how natural killer (NK) cells, CD4+ and CD8+ T lymphocytes, and B lymphocytes interact, and of the role of CMV infection in the context of recently introduced drugs such as Bruton tyrosine kinase (BTK) inhibitors, phosphoinosytol-3-kinase inhibitors, anti-BCL2 drugs, and even CAR-T cells. We analyse the immunological basis and recommendations regarding these scenarios.

CMV Infection Is Directly Related to the Inflammatory Status in Chronic Heart Failure Patients.

High levels of inflammation play an important role in chronic heart failure (CHF). Patients with CHF have elevated levels of pro-inflammatory cytokines circulating systemically, mainly TNF and IL-6. However, there are almost no studies that relate these levels to the functional status of patients in CHF, much less to their CMV serostatus. In this study, patients with CHF (n=40; age=54.9 ± 6.3; New York Heart Association functional classification (NYHA, I-III) and healthy controls (n=40; age=53.5 ± 7.1) were analyzed. The serum concentrations of nine pro- and anti-inflammatory cytokines were measured by Luminex® xMap Technology and the basal level of mRNA expression of some immune molecules was quantified by TaqMan™ Array in CD4+ T-lymphocytes. The concentration of these cytokines in culture supernatants in response to anti-CD3 and LPS was also measured. The percentage of CD28null T-cells was determined, as well as the antibody titer against CMV. We found a higher concentration of all cytokines studied in CHF serum compared to healthy controls, as well as a direct correlation between functional status in CHF patients and levels of inflammatory cytokines. Moreover, the highest cytokine concentrations were found in patients with higher concentrations of lymphocytes lacking CD28 molecule. The cytokine production was much higher in CMV+ patients, and the production of these cytokines was found mainly in the T-lymphocytes of CMV+ patients in response to anti-CD3. Anti-CMV antibody levels were positively correlated with cytokine levels. The baseline expression of specific mRNA of the main molecules involved in the Th1 response, as well as molecules related to the CD4+CD28 null subset was higher in CMV+ patients. The cytokine concentrations are higher in CHF CMV+ patients and these concentrations are related to the production of antibodies against CMV. These high levels of cytokines are also associated with the more differentiated CD28null lymphocyte populations. All this, together with the dynamics of the pathology itself, makes CMV+ patients present a worse functional status and possibly a worse evolution of the pathology.

Neoplasia and Tumor-Like Lesions in Pet Rabbits (Oryctolagus cuniculus): A Retrospective Analysis of Cases Between 1995 and 2019.

Prevalence and age distribution of tumors is largely unknown in pet rabbits. Currently available studies focused on specific organ systems or specific tumor types and never covered a comparative examination of all tumor types. Previous studies on laboratory rabbits suggested a low tumor prevalence but were mostly limited to young adult animals. In the present study, all tumor types and several tumor-like lesions of all organ systems were analyzed retrospectively in archived pet rabbit samples of all ages. Cases included necropsy cases (n = 2,014) or postmortem tissue samples (n = 102) as well as surgical biopsies (n = 854). All lesions suspicious of neoplasia were reevaluated by histopathology and, when indicated, by immunohistochemistry. Necropsy cases had a tumor prevalence of 14.4% in both sexes or 19.8% in female intact rabbits of all age groups, and up to 47.2% or 66.7%, respectively, in rabbits older than 6 years. Overall, the most common tumor types were uterine adenocarcinoma (prevalence in female intact animals: 13.1%), lymphoma (prevalence: 2.8%), and thymoma (prevalence: 2.1%). Lymphoma, the most common tumor of rabbits ≤24 months of age, were of B-cell immunophenotype in 96% of cases and most commonly located in the lymph nodes (57%), gastrointestinal tract (54%), kidneys (48%), spleen (42%), and liver (41%). Tumors accounted for 81.1% of surgical biopsies and mostly comprised cutaneous, mammary, and uterine tumors. In conclusion, tumor types and prevalence varied significantly with respect to age, revealing some differences from previous studies on laboratory rabbits.

Establishing consensus on the perioperative management of cholecystectomy in public hospitals: a Delphi study with an expert panel in Mexico.

BACKGROUND: Several guidelines have put forward recommendations about the perioperative process of cholecystectomy. Despite the recommendations, controversy remains concerning several topics, especially in low- and middle-income countries. The aim of this study was to develop uniform recommendations for perioperative practices in cholecystectomy in Mexico to standardize this process and save public health system resources. METHODS: A modified Delphi method was used. An expert panel of 23 surgeons anonymously completed two rounds of responses to a 29-item questionnaire with 110 possible answers. The consensus was assessed using the percentage of responders agreeing on each question. RESULTS: From the 29 questions, the study generated 27 recommendations based on 20 (69.0%) questions reaching consensus, one that was considered uncertain (3.4%), and six (20.7%) items that remained open questions. In two (6.9%) cases, no consensus was reached, and no recommendation could be made. CONCLUSIONS: This study provides recommendations for the perioperative management of cholecystectomy in public hospitals in Mexico. As a guide for public institutions in low- and middle-income countries, the study identifies recommendations for perioperative tests and evaluations, perioperative decision making, postoperative interventions and institutional investment, that might ensure the safe practice of cholecystectomy and contribute to conserving resources.