Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity ...contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
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•Methotrexate (MTX) causes a microglia-dependent reduction in Bdnf expression•Activity-regulated myelination requires Bdnf-TrkB signaling and fails after MTX•Conditional, inducible TrkB loss in OPCs impairs cognitive behavioral performance•TrkB agonism rescues cognitive performance after MTX only if OPCs express TrkB
Methotrexate chemotherapy results in a microglial-dependent reduction of Bdnf expression and loss of activity-regulated myelination, which requires Bdnf to TrkB signaling. OPC-specific loss of TrkB results in cognitive impairment. Stimulating OPC TrkB signaling restores myelination and rescues cognition after MTX.
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to ...this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment.
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•Chemotherapy depletes oligodendrocyte lineage (OL) cells in humans•Methotrexate chemotherapy disrupts OL dynamics, myelin, and cognition in mice•Methotrexate induces chronic microglial activation and astrocyte reactivity•Microglial depletion rescues glial cell dysregulation and cognitive deficits
Microglial activation by methotrexate leads to a persistent disruption of oligodendrocyte lineage dynamics and astrocyte reactivity, resulting in the long-term cognitive impairment associated with chemotherapy.
Serum levels of procalcitonin (PCT), a protein produced by the thyroid C cells under physiologic conditions, are high during sepsis.
To assess the test performance of serum PCT in predicting ...bacterial sepsis and septic shock in patients with hypothyroidism compared with those who have euthyroidism.
This retrospective study evaluated patients with no history of thyroid dysfunction (euthyroid), primary hypothyroidism medical hypothyroidism (MH), and postsurgical hypothyroidism from total thyroidectomy (TT) identified from a prospectively maintained database who had PCT testing from 2005 to 2018. Quick Sequential Organ Failure Assessment score ≥ 2 or positive bacterial cultures identified bacterial sepsis, and a mean arterial pressure less than 65 mm Hg or a vasopressor requirement defined septic shock. Sensitivity and specificity of PCT for evaluation of bacterial sepsis and septic shock were measured.
We identified 217 euthyroid patients, 197 patients with MH, and 84 patients with TT. Bacterial sepsis was found in 98 (45.2%), 92 (46.7%), and 36 (42.9%) of these patients, respectively (P > 0.05). Septic shock was identified in 13 (6.0%), 13 (6.6%), and 5 (6.0%) patients (P > 0.05), respectively. With use of a PCT cutoff of 0.5 µg/L for bacterial sepsis, the sensitivity was 59%, 61%, and 53% (P > 0.05) and specificity was 81%, 77%, and 81% (P > 0.05) for the diagnosis of bacterial sepsis in euthyroid, MH, and TT patients, respectively. With use of a PCT cutoff of 2.0 µg/L for septic shock, the sensitivity was 46%, 62%, and 63% (P > 0.05) and specificity was 86%, 82%, and 91% (P > 0.05) for the diagnosis of septic shock in these patients, respectively.
Despite the thyroidal origin of PCT, hypothyroidism did not affect the diagnostic performance of serum PCT levels in predicting bacterial sepsis or septic shock.
Renal disease including chronic renal disease and end-stage renal disease has been associated with the development of primary glenohumeral osteoarthritis. However, little is known about how renal ...disease affects outcomes after shoulder arthroplasty. Thus, the purpose of this study was to evaluate the impact of renal disease on outcomes of shoulder arthroplasty for glenohumeral osteoarthritis.
This was a retrospective review using the Nationwide Readmissions Database. Using International Classification of Diseases, 9th Revision, codes, patients who underwent shoulder arthroplasty (including total shoulder arthroplasty and reverse total shoulder arthroplasty) for primary glenohumeral osteoarthritis were identified. These patients were divided into 3 groups: no renal disease, predialysis chronic renal disease (including stages 1-5), and end-stage renal disease. Primary outcomes of interest included the risk of complications during index hospitalization as well as within 90 days of index surgery. Secondary outcomes included index hospitalization length of stay, cost, and discharge location.
From 2010 to 2014, a total of 29,336 patients underwent shoulder arthroplasty for glenohumeral osteoarthritis. Of these 29,336, 27,928 (95.2%) patients had no renal disease, 1355 (4.6%) had predialysis chronic renal disease, and 53 (0.2%) patients had end-stage renal disease. Compared with patients with no renal disease, both predialysis chronic renal disease and end-stage renal disease patients had an increased risk of receiving blood transfusions (odds ratio OR = 2.04, P < .0001, and 5.37, P = .04, respectively) and experiencing any postoperative complication during the index hospitalization (OR = 2.31, P < .0001, and 3.94, P = .003, respectively). Specifically, predialysis chronic renal disease patients were at an increased risk for cardiac (OR = 1.96, P < .0001) and respiratory (OR = 1.55, P < .0001) complications as well as acute renal failure (OR = 14.70, P < .0001) postoperatively. End-stage renal disease patients were at an increased risk for cardiac (OR = 3.87, P = .003) complications as well as acute renal failure (OR = 10.35, P = .002) postoperatively. Within 90 days, end-stage renal disease patients had an increased risk of hospital readmission (OR = 8.01, P < .0001), dislocation (OR = 8.70, P = .039), and surgical site infection (OR = 19.06, P = .001). Finally, compared with patients with no renal disease, predialysis chronic renal disease and end-stage renal disease patients both had increased hospital length of stay and cost; predialysis chronic renal disease patients had an increased risk of discharge to a skilled nursing facility (OR = 1.39, P = .039).
This retrospective cohort study demonstrates that even predialysis chronic renal disease patients have worse outcomes compared with patients with no renal disease after shoulder arthroplasty for glenohumeral osteoarthritis. These findings serve to highlight the importance of close perioperative monitoring to prevent complications in a potentially overlooked patient population.
A previously healthy, immunocompetent 67-year-old female presented with a one-month history of general symptoms, weight loss, night fevers, and bilateral lower extremity edema. On admission she had ...severe anemia, acute kidney injury, and multiple lymphadenopathies. An excisional biopsy of one of the axillary lymphadenopathies confirmed hyaline-vascular Castleman's disease. This rare disease is a polyclonal lymphoproliferative disorder that affects the normal lymph node architecture. According to its location it can be divided in unicentric (localized) or multicentric disease; it can be further divided according to histopathology in hyaline-vascular or plasmatic cells variety. Clinical presentation relates more to histopathological variety than to centricity. Human herpes virus 8 is ubiquitous in this disease and, along with interleukin 6, plays an important role in pathogenesis and symptoms presentation. Surgery is the go-to treatment of localized disease, while systemic chemotherapy is the option in multicentric disease. Communication between the clinical and anatomopathological teams is crucial; lag in diagnosis can lead to futile investigations in search of other diseases and delay in treatment.
Las transferencias tendinosas son consideradas para mejorar la función de la escápula y restablecer la biomecánica de la cintura escapular en aquellos pacientes con escápula alada que tienen ...alteración en la funcionalidad y que no han progresado con tratamiento conservador. Existen diferentes técnicas de transferencias tendinosas como parte del tratamiento. En este artículo realizamos una revisión narrativa, además, ilustramos con videos las siguientes técnicas: la triple transferencia tendinosa en parálisis del trapecio y la transferencia del pectoral mayor hacia la escápula en disfunción del serrato anterior.
Base excision repair (BER) of oxidized pyrimidine residues is initiated by E. coli endonuclease III (Nth), E. coli endonuclease VIII (Nei), and their human homologs (hNth1 and hNeil1,2,3 ...respectively). These enzymes are bifunctional DNA N-glycosylase/AP lyases, which catalyze release of the damaged base from the DNA backbone, and then cleave the DNA strand at the resulting apurinic/apyrimidinic (AP) site via elimination. Among the damaged pyrimidine residues repaired by the hNth1 and hNeil1 is 5,6-dihydroxy-5,6-dihydrothymine (thymine glycol, Tg). In DNA, Tg may be formed either by oxidation of thymine, yielding Tg opposite adenine (Tg:A), or by oxidation and deamination of 5-methylcytosine (5meCyt), yielding Tg opposite guanine (Tg:G). Moreover, the Tg 2'-deoxyribonucleoside exists as cis 5S,6R (Tg1) and 5R,6S (Tg2) diastereoisomers, which are in equilibrium with their corresponding trans forms, and the Tg bases are enantiomers. Therefore, DNA may contain Tg1:A, Tg2:A, Tg1:G, or Tg2:G. To elucidate the mechanism of BER of oxidized pyrimidines, we first measured the excision of Tg-containing substrates by hNth1 and hNeil1 in vitro. hNth1 repaired Tg stereoselectively, with Tg2 excised at a significantly faster rate than Tg1, regardless of the nature of the opposing. In contrast, the nature of the opposing purine determined the rate of Tg excision by hNeil1, with Tg:G more rapidly excised. We then generated single and double knockout (KO) mice to assess the functional consequences of the loss of Nth1 and/or Neil1. mNth1 KO, mNeil1 KO, and mNth1/mNeil1 double KO animals were viable and fertile, and DNA cleavage assays revealed that Nth1 is the predominant Tg repair activity in the liver. Little to no repair was catalyzed by mNth1 KO liver lysate, in contrast to wildtype (WT), which excised all Tg-containing substrates. Surprisingly, unlike WT liver lysate, WT thymus lysates exhibited selective excision of Tg:G, demonstrating tissue specificity in BER. Moreover, mNth1 KO and mNeil1 KO thymus lysates both showed similar Tg:G specificity, suggesting a compensation mechanism. However, loss of both mNth and mNeil1 (double KO) eliminated all Tg excision activity in thymus and liver. Thus, Nth1 and Neil1 are the primary enzymes which catalyze BER of Tg in mammalian cells.
El presente trabajo busca analizar las razones de la exclusión de los colectivos;
LGTBIQ dentro de las discusiones referidas a los Objetivos de Desarrollo Sostenible.;
El trabajo propone que a pesar ...de la exclusión decidida por parte de los colectivos de;
Estados islámicos conservadores y grupos profamilia, los Objetivos de Desarrollo;
Sostenible deben satisfacer las necesidades de estos colectivos excluidos,;
interpretando los diferentes objetivos de conformidad con el Derecho internacional de;
los Derechos Humanos.
Trabajo académico
04-04-2020
El presente trabajo busca analizar las razones de la exclusión de los colectivos;
LGTBIQ dentro de las discusiones referidas a los Objetivos de Desarrollo Sostenible.;
El trabajo propone que a pesar ...de la exclusión decidida por parte de los colectivos de;
Estados islámicos conservadores y grupos profamilia, los Objetivos de Desarrollo;
Sostenible deben satisfacer las necesidades de estos colectivos excluidos,;
interpretando los diferentes objetivos de conformidad con el Derecho internacional de;
los Derechos Humanos.
04-04-2020
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