Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.

CIGB-258, a peptide derived from human heat-shock protein 60, decreases hyperinflammation in COVID-19 patients.

Hyperinflammation distinguishes COVID-19 patients who develop a slight disease or none, from those progressing to severe and critical conditions. CIGB-258 is a therapeutic option for the latter group of patients. This drug is an altered peptide ligand (APL) derived from the cellular stress protein 60 (HSP60). In preclinical models, this peptide developed anti-inflammatory effects and increased regulatory T cell (Treg) activity. Results from a phase I clinical trial with rheumatoid arthritis (RA) patients indicated that CIGB-258 was safe and reduced inflammation. The aim of this study was to examine specific biomarkers associated with hyperinflammation, some cytokines linked to the cytokine storm granzyme B and perforin in a cohort of COVID-19 patients treated with this peptide. All critically ill patients were under invasive mechanical ventilation and received the intravenous administration of 1 or 2 mg of CIGB-258 every 12 h. Seriously ill patients were treated with oxygen therapy receiving 1 mg of CIGB-258 every 12 h and all patients recovered from their severe condition. Biomarker levels associated with hyperinflammation, such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF-α), granzyme B, and perforin, significantly decreased during treatment. Furthermore, we studied the ability of CIGB-258 to induce Tregs in COVID-19 patients and found that Tregs were induced in all patients studied. Altogether, these results support the therapeutic potential of CIGB-258 for diseases associated with hyperinflammation. Clinical trial registry: RPCEC00000313.

Urinary vanillylmandelic acid:creatinine ratio in dogs with pheochromocytoma.

Pheochromocytoma diagnosis in dogs is challenging because biochemical tests are not always available. In humans, urinary vanillylmandelic acid (VMA) is part of a pheochromocytoma biochemical diagnostic profile, whereas its diagnostic accuracy is currently unknown in dogs with pheochromocytoma. Prospectively, VMA was determined by HPLC and expressed as the ratio with respect to urinary creatinine (VMA:C). The diagnostic accuracy of the VMA:C ratio was evaluated by analyzing the receiver operating characteristic (ROC) curve in 10 healthy dogs, 8 dogs with pituitary-dependent hypercortisolism, 8 dogs with adrenal-dependent hypercortisolism, and 7 dogs with pheochromocytoma. The pheochromocytoma diagnosis was confirmed by histology and immunohistochemistry in all tumors. The VMA:C ratio was significantly higher in dogs with pheochromocytoma (158 [53.4 to 230.8] × 10-3) than in dogs with adrenal-dependent hypercortisolism (48.1 [24.3 to 144.9] × 10-3; P < 0.05), dogs with pituitary-dependent hypercortisolism (37.5 [32 to 47.1] × 10-3; P < 0.001), and healthy dogs (33.8 [13.3 to 87.9] × 10-3; P < 0.001). When using a VMA:C ratio >58.2 × 10-3 for pheochromocytoma diagnosis, a sensitivity of 85.7% and a specificity of 88.4% were obtained. Nevertheless, when using a cut-off ratio of 4 times the median VMA:C ratio determined in healthy dogs, there was no overlap (100% specificity). The area under the ROC curve indicated that the VMA:C ratio test could be used to discriminate between dogs with and without pheochromocytoma, what leads to the conclusion that it is useful for pheochromocytoma diagnosis in dogs.

Recomendaciones de consenso respecto al soporte respiratorio no invasivo en el paciente adulto con insuficiencia respiratoria aguda secundaria a infección por SARS-CoV-2 / Clinical Consensus Recommendations Regarding Non-Invasive Respiratory Support in the Adult Patient with Acute Respiratory Failure Secondary to SARS-CoV-2 infection

La enfermedad por coronavirus 2019 (COVID-19) es una infección del tracto respiratorio causada por un nuevo coronavirus emergente que se reconoció por primera vez en Wuhan, China, en diciembre de 2019. Actualmente la Organización Mundial de la Salud (OMS) ha definido la infección como pandemia y existe una situación de emergencia sanitaria y social para el manejo de esta nueva infección. Mientras que la mayoría de las personas con COVID-19 desarrollan solo una enfermedad leve o no complicada, aproximadamente el 14% desarrollan una enfermedad grave que requiere hospitalización y oxígeno, y el 5% pueden requerir ingreso en una Unidad de Cuidados Intensivos. En casos severos, COVID-19 puede complicarse por el síndrome de dificultad respiratoria aguda (SDRA), sepsis y shock séptico y fracaso multiorgánico. Este documento de consenso se ha preparado sobre directrices basadas en evidencia desarrolladas por un panel multidisciplinario de profesionales médicos de cuatro sociedades científicas españolas (Sociedad Española de Medicina Intensiva y Unidades Coronarias [SEMICYUC], Sociedad Española de Neumología y Cirugía Torácica [SEPAR], Sociedad Española de Urgencias y Emergencias [SEMES], Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor [SEDAR]) con experiencia en el manejo clínico de pacientes con COVID-19 y otras infecciones virales, incluido el SARS, así como en sepsis y SDRA. El documento proporciona recomendaciones clínicas para el soporte respiratorio no invasivo (ventilación no invasiva, oxigenoterapia de alto flujo con cánula nasal) en cualquier paciente con presentación sospechada o confirmada de COVID-19 con insuficiencia respiratoria aguda. Esta guía de consenso debe servir como base para una atención optimizada y garantizar la mejor posibilidad de supervivencia, así como permitir una comparación fiable de las futuras intervenciones terapéuticas de investigación que formen parte de futuros estudios observacionales o de ensayos clínicos

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus, that was first recognized in Wuhan, China, in December 2019. Currently, the World Health Organization (WHO) has defined the infection as a global pandemic and there is a health and social emergency for the management of this new infection. While most people with COVID-19 develop only mild or uncomplicated illness, approximately 14% develop severe disease that requires hospitalization and oxygen support, and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by the acute respiratory distress syndrome (ARDS), sepsis and septic shock, and multiorgan failure. This consensus document has been prepared on evidence-informed guidelines developed by a multidisciplinary panel of health care providers from four Spanish scientific societies (Spanish Society of Intensive Care Medicine [SEMICYUC], Spanish Society of Pulmonologists [SEPAR], Spanish Society of Emergency [SEMES], Spanish Society of Anesthesiology, Reanimation, and Pain [SEDAR]) with experience in the clinical management of patients with COVID-19 and other viral infections, including SARS, as well as sepsis and ARDS. The document provides clinical recommendations for the noninvasive respiratory support (noninvasive ventilation, high flow oxygen therapy with nasal cannula) in any patient with suspected or confirmed presentation of COVID-19 with acute respiratory failure. This consensus guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival and to allow for reliable comparison of investigational therapeutic interventions as part of randomized controlled trials

Recomendaciones de consenso respecto al soporte respiratorio no invasivo en el paciente adulto con insuficiencia respiratoria aguda secundaria a infección por SARS-CoV-2 / Clinical Consensus Recommendations Regarding Non-Invasive Respiratory Support in the Adult Patient with Acute Respiratory Failure Secondary to SARS-CoV-2 infection

La enfermedad por coronavirus 2019 (COVID-19) es una infección del tracto respiratorio causada por un nuevo coronavirus emergente que se reconoció por primera vez en Wuhan, China, en diciembre de 2019. Actualmente la Organización Mundial de la Salud (OMS) ha definido la infección como pandemia y existe una situación de emergencia sanitaria y social para el manejo de esta nueva infección. Mientras que la mayoría de las personas con COVID-19 desarrollan solo una enfermedad leve o no complicada, aproximadamente el 14% desarrollan una enfermedad grave que requiere hospitalización y oxígeno, y el 5% pueden requerir ingreso en una Unidad de Cuidados Intensivos. En casos severos, COVID-19 puede complicarse por el síndrome de dificultad respiratoria aguda (SDRA), sepsis y shock séptico y fracaso multiorgánico. Este documento de consenso se ha preparado sobre directrices basadas en evidencia desarrolladas por un panel multidisciplinario de profesionales médicos de cuatro sociedades científicas españolas (Sociedad Española de Medicina Intensiva y Unidades Coronarias [SEMICYUC], Sociedad Española de Neumología y Cirugía Torácica [SEPAR], Sociedad Española de Urgencias y Emergencias [SEMES], Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor [SEDAR]) con experiencia en el manejo clínico de pacientes con COVID-19 y otras infecciones virales, incluido el SARS, así como en sepsis y SDRA. El documento proporciona recomendaciones clínicas para el soporte respiratorio no invasivo (ventilación no invasiva, oxigenoterapia de alto flujo con cánula nasal) en cualquier paciente con presentación sospechada o confirmada de COVID-19 con insuficiencia respiratoria aguda. Esta guía de consenso debe servir como base para una atención optimizada y garantizar la mejor posibilidad de supervivencia, así como permitir una comparación fiable de las futuras intervenciones terapéuticas de investigación que formen parte de futuros estudios observacionales o de ensayos clínicos

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus, that was first recognized in Wuhan, China, in December 2019. Currently, the World Health Organization (WHO) has defined the infection as a global pandemic and there is a health and social emergency for the management of this new infection. While most people with COVID-19 develop only mild or uncomplicated illness, approximately 14% develop severe disease that requires hospitalization and oxygen support, and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by the acute respiratory distress syndrome (ARDS), sepsis and septic shock, and multiorgan failure. This consensus document has been prepared on evidence-informed guidelines developed by a multidisciplinary panel of health care providers from four Spanish scientific societies (Spanish Society of Intensive Care Medicine [SEMICYUC], Spanish Society of Pulmonologists [SEPAR], Spanish Society of Emergency [SEMES], Spanish Society of Anesthesiology, Reanimation, and Pain [SEDAR]) with experience in the clinical management of patients with COVID-19 and other viral infections, including SARS, as well as sepsis and ARDS. The document provides clinical recommendations for the noninvasive respiratory support (noninvasive ventilation, high flow oxygen therapy with nasal cannula) in any patient with suspected or confirmed presentation of COVID-19 with acute respiratory failure. This consensus guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival and to allow for reliable comparison of investigational therapeutic interventions as part of randomized controlled trials

Clinical Consensus Recommendations Regarding Non-Invasive Respiratory Support in the Adult Patient with Acute Respiratory Failure Secondary to SARS-CoV-2 infection. / Recomendaciones de consenso respecto al soporte respiratorio no invasivo en el paciente adulto con insuficiencia respiratoria aguda secundaria a infección por SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus, that was first recognized in Wuhan, China, in December 2019. Currently, the World Health Organization (WHO) has defined the infection as a global pandemic and there is a health and social emergency for the management of this new infection. While most people with COVID-19 develop only mild or uncomplicated illness, approximately 14% develop severe disease that requires hospitalization and oxygen support, and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by the acute respiratory distress syndrome (ARDS), sepsis and septic shock, and multiorgan failure. This consensus document has been prepared on evidence-informed guidelines developed by a multidisciplinary panel of health care providers from four Spanish scientific societies (Spanish Society of Intensive Care Medicine [SEMICYUC], Spanish Society of Pulmonologists [SEPAR], Spanish Society of Emergency [SEMES], Spanish Society of Anesthesiology, Reanimation, and Pain [SEDAR]) with experience in the clinical management of patients with COVID-19 and other viral infections, including SARS, as well as sepsis and ARDS. The document provides clinical recommendations for the noninvasive respiratory support (noninvasive ventilation, high flow oxygen therapy with nasal cannula) in any patient with suspected or confirmed presentation of COVID-19 with acute respiratory failure. This consensus guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival and to allow for reliable comparison of investigational therapeutic interventions as part of randomized controlled trials.

Monitoring spatiotemporal changes in chaperone-mediated autophagy in vivo.

Autophagy malfunctioning occurs in multiple human disorders, making attractive the idea of chemically modulating it with therapeutic purposes. However, for many types of autophagy, a clear understanding of tissue-specific differences in their activity and regulation is missing because of lack of methods to monitor these processes in vivo. Chaperone-mediated autophagy (CMA) is a selective type of autophagy that until now has only been studied in vitro and not in the tissue context at single cell resolution. Here, we develop a transgenic reporter mouse that allows dynamic measurement of CMA activity in vivo using image-based procedures. We identify previously unknown spatial and temporal differences in CMA activity in multiple organs and in response to stress. We illustrate the versatility of this model for monitoring CMA in live animals, organotypic cultures and cell cultures from these mice, and provide practical examples of multiorgan response to drugs that modulate CMA.

The role of iturin A from B. amyloliquefaciens BUZ-14 in the inhibition of the most common postharvest fruit rots.

The aim of this work was to elucidate the role of the secondary metabolites produced by B. amyloliquefaciens BUZ-14 against B. cinerea, M. fructicola, M. laxa, P. digitatum, P. italicum and P. expansum both in vitro and in planta. The entire cell free supernatant (CFS) and the lipopeptide fraction (LPF) showed similar antifungal activities, completely inhibiting all the fungi at dilutions of 1:24 or even lower, whereas the non-butanolic fraction (NBF) barely inhibited the fungi. However, when the LPF and CFS were applied on fruit, only brown rot in peaches and blue rot in apples was totally inhibited. The main families of metabolites in the LPF were iturin A, fengycin and surfactin with maximum concentrations of 407, 853 and 658 µg mL-1, respectively. Subsequently, a TLC-bioautography revealed iturin A as the key metabolite in the inhibitions and allowed us to establish in vivo MICs of 16.9 and 33.9 µg mL-1 for Monilinia species and P. expansum, respectively. The application of 24 h-old BUZ-14 cultures suppressed brown rot in peaches and also blue rot in apples but failed to inhibit the other diseases. However, BUZ-14 was only able to grow and produce iturin A in peaches so we can deduce that the amount of iturin A brought with the cultures (36 ±â€¯14 µg mL-1) could be enough to control both diseases. The strong antifungal activity of the iturin A present in the BUZ-14 CFS suggests that it could be successfully used for postharvest disease control. However, future research is necessary to maximize the iturin A production by B. amyloliquefaciens BUZ-14 in order to optimize a commercial application.

Inadequate response to imatinib treatment in chronic myeloid leukemia due to a drug interaction with phenytoin.

Imatinib mesylate and the newer BCR-ABL tyrosine kinase inhibitors are the standard therapy for chronic myeloid leukemia. Although these are remarkably effective drugs, some mechanisms of resistance have been identified including drug-to-drug interactions. Here we present the case of a chronic myeloid leukemia patient with an inadequate response to imatinib due to concurrent phenytoin administration. Conspicuously low imatinib plasma trough levels were documented. Imatinib dose was increased from 400 to 800 mg with good response. In conclusion, drug-to-drug interactions should be ruled out in cases of resistance to tyrosine kinase inhibitor treatment. Potent inducers of cytochrome P450 isoenzyme CYP3A4, as phenytoin, could induce inadequate responses due to increased imatinib clearance and low imatinib trough plasma levels. Thus, this interaction should be avoided. When this is not possible, dose escalation of imatinib and measurement of plasma levels, if available, is recommended.

The 50th Anniversary of the Atomic Second.

This paper gives a brief account of the history of time standards and timekeeping beginning with John Harrison's seagoing clocks for navigation up to today's optical frequency standards and prospects for the future definition of the second.

Congenital dyshormonogenic hypothyroidism with goiter caused by a sodium/iodide symporter (SLC5A5) mutation in a family of Shih-Tzu dogs.

An iodide transport defect (ITD) in the thyroid gland was determined to cause congenital dyshormonogenic hypothyroidism with goiter (CDHG) in 2 members of a family of Shih-Tzu dogs. Strikingly, both dogs were also diagnosed with dilated cardiomyopathy at 24 and 1.5 mo of age. The only sign of hypothyroidism was a moderate growth delay in the adult dog. The ITD was recognized by the absence of uptake of technetium-99m in the salivary glands (sg) and goiter observed by scintigraphy. In the same scan, radiopharmaceutical uptake was found in the anterior mediastinum of both dogs and in the right axillary lymph node in the oldest dog. A follicular thyroid carcinoma was diagnosed by histopathology after thyroidectomy of the older dog. An adenomatous goiter with ectopic thyroid tissue, and degenerative changes in myocardium were the findings after necropsy in the youngest dog. A homozygous mutation of the intron 9 splice acceptor site of SLC5A5 gene, encoding the sodium/iodine symporter (NIS), was found in the DNA of one of the affected dogs. The mutation was a single base transition of guanine > adenine (G > A) at position 45,024,672 of dog chromosome 20 (CFA20). Five of eight healthy dogs, including both parents of one of the dogs exhibiting CDHG, were heterozygous A/G, and the other 3 were homozygous for the wild-type allele G/G. No sequence variant was found in thyroid peroxidase of the affected dog. Congenital dyshormonogenic hypothyroidism with goiter in this family is an autosomal recessive trait. Our findings are the first evidence of an SLC5A5 mutation in dogs and establish a new genetic cause of CDHG.

Eosinophilia secondary to lenalidomide therapy.

WHAT IS KNOWN AND OBJECTIVE: Limited data are available on eosinophilia as a drug adverse event. We describe a case of eosinophilia from lenalidomide therapy. CASE DESCRIPTION: A 50-year-old woman received lenalidomide, dexamethasone and cyclophosphamide as POEMS syndrome treatment. Eosinophil count rose during lenalidomide treatment and decreased in the periods off treatment. Naranjo nomogram suggested a probable association between the use of lenalidomide and eosinophilia. WHAT IS NEW AND CONCLUSION: Eosinophilia has rarely been described with lenalidomide. This case shows a clear temporal relationship between lenalidomide and eosinophilia.

Akt substrate of 160 kDa dephosphorylation rate is reduced in insulin-stimulated rat skeletal muscle after acute exercise.

Because greater Akt substrate of 160 kDa (AS160) phosphorylation has been reported in insulin-stimulated skeletal muscles without improved Akt activation several hours post-exercise, we hypothesized that prior exercise would result in attenuated AS160 dephosphorylation in insulin-stimulated rat skeletal muscle. Epitrochlearis muscles were isolated from rats that were sedentary (SED) or exercised 3 h earlier (3 h post-exercise; 3hPEX). Paired muscles were incubated with [(3)H]-2-deoxyglucose (2-DG) without insulin or with insulin. Lysates from other insulin-stimulated muscles from SED or 3hPEX rats were evaluated using AS160(Thr642) and AS160(Ser588) dephosphorylation assays. Prior exercise led to greater 2-DG uptake concomitant with greater AS160(Thr642) phosphorylation and a non-significant trend (P=0.087) for greater AS160(Ser588). Prior exercise also reduced AS160(Thr642) and AS160(Ser588) dephosphorylation rates. These results support the idea that attenuated AS160 dephosphorylation may favor greater AS160 phosphorylation post-exercise.

Algorithm based on the Thomson problem for determination of equilibrium structures of metal nanoclusters.

A new algorithm for the determination of equilibrium structures suitable for metal nanoclusters is proposed. The algorithm performs a stochastic search of the minima associated with the nuclear potential energy function restricted to a sphere (similar to the Thomson problem), in order to guess configurations of the nuclear positions. Subsequently, the guessed configurations are further optimized driven by the total energy function using the conventional gradient descent method. This methodology is equivalent to using the valence shell electron pair repulsion model in guessing initial configurations in the traditional molecular quantum chemistry. The framework is illustrated in several clusters of increasing complexity: Cu7, Cu9, and Cu11 as benchmark systems, and Cu38 and Ni9 as novel systems. New equilibrium structures for Cu9, Cu11, Cu38, and Ni9 are reported.

Methods to Study Chaperone-Mediated Autophagy.

Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are selectively recognized and delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. Defective or dysfunctional CMA has been associated with human pathologies such as neurodegeneration, cancer, immunodeficiency, or diabetes, increasing the overall interest in methods to monitor this selective autophagic pathway. In this chapter, we review the different experimental approaches used to evaluate CMA activity in different organs from animals or in cell cultures in vitro.

Megacolon tóxico en una paciente con colitis seudomembranosa / Toxic megacolon in a patient with colitis pseudomembranous

La colitis seudomembranosa es una patología relacionada con el uso de antibióticos. En raras ocasiones, evoluciona a megacolon tóxico que podría requerir resolución quirúrgica. Comunicamos el caso de una mujer de 22 años, que recibió amoxicilina/ácido clavulánico unos días antes de la consulta. Presentó diarrea, fiebre y vómitos. Radiografía y tomografía computarizada de abdomen: distensión de colon derecho >6 cm. Toxina para Clostridium: positiva. Comienza con el tratamiento médico y requiere cirugía por megacolon tóxico. El megacolon tóxico es una complicación infrecuente de la colitis seudomembranosa. Es rara en pacientes jóvenes y sin comorbilidades. Se llega al diagnóstico mediante los criterios de Jalan. La tasa de mortalidad se aproxima al 70%. Se debe mantener alto nivel de alerta ante signos de toxicidad sistémica y la dilatación colónica es diagnóstica de la entidad. El uso indiscriminado de antibióticos constituye un serio factor de riesgo.(AU)

Pseudomembranous colitis is a condition associated with the use of antibiotics. On rare occasions, it evolves to toxic megacolon which may require surgical resolution. We report the case of a 22-year-old woman who received amoxicillin/clavulanic acid a few days before the consultation. She referred diarrhea, fever and vomiting. Radiography and computed tomography of abdomen: distension of the right colon >6 cm. Clostridium toxin: positive. Medical treatment is administered and surgery is needed for toxic megacolon. Toxic megacolon is an infrequent complication of pseudomembranous colitis. It is rare in young patients without comorbidities. The diagnosis is reached using the Jalan criteria. The mortality rate approaches 70%. A high level of alertness should be maintained for signs of systemic toxicity and colonic dilation is diagnostic of the entity. Indiscriminate use of antibiotics is a serious risk factor.(AU)

Calcitonin-negative primary neuroendocrine tumor of the thyroid (nonmedullary) in a dog.

The Calcitonin-negative neuroendocrine tumor of the thyroid (CNNET) or "nonmedullary" in humans is a rare tumor that arises primarily in the thyroid gland and may be mistaken for medullary thyroid carcinoma; it is characterized by the immunohistochemical (IHC) expression of neuroendocrine markers and the absence of expression for calcitonin. An Argentine dogo bitch showed a solid, compact thyroid tumor, which was IHC negative for the expression of calcitonin, carcinoembryonic antigen, thyroglobulin and S100 protein, and positive for synaptophysin and cytokeratin AE1-AE3. The Ki-67 proliferation index was low. We cite this case not only because it is the first case report of calcitonin-negative primary neuroendocrine tumor of the thyroid in dogs but also because we want to highlight the diagnostic importance of IHC in this regard.