Reliability of blood eosinophil count in steady-state bronchiectasis.

RATIONALE: The baseline value of eosinophils in peripheral blood (BEC) has been associated with different degrees of severity, prognosis and response to treatment in patients with bronchiectasis. It is not known, however, if this basal value remains constant over time. OBJECTIVES: The aim of this study was to assess whether the BEC remains stable in the long term in patients with bronchiectasis. METHODS AND MEASUREMENTS: Patients from the RIBRON registry of bronchiectasis diagnosed by computed tomography with at least 2 BEC measurements one year apart were included in the study. Patients with asthma and those taking anti-eosinophilic drugs were excluded. Reliability was assessed using the intra-class correlation coefficient (ICC). A patient with a BEC of at least 300 cells/uL or less than 100 cells/uL was considered eosinophilic or eosinopenic, respectively. Group changes over time were also calculated. MAIN RESULTS: Seven hundred and thirteen patients were finally included, with a mean age of 66.5 (13.2) years (65.8 % women). A total of 2701 BEC measurements were performed, with a median number of measurements per patient of 4 (IQR: 2-5) separated by a median of 12.1 (IQR: 10.5-14.3) months between two consecutive measurements. The ICC was good (>0.75) when calculated between two consecutive measurements (approximately one year apart) but had dropped significantly by the time of the next annual measurements. Similarly, the change from an eosinophilic or eosinopenic patient to a non-eosinophilic or non-eosinopenic patient, respectively, was less than 30 % during the first year with respect to the baseline value but was close to 50 % in later measurements. CONCLUSIONS: Given the significant changes observed in the baseline value of the BEC over time, its monitoring is necessary in patients with bronchiectasis in order to more reliably assess its usefulness.

New evidence in severe pneumonia: imipenem/ cilastatin/relebactam.

Imipenem combined with beta-lactamase inhibitor relebactam (IMI/REL) has an extensive bactericidal activity against Gram-negative pathogens producing class A or class C beta-lactamases, not active against class B and class D. The phase 3 clinical trial (RESTORE-IMI-2), double-blind, randomized, evaluated IMI/REL vs. piperacillin-tazobactam (PIP/TAZ) for treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), demonstrated non-inferiority at all-cause mortality at 28 days (15.9% vs 21.3%), favorable clinical response at 7-14 days end of treatment (61% vs 59.8%) and with minor serious adverse effects (26.7% vs 32%). IMI/REL is a therapeutic option in HAP and VAP at approved dosage imipenem 500 mg, cilastatin 500 mg and relebactam 250 mg once every 6h, by an IV infusion over 30 min.

Behavior and electrophysiology studies of the peripheral neuropathy induced by individual and co-administration of paclitaxel and oxaliplatin in rat.

AIMS: Antitumor agents, as taxanes and platinum compounds, induce peripheral neuropathies which can hamper their use for cancer treatment. The study of chemotherapy-induced neuropathies in humans is difficult because of ethical reasons, differences among administration protocols and intrinsic characteristics of patients. The aim of the present study is to compare the neuropathic signs induced by individual or combined administration of paclitaxel and oxaliplatin. MAIN METHODS: Oxaliplatin and paclitaxel were administered individually and combined to induce peripheral neuropathy in rats, sensory neuropathic signs were assessed in the hind limbs and orofacial area. The in vitro skin-saphenous nerve preparation was used to record the axonal activity of Aδ sensory neurons. KEY FINDINGS: Animals treated with the combination developed mechanical allodynia in the paws and muscular hyperalgesia in the orofacial area, which was similar to that in animals treated with monotherapy, the latter also developed cold allodynia in the paws. Aδ-fibers of the rats treated with the combination were hyperexcited and presented hypersensitivity to pressure stimulation of the innervated skin, also similar to that recorded in the fibers of the animals treated with monotherapy. SIGNIFICANCE: Our work objectively demonstrates that the combination of a platinum compound with a taxane does not worsen the development of sensorial neuropathies in rats, which is an interesting data to take into account when the combination of antitumor drugs is necessary. Co-administration of antitumor drugs is more effective in cancer treatment without increasing the risk of the disabling neuropathic side effects.

Short-term interaction between silent and devastating earthquakes in Mexico.

Either the triggering of large earthquakes on a fault hosting aseismic slip or the triggering of slow slip events (SSE) by passing seismic waves involve seismological questions with important hazard implications. Just a few observations plausibly suggest that such interactions actually happen in nature. In this study we show that three recent devastating earthquakes in Mexico are likely related to SSEs, describing a cascade of events interacting with each other on a regional scale via quasi-static and/or dynamic perturbations across the states of Guerrero and Oaxaca. Such interaction seems to be conditioned by the transient memory of Earth materials subject to the "traumatic" stress produced by seismic waves of the great 2017 (Mw8.2) Tehuantepec earthquake, which strongly disturbed the SSE cycles over a 650 km long segment of the subduction plate interface. Our results imply that seismic hazard in large populated areas is a short-term evolving function of seismotectonic processes that are often observable.

Pseudomonas aeruginosa and lung function decline in patients with bronchiectasis.

OBJECTIVES: The objective of this study was to analyse lung function decline over time in bronchiectasis, along with the factors associated with it. METHODS: Spirometry was measured every year in this observational, prospective study in 849 patients from the Spanish Bronchiectasis Registry (RIBRON). The main outcome was the decline in the rate of forced expiratory volume during the first second (FEV1). To be included in this study, patients needed a baseline assessment and at least one subsequent assessment. FEV1 decline was analysed using a mixed-effects linear regression model adjusted for clinically significant variables. RESULTS: We recruited 849 bronchiectasis patients with at least two annual lung function measurements (follow-up range 1-4 years). A total of 2262 lung function tests were performed (mean 2.66 per patient, range 2-5). Mean baseline FEV1 was 1.78 L (standard deviation (SD) 0.76; 71.3% predicted). Mean age was 69.1 (SD 15.4) years; 543 (64% women. The adjusted rates of FEV1 decline were -0.98% predicted/year (95% confidence interval (CI) -2.41 to -0.69) and -31.6 (95% CI -44.4 to -18.8) mL. The annual FEV1 decline was faster in those patients with chronic bronchial infection by Pseudomonas aeruginosa (-1.37% (52.1 mL) vs -0.37% (-24.6 mL); p < 0.001), greater age, increased number of severe exacerbations in the previous year and higher baseline FEV1 value. DISCUSSION: In patients with bronchiectasis, the annual rate of FEV1 decline was -31.6 mL/year and it was faster in older patients and those with chronic bronchial infection by P. aeruginosa, increased number of previous severe exacerbations and higher baseline FEV1 value.

Puesta al día en la miastenia gravis / An update on myasthenia gravis

La miastenia gravis es el trastorno más común dentro de las enfermedades que afectan a la transmisión neuromuscular. Actualmente es uno de los trastornos autoinmunes mejor definidos y entendidos. Esta se caracteriza por debilidad y fatiga de forma fluctuante y en combinación variable de los músculos oculares, funciones bulbares, de las extremidades y de los músculos respiratorios. Estos síntomas son el resultado de un ataque inmunológico contra la membrana postsináptica de la unión neuromuscular. El diagnóstico de la miastenia gravis depende tanto de pruebas clínicas como serológicas. Es una enfermedad que puede ser controlada de forma efectiva con las distintas líneas terapéuticas actuales, incluso logrando la remisión de esta. A continuación, presentamos una actualización de esta interesante enfermedad

Myasthenia gravis is one of the most common disorders that affect neuromuscular transmission. It is currently one of the most understood and characterised autoimmune disorders Its typical symptoms are fluctuating weakness and fatigue that affects a combination of ocular muscles, bulbar functions, as well as limb and respiratory muscles, which are due to an immune attack against the postsynaptic membrane of the neuromuscular junction. The diagnosis of myasthenia gravis is based on clinical and serological test. It is a disease that can be effectively controlled with the current therapeutic lines, even achieving a complete remission. An update of this interesting disorder is now presented

Preclinical evaluation of the effects on the gastrointestinal tract of the antineoplastic drug vincristine repeatedly administered to rats.

BACKGROUND: Vincristine is a commonly used chemotherapeutic agent. It is associated with undesirable digestive side effects. However, the impact of vincristine on gastrointestinal structure and motility or its long-term effects have not been deeply studied in animal models. This could be useful in order to develop therapeutic or preventive strategies for cancer patients. The aim of this study was to analyze such effects. METHODS: Rats received saline or vincristine (0.1 mg kg-1 , ip) daily for 10 days. Evaluations were performed during treatment and 2-6 weeks after. Somatic mechano-sensitivity was assessed using von Frey hairs. Gastrointestinal motor function was studied by means of radiographic still images and colonic propulsion of fecal pellets using fluoroscopy videos. Histological assessment of the gut morphology and immunohistochemistry for HuC/D and nNOS were performed in whole-mount myenteric plexus preparations. KEY RESULTS: Peripheral sensitivity was increased in animals treated with vincristine and did not subside 2 weeks after treatment finalization. Vincristine treatment inhibited gastrointestinal motility although this was recovered to normal values with time. Damage in the digestive wall after vincristine treatment was greater in the ileum than in the colon. Villi shortening (in ileum) and large inflammatory nodules still remained 2 weeks after treatment finalization. Finally, the proportion of nNOS-immunoreactive neurons was increased with vincristine and continued to be increased 2 weeks after treatment finalization. CONCLUSIONS AND INFERENCES: Vincristine alters gastrointestinal motility, peripheral sensitivity and mucosal architecture. Vincristine-induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long-lasting.

Flagellated protozoa detected in Dermatophagoides by light microscopy

House dust mites (HDM) are arthropods of medical importance due to their relationship with allergic diseases. House dust provides a detrital habitat for these organisms, in which human skin scales are a primary food source. For digestion, wall gut cells elaborate potent proteases. Nevertheless, the observation of flagellated protozoa in intestinal extracts of HDM by light microscopy might contribute to digestive processes in mites, opening a new avenue of research regarding the ecological interactions between mites and these microorganisms in the utilisation of such substrates, as well as with regard to allergic diseases

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[An update on myasthenia gravis]. / Puesta al día en la miastenia gravis.

Myasthenia gravis is one of the most common disorders that affect neuromuscular transmission. It is currently one of the most understood and characterised autoimmune disorders Its typical symptoms are fluctuating weakness and fatigue that affects a combination of ocular muscles, bulbar functions, as well as limb and respiratory muscles, which are due to an immune attack against the postsynaptic membrane of the neuromuscular junction. The diagnosis of myasthenia gravis is based on clinical and serological test. It is a disease that can be effectively controlled with the current therapeutic lines, even achieving a complete remission. An update of this interesting disorder is now presented.

Flagellated protozoa detected in Dermatophagoides by light microscopy.

House dust mites (HDM) are arthropods of medical importance due to their relationship with allergic diseases. House dust provides a detrital habitat for these organisms, in which human skin scales are a primary food source. For digestion, wall gut cells elaborate potent proteases. Nevertheless, the observation of flagellated protozoa in intestinal extracts of HDM by light microscopy might contribute to digestive processes in mites, opening a new avenue of research regarding the ecological interactions between mites and these microorganisms in the utilisation of such substrates, as well as with regard to allergic diseases.

Caracterización fluoroscópica en rata de la dismotilidad colónica asociada a tratamiento con morfina / Fluoroscopic characterization of colonic dysmotility in rat associated with morphine treatment

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Predicting high risk of exacerbations in bronchiectasis: the E-FACED score.

BACKGROUND: Although the FACED score has demonstrated a great prognostic capacity in bronchiectasis, it does not include the number or severity of exacerbations as a separate variable, which is important in the natural history of these patients. OBJECTIVE: Construction and external validation of a new index, the E-FACED, to evaluate the predictive capacity of exacerbations and mortality. METHODS: The new score was constructed on the basis of the complete cohort for the construction of the original FACED score, while the external validation was undertaken with six cohorts from three countries (Brazil, Argentina, and Chile). The main outcome was the number of annual exacerbations/hospitalizations, with all-cause and respiratory-related deaths as the secondary outcomes. A statistical evaluation comprised the relative weight and ideal cut-off point for the number or severity of the exacerbations and was incorporated into the FACED score (E-FACED). The results obtained after the application of FACED and E-FACED were compared in both the cohorts. RESULTS: A total of 1,470 patients with bronchiectasis (819 from the construction cohorts and 651 from the external validation cohorts) were followed up for 5 years after diagnosis. The best cut-off point was at least two exacerbations in the previous year (two additional points), meaning that the E-FACED has nine points of growing severity. E-FACED presented an excellent prognostic capacity for exacerbations (areas under the receiver operating characteristic curve: 0.82 for at least two exacerbations in 1 year and 0.87 for at least one hospitalization in 1 year) that was statistically better than that of the FACED score (0.72 and 0.78, P<0.05, respectively). The predictive capacities for all-cause and respiratory mortality were 0.87 and 0.86, respectively, with both being similar to those of the FACED. CONCLUSION: E-FACED score significantly increases the FACED capacity to predict future yearly exacerbations while maintaining the score's simplicity and prognostic capacity for death.

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats.

BACKGROUND: E-52862 (S1RA, 4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl]-morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E-52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model. METHODS: Mechanical and thermal response thresholds were tested on 7-, 13-, 14- and 15-week-old ZDF rats treated with saline or with E-52862 acutely administered on week 13, followed by sub-chronic administration (14 days). Axonal peripheral activity (skin-saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15-week-old ZDF rats treated with saline or E-52862 and in LEAN rats. RESULTS: Zucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single-dose and sub-chronic E-52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E-52862 treatment increased the mean mechanical threshold (77.3 ± 21 mN vs. 19.6 ± 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 ± 36.5 vs. 352.8 ± 41.4 spikes) or by repeated mechanical supra-threshold steps (39.4 ± 1.4 vs. 83.5 ± 0.9). E-52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed. CONCLUSIONS: E-52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat. SIGNIFICANCE: Blockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients. WHAT DOES THIS STUDY ADD?: This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats. The methodology includes behavioural evidences, electrophysiological data and vascular-isolated models.

May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat.

BACKGROUND: The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. METHODS: Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg-1 injection-1 , 1 injection day-1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg-1 injection-1 , cumulative dose of 300 mg kg-1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. KEY RESULTS: As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. CONCLUSIONS AND INFERENCES: 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.

Prevalence and factors associated with nontuberculous mycobacteria in non-cystic fibrosis bronchiectasis: a multicenter observational study.

BACKGROUND: Data on the prevalence of and factors associated with nontuberculous mycobacteria (NTM) in patients with non-cystic fibrosis (CF) bronchiectasis are limited. Our aim was to determine the prevalence and factors associated with isolation of NTM in this population. METHODS: We performed a multicenter observational study of historical cohorts comprising consecutive patients with non-CF bronchiectasis and at least 2 sputum samples cultured for mycobacteria over a period of 5 years. RESULTS: The study population included 218 adult patients (61.9 % women) with a mean (SD) age of 55.7 (16) years and a mean (SD) of 5.1 (3.3) cultures/patient. NTM was isolated from sputum in 18 patients (8.3 %). Of these, 5 patients (28 %) met the American Thoracic Society criteria for NTM disease. Mycobacterium avium complex was the most frequently isolated microorganism (9 patients, 4.1 %). The variables independently associated with isolation of NTM were FVC ≥ 75 % predicted (OR, 4.84; 95 % CI 1.47 to 15.9; p < 0.05), age ≥ 50 years (OR, 4.74; 95 % CI 1.25 to 17.97; p < 0.05), and body mass index (BMI) ≤ 23 kg/m(2) (OR, 2.97; 95 % CI 1.03-8.58; p < 0.05). Patients with these three characteristics had a 40 % probability of having at least one isolation of NMT. CONCLUSIONS: A significant number of patients with non-CF bronchiectasis are positive for the isolation of NTM. M. avium complex is the most frequently isolated mycobacteria. FVC ≥ 75 % predicted, age ≥ 50 years, and a BMI ≤ 23 kg/m(2) were independently associated with the presence of NTM in patients with non-CF bronchiectasis.