Utilidad en la práctica clínica de la determinación de eosinófilos en el esputo inducido del paciente con asma grave / Usefulness in clinical practice of the determination of eosinophils in the induced sputum of patients with severe asthma

En los últimos años, la determinación demarcadores inflamatorios ha cobrado importancia. Los eosinófilos en el esputo inducido son un ejemplo de ello en el caso del asma grave. Objetivo: Valorar la eosinofilia en esputo como marcador de exacerbaciones, control de la enfermedad y decisión terapéutica. Determinar un punto de corte que indique un peor control del asma. Metodología: Estudio descriptivo prospectivo de serie de casos de asma grave eosinofílico, a los que se le realizó una prueba de esputo inducido, cuantificando el porcentaje de eosinófilos.Resultados: Se estudiaron 59 pacientes, con edad media de 51,55 ± 13,5 años. La mayoría con Índice de Masa Corporal (IMC) > 25. Un 65% fueron mujeres. Respecto a la función pulmonar, lo más frecuente fue la obstrucción moderada y el 68,4% algún biológico. La media de eosinófilos en sangre fue 333,62 ± 475 y en el esputo 7,94 ± 11,43%. Se logró establecer un punto de corte del 4% en el nivel de eosinófilos, relacionado con variables clínicas de control de enfermedad (tandas de corticoides y agudizaciones) para definir peor control (p = 0,013 y 0,033). Fue más significativo en tratados con biológicos. Supuso cambios terapéuticos en el 62,3% y al año una mejora en el ACT de 2,65 puntos. Se estableció correlación entre FeNO y eosinófilos en esputo (coef Pearson -0,280; p = 0,033).Conclusiones: El contaje de eosinófilos en el esputo inducido podría ser un marcador de utilidad en la valoración del control del asma grave eosinofílico y en la toma de decisiones.

In recent years, the determination of inflammatory markers has gained importance.Eosinophils in induced sputum are an example of this in severe asthma. Objetive: Assess sputum eosinophilia as a marker of exacerbations, disease control and therapeutic decision. Determine a cut-off point that indicates worse asthma control. Methodology: Prospective descriptive study of a series of cases of severe eosinophilic asthma, who underwent an induced sputum test, quantifying the percentage of eosinophils. Results: 59 patients were studied, with a mean age of 51.55 ± 13.5 years. The majority had a Body Mass Index (BMI) > 25. 65% were women. Regarding lung function, the most frequent was moderate obstruction and 68.4% some biological. The mean number of eosinophils in blood was 333.62 ± 475 and in sputum 7.94 ± 11.43%. It was possible to establish a cut-off point of 4% in the level of eosinophils, related to clinical variables of disease control (courses of corticosteroids and exacerbations) to define worse control (p = 0.013 and 0.033). It was more significant in those treated with biologicals. It involved therapeutic changes in 62.3% and meant an improvement in the ACT of 2.65 points after one year. A correlation was established between FeNO and sputum eosinophils (Pearson coefficient -0.280; p = 0.033). Conclusions: Eosinophil count in induced sputum could be a useful marker in assessing control of severe eosinophilic asthma and in decision making. (AU)

Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Calciphylaxis in uraemic and nonuraemic settings: clinical risk factors and histopathological findings.

BACKGROUND: Calciphylaxis is a life-threatening cutaneous ulcerative/necrotic disease characterized by vascular calcification/occlusion. It occurs most commonly in end-stage kidney disease (ESKD), known as uraemic calciphylaxis (UC) but can also occur in patients with chronic kidney disease (CKD) and normal kidney function (nonuraemic calciphylaxis; NUC). There are few large series of NUC in the literature. AIM: To compare the clinicopathological features of UC and NUC. METHODS: We retrospectively compared the clinicopathological features of 35 patients with NUC during the period 2010-2020 with those of 53 patients with UC (control group). Cases were classified as NUC in the absence of all of the following: ESKD, significant CKD (defined as serum creatinine > 3 mg/dL or creatinine clearance < 15 mL/min) and acute kidney injury requiring kidney replacement therapy or kidney transplantation. RESULTS: NUC represented 40% of the total cases, and there was a higher number of women (P < 0.01) and a higher median body mass index (P = 0.06) compared with the control UC group. Elevated parathyroid hormone was present in 44% of patients with NUC. Most of the tested patients were positive for lupus anticoagulants (56%). NUC biopsies showed a higher rate of extravascular calcium deposits (73% vs. 47%, P = 0.03). Dermal reactive vascular proliferation was the most common dermal change (32%). CONCLUSIONS: NUC is more common than previously reported and shows a higher predilection for obese postmenopausal women. Undiagnosed hyperparathyroidism shows a possible association with NUC. Lupus anticoagulants were positive in most patients. NUC biopsies are more likely than UC biopsies to display extravascular calcium deposition.

Depression and anxiety in Malaysian population during third wave of the COVID-19 pandemic.

INTRODUCTION: The outbreak of coronavirus posits deleterious consequences on global healthcare system while affecting human life in every aspect. Despite several measures undertaken to limit the socio-economic effect of coronavirus, various challenges remain pervasive, and one such challenge is mental health, particularly depression and anxiety. Therefore, this study examines the prevalence and determinants of depression and anxiety in Malaysian population during third wave of COVID-19. METHODS: A cross-sectional online survey was carried out via social media platforms and 1544 Malaysians were selected. The level of depression was assessed by Patient Health Questionnaires (PHQ-9) and scored accordingly for categorization. Zung's Self-Rating Anxiety Scale (SAS) was used as a self-assessment survey to quantify the level of anxiety of persons experiencing anxiety-related symptoms. Percentage distribution and logistic regression analysis were used in the data analysis. RESULTS: Results showed that one-fourth (25.1%) of the participants had severe depressive symptoms. Almost one-sixth (18.7%) had mild depressive symptoms and one-third (34.1%) had mild to moderate anxiety symptoms. Age, gender, and friends infected with virus were the three important predictors of depression and anxiety. The odds of having depression (OR = 1.44; C·I. = 1.32-1.62) and anxiety (OR = 1.36; C·I. = 1.27-1.47) were significantly higher among females than in males. CONCLUSION: A significant proportion of the study participants were facing mild to severe depression and anxiety symptoms which is very alarming as the pandemic is still now increasing across the country. Immediate interventions including community counselling programmes, TV and social media campaigns are urgently needed to reduce the psychological stress among the Malaysian population.

Intravenous immunoglobulin is an effective treatment for refractory cutaneous dermatomyositis.

BACKGROUND: Cutaneous dermatomyositis (DM) is often refractory to multiple systemic medications, suggesting a need for effective alternative treatments. AIM: To investigate the effects of intravenous immunoglobulin (IVIG) on patients with refractory cutaneous DM. METHODS: This was a retrospective review of 42 patients treated with IVIG for refractory cutaneous DM at our institution with clinical data available at DM diagnosis. IVIG was initiated for refractory cutaneous DM alone (n = 15) or refractory cutaneous and muscle/lung disease (n = 27) in patients with various DM subtypes. RESULTS: Overall, 83% of patients had cutaneous DM improvement, including 87% treated for refractory skin disease alone and 81% treated for refractory skin/muscle/lung disease. Cutaneous DM improvement occurred regardless of DM subtype, and was observed after a mean of 1.82 ± 1.38 IVIG cycles. No statistically significant clinical predictors of IVIG response or lack of response were detected. IVIG use resulted in decreased systemic glucocorticoid exposure with or without a decrease in steroid-sparing immunosuppressive medications in 80% of patients. This study is limited by its retrospective nature and lack of objective cutaneous DM activity assessment. CONCLUSION: Use of IVIG resulted in improvement of refractory cutaneous DM in the vast majority of patients relatively soon after initiation and regardless of DM subtype or clinical manifestations. Additionally, IVIG allowed decrease or discontinuation of immunosuppressive medications in 80% of patients. These findings suggest that IVIG can be a clinically efficacious and cost-effective treatment for refractory cutaneous DM and warrants prospective study.

Revisão sistemática de pesquisas sobre eficácia coletiva docente / Systematic review on researches about collective teacher efficacy

A eficácia coletiva docente é a percepção compartilhada pelos professores sobre a capacidade do corpodocentede organizar e executar ações necessárias a um efeito positivo no desempenho acadêmico dosalunos. Este artigo tem o objetivo de construir um panorama das pesquisas sobre eficácia coletiva deprofessores, analisando seus principais resultados. Para tanto, foram realizadas buscas de artigospublicados entre 2000 e 201 3, na base de dados Portal de Periódicos Capes. Os resultados indicam que aeficácia coletiva de professores está diretamente relacionada ao desempenho acadêmico dos alunos.Notou-se ainda que outras variáveis podem influenciar as crenças coletivas, tais como a autoeficácia e asituação socioeconômicada escola(AU)

Sarcoidosis following successful treatment of pemphigus vulgaris with rituximab: a rituximab-induced reaction further supporting B-cell contribution to sarcoidosis pathogenesis?

The anti-CD20 peripheral B-cell depleting monoclonal antibody, rituximab, has been shown to be a safe and effective treatment for refractory pemphigus vulgaris (PV), a potentially fatal autoimmune blistering disease. We report a patient who developed skin nodules and arthralgias following successful treatment of refractory PV with rituximab. Clinical, serological and histological findings were consistent with a diagnosis of sarcoidosis. The nodules promptly responded to treatment with corticosteroids, and resolved without recurrence when the medication was tapered several months later. The temporal onset of sarcoidosis following treatment with rituximab and the eventual resolution, coupled with the remarkable similarities between the B-cell immunological environment expected in our patient during the post-rituximab period and the immunological environment described in patients with idiopathic sarcoidosis, strongly implicates exposure to rituximab as the trigger for sarcoidosis development in our patient. We propose that rituximab-induced sarcoidal granulomas may be a rare adverse effect of treatment with this medication, providing further support for an important role of B cells in the pathogenesis of sarcoidosis. With better understanding of the circumstances surrounding sarcoidosis development following rituximab administration, this medication could potentially be used to induce sarcoidosis in animal research models to study the immunopathogenesis of this disease.

Clinically amyopathic dermatomyositis: clinical features, response to medications and malignancy-associated risk factors in a specific tertiary-care-centre cohort.

BACKGROUND: Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) characterized by the typical DM cutaneous manifestations but without myositis. There is a relative paucity of characterized cases of CADM in the peer-reviewed medical literature. OBJECTIVES: To characterize the clinical features, response to medications and malignancy-associated risk factors of patients with CADM with available baseline data seen at a single tertiary-care centre. METHODS: A retrospective review was undertaken of 44 patients with CADM with available clinical and serological data prior to onset of treatment. RESULTS: Patients with CADM comprised 18% of all patients with DM with baseline data available at our institution. Although the majority of patients showed improvement with the first prescribed treatment, most required additional medications to control their CADM. Six of 44 patients had an associated malignancy. Photosensitivity and periungual erythema were found to be associated with absence of malignancy (P = 0·03 and P = 0·02, respectively). Patients with malignancy-associated CADM were found to be more likely to have a cutaneous response with the first prescribed treatment than patients without malignancy (P = 0·04). CONCLUSIONS: CADM represents a significant subset of the DM population. As with classic DM, the cutaneous manifestations of CADM often represent a therapeutic challenge. A subset of patients with CADM has underlying malignancies, and these may differ from those typically associated with classic DM. Differences in serological abnormalities, cutaneous manifestations and response to first treatment among patients with CADM with and without malignancy were found, and suggest distinct pathophysiologies among CADM subsets. Characterization of this cohort expands the knowledge about this unique DM subset.

Impact of smoking on response to systemic treatment in patients with psoriasis: a retrospective case-control study.

BACKGROUND: Smoking is a well-established risk factor for developing psoriasis and is associated with development of more severe disease. Smoking cessation does not appear to result in clinical improvement of psoriasis. Whether smoking in patients with psoriasis impacts response to systemic therapy is unknown. OBJECTIVES: To determine whether smokers with psoriasis with or without psoriatic arthritis respond to systemic agents as well as nonsmokers do. METHODS: We performed a retrospective review of patients with moderate-to-severe psoriasis with or without psoriatic arthritis seen at our institution, who were either active smokers or nonsmokers, and calculated changes in Physician's Global Assessment (PGA) scores after 3-16 months of systemic treatment. We also calculated the average number of systemic treatments tried per patient. RESULTS: Sixty-six patients (46 nonsmokers, 20 smokers) met our inclusion criteria. Changes in PGA scores between baseline and 3-16 months after initiation of systemic treatment did not significantly differ between smokers and nonsmokers, nor did the average number of systemic treatments tried per patient. We detected a borderline significant trend in the percentage of patients who had significant outcomes after treatment, with a higher percentage of patients smoking < 10 cigarettes daily achieving target PGA scores compared with those smoking > 10 cigarettes daily. Limitations of our study include its retrospective nature and the relatively small number of patients meeting our inclusion criteria. CONCLUSIONS: In our retrospectively studied cohort, smoking did not affect response to systemic treatment in patients with psoriasis. A prospective study examining the complex relationship between smoking, psoriasis and response to systemic therapy is warranted to explore this association better.

Lack of adrenomedullin, but not complement factor H, results in larger infarct size and more extensive brain damage in a focal ischemia model.

Adrenomedullin (AM) and its binding protein, complement factor H (FH), are expressed throughout the brain. In this study we used a brain-specific conditional knockout for AM and a complete knockout for FH to investigate the effect of these molecules on the pathophysiology of stroke. Following 48 h of middle cerebral artery permanent occlusion, there was a statistically significant infarct size increase in animals lacking AM when compared to their wild type littermates. In contrast, lack of FH did not affect infarct volume. To investigate some of the mechanisms by which lack of AM may augment brain damage, markers of nitrosative stress, apoptosis, and autophagy were studied at the mRNA and protein levels. There was a significant increase of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP9), fractin, and Beclin-1 in the peri-infarct area of AM-deficient mice when compared to their wild type counterparts and to contralateral and sham-operated controls. These data suggest that AM exerts a neuroprotective action in the brain and that this protection may be mediated by regulation of iNOS, matrix metalloproteases, and inflammatory mediators. In the future, substances that increase AM actions in the central nervous system may be used as potential neuroprotective agents in stroke.

Nitric oxide: target for therapeutic strategies in Alzheimer's disease.

Alzheimer's disease (AD) constitutes a progressive neurodegenerative disorder and the main cause of dementia. Numerous studies have focused on the pathogenic mechanism of AD to cure or prevent this devastating disease. But, despite recent advances, our understanding on the pathophysiology of this genetically complex and heterogeneous disorder is rather limited and treatment of the disease consists of medications to control the symptoms. Acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are the only available treatments recommended to manage the cognitive deficits caused by the disease. Therefore, the production of new drugs that may be able to cure the underlying cause of this chronic disease, not just the symptoms, is a matter of clinical interest. There is data implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aß) action, giving rise to elevated levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease. Reducing Aß production and the cholinergic deficit is a goal in the treatment of AD. In addition, a possible way to delay the progression of the illness must include a rationale design of enzyme inhibitors, subtype selective, targeting NOS isoforms implicated in damage to brain cells in AD. We are now presenting an overview regarding approved drugs for AD treatment and substances that although are not in use for the treatment of AD, including NOS inhibitors, may represent useful tools to unravel the pathophysiologic enigma of AD.

High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease.

Cancer and Alzheimer's disease (AD) are commonly found among elderly patients. Chronic inflammation is the characteristic of both diseases. Amyloid-beta peptide is the main inducer of inflammation in AD. Moreover, chronic inflammation promotes cancer, suggesting that AD patients may be more prone to develop cancer than non-demented people. To test this hypothesis, we injected the carcinogen 20-methylcholanthrene in the brain of transgenic mice overexpressing the mutant forms of amyloid precursor protein (APP) and presenilin 1 (PS1), as a model of AD, and their wild-type (WT) littermates. Mutant mice developed tumors faster and with higher incidence than their WT counterparts. Expression of the inflammatory markers interleukin (IL)-1alpha, IL-1beta, IL-6, IP-10 and tumor necrosis factor-alpha (TNF-alpha) was measured in AD and WT mice of 3 and 12 months of age that had not been exposed to the carcinogen. These cytokines were elevated in older AD mice, indicating the existence of a highly inflammatory milieu in these animals. We also found elevated expression of a mutated form of p53 in older AD mice, suggesting an alternative mechanism for the predisposition of AD brains to develop brain tumors. Clinical studies reporting comorbidity of AD and brain cancer are needed to understand whether our observations hold true for humans.

Whole-body periodic acceleration reduces brain damage in a focal ischemia model.

Stroke is the second most common cause of death and major cause of disability worldwide. Actual treatment involves surgery and/or thrombolytic drugs, but there is an urgent need for new approaches. Periodic acceleration, a rocking headward to footward movement of the whole body, is a non-invasive method to induce pulsatile shear stress on the vascular endothelium eliciting an enhanced production and secretion of endothelium-derived products such as nitric oxide, prostacyclin, prostaglandin E2, tissue plasminogen activator (tPA), and adrenomedullin. All these products have been shown to protect the brain from ischemic injuries. A rat model of focal brain ischemia was treated with application of periodic acceleration for 3 h immediately after the onset of ischemia. Controls remained static for the same period of time. Brain damage was assessed by magnetic resonance imaging (MRI) and biochemical markers. A significant reduction in brain damage was observed, 7 days post-ischemia, in rocked rats when compared with the static controls, through MRI. Furthermore, rocked animals had significantly lower levels of Beclin 1 and fractin than their static counterparts, and some isoforms of nitric oxide synthase were regulated by periodic acceleration. Our results show that periodic acceleration may provide a novel, affordable, non-invasive therapeutic option for the treatment of stroke.

Effects of acute hypobaric hypoxia on the nitric oxide system of the rat cerebral cortex: Protective role of nitric oxide inhibitors.

Exposure to hypobaric hypoxia produces neuropsychological disorders. The brain nitrergic system was investigated following hypobaric hypoxia in the presence or absence of nitric oxide synthase (NOS) inhibitors. Adult rats were exposed to a simulated altitude of 8325 m (27,000 ft) for 7 h and killed after 0, 1, 3, 5, and 10 days of recovery. In addition to normobaric controls, three experimental groups were studied: i) subjected to hypobaric hypoxia without inhibitors; ii) subjected to hypobaric hypoxia and treated with 7-nitroindazole; iii) subjected to hypobaric hypoxia and treated with N(omega)-nitro-l-arginine methyl ester (l-NAME). Cerebral cortex was assayed by immunohistochemistry, Western blotting, and enzymatic assays. In animals subjected to hypobaric hypoxia without inhibitors, there was an increase in neuronal nitric oxide synthase (nNOS) immunoreactivity and Ca(2+)-dependent NOS activity from 0 to 1 days of reoxygenation. In these animals, inducible nitric oxide synthase (iNOS) expression and Ca(2+)-independent activity were undetectable, but nitrotyrosine immunoreactivity was found in some neurons. Administration of either inhibitor prevented the increase in nNOS immunoreactivity and enzymatic activity provoked by hypobaric hypoxia. Concomitantly, nitrotyrosine immunoreactivity decreased progressively. In conclusion, activation of the nitrergic system constitutes a cortical response to hypobaric hypoxia and the administration of NOS inhibitors could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia.