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INTRODUCTION: Diabetes prevalence is increasing rapidly; estimates from the International Diabetes Federation put the number at 381 million people have diabetes. Hypoglycemia is a commonly encountered complication in diabetic patients, which, in the short-term, can lead to mortality and, in the long-term, precludes maintenance of euglycemic control. Over 65.2 % of patients have reported at least one incidence of severe and nonsevere hypoglycemia when on oral hypoglycemic agents (OHA) at an annual crude incidence density of 35.1 events per year per person. Insulin more commonly causes hypoglycemia than OHA. However, this study was done with the aim of studying the hypoglycemia specifically caused by OHAs-clinical profile of patients, medications causing hypoglycemia, and the outcome. MATERIALS AND METHODS: This prospective observational study was conducted in the Department of Medicine at a tertiary care hospital in Western Maharashtra. Data was collected over a period of 18 months from Indoor patients on admission having hypoglycemic symptoms with strip blood sugar levels of <70 and on OHAs. Patients on insulin were excluded from the study. RESULTS: There were 60 patients with hypoglycemia with a mean age of 53.65 years and a higher incidence of hypoglycemia in females, 35 (58.3%) compared to males. There was a statistically significant difference between outcome (i.e., discharged or death) and urine protein-creatinine ratio (UPCR), a deranged liver function, that is, serum albumin, serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase, and serum glutamic pyruvic transaminase (SGPT)/alanine transaminase (p < 0.05). However, there was no statistically significant difference between outcome (discharged or death) and mean age, gender, mean duration of diabetes mellitus (DM), GCS scoring, and drug type of study subjects (p > 0.05). CONCLUSION: The risk factors for hypoglycemia were middle-aged patients. Females are at higher risk of hypoglycemia than men. Hypoglycemia due to OHAs is known to have a recurrence of hypoglycemia due to the long half-life of the drug; however, patients who were hospitalized were well monitored and did not have any recurrence of hypoglycemia. Deranged liver function or raised UPCR have high mortality after OHA-induced hypoglycemia.
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Diabetes Mellitus Tipo 2 , Hipoglicemia , Hipoglicemiantes , Centros de Atenção Terciária , Humanos , Masculino , Feminino , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Pessoa de Meia-Idade , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Estudos Prospectivos , Administração Oral , Adulto , Índia/epidemiologia , Idoso , IncidênciaRESUMO
INTRODUCTION: Swallowing dysfunction is common after acute stroke. It increases the risk of aspiration pneumonia and affects nutrition. In this study, we aimed to determine the incidence of dysphagia after a single episode of acute stroke in conscious patients and the factors predisposing the patient to dysphagia. We also assessed the course of dysphagia over a period of 8 weeks after stroke. MATERIALS AND METHODS: It was a prospective observational study. We included patients of acute stroke (ischemic, hemorrhagic, lacunar, anterior, as well as posterior circulation) with Glasgow Coma Scale (GCS) of ≥12; within 48 hours of onset. Patients were screened for dysphagia by the Gugging Swallowing Screen (GUSS) screening tool; then assessed in detail using by Mann Assessment of Swallowing Ability (MASA) scoring scale. Patients with dysphagia were reassessed at 7 days and at 8 weeks after stroke for the presence and severity of dysphagia. RESULTS: We included 150 patients. The incidence of dysphagia at day 1, day 7, and 8 weeks was 42, 24, and 9%, respectively. The proportion of patients with moderate and severe dysphagia also decreased during a follow-up period of 8 weeks from 18 to 3% and from 20 to 6%, respectively. The incidence of dysphagia was significantly greater in moderately severe stroke [National Institutes of Health Stroke Scale (NIHSS 5-14)] than in mild stroke (NIHSS 1-4). It was also more common in total anterior circulation infarct (TACI) than partial anterior circulation or lacunar infarct (LacI) and in posterior circulation strokes than the strokes involving anterior circulation. Patients with dysphagia had longer hospital stays (7.29 ± 3.4 days vs 3.62 ± 1.5 days, p = 0.001) and higher mean modified Rankin score at discharge (3.45 vs 2.17, p = 0.001). CONCLUSION: Swallowing dysfunction should be checked in all cases of strokes, including unilateral hemispheric strokes and in fully conscious patients. Swallowing improves with time, but the patient may require feeding assistance in an acute setting. Dysphagia is more common in strokes with higher NIHSS, involving more brain parenchyma and posterior circulation strokes.
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Infarto Miocárdico de Parede Anterior , Transtornos de Deglutição , Acidente Vascular Cerebral , Estados Unidos , Humanos , Deglutição , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Incidência , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , EncéfaloRESUMO
Anemia is a common complication of chronic kidney disease (CKD) that has been classically attributed to inadequate production of endogenous erythropoietin.1 Though there are many other common causes of refractory anemia in CKD like iron deficiency, vitamin B12, and folic acid deficiency, noncompliance to dialysis and erythropoietin therapy rare causes like blood loss, bone marrow failure, infections causing aplastic crisis like CMV, parvovirus B19 should be ruled out. Parvovirus has an extreme tropism for erythroid cells and is an uncommon cause of anemia in patients with CKD on maintenance dialysis (MHD) and on erythropoietin.2 Here we are reporting a rare case of refractory anemia in a patient of CKD on MHD secondary to parvovirus-related aplastic crisis. How to cite this article: Gade K, Londhe C, Pednekar S, et al. A Case of Refractory Anemia in Patient of Chronic Kidney Disease and the Challenges in its Management. J Assoc Physicians India 2023;71(10):94-95.
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Anemia Refratária , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Anemia Refratária/etiologia , Anemia Refratária/terapia , Anemia Refratária/diagnóstico , Anemia Refratária/complicações , Diálise Renal , Masculino , Infecções por Parvoviridae/complicações , Infecções por Parvoviridae/diagnóstico , Eritropoetina/uso terapêutico , Anemia Aplástica/complicações , Anemia Aplástica/terapia , Pessoa de Meia-IdadeRESUMO
BACKGROUND: At 140 million, India has the second largest population of old people in the world, as per the 2011 census.1 The covid 19 pandemic has wreaked havoc in millions of lives. Elderly are especially vulnerable to COVID-19 and experience high morbidity and mortality as a result of immunosenescence. Age is independently linked with mortality, but age alone does not adequately capture the robustness of older adults who are a heterogeneous group. The current research was done in a tertiary healthcare hospital in Maharashtra to understand the clinical profile and factors that affected the outcome of elderly during the second wave of the COVID pandemic. METHOD: This was a single centre retrospective observational study done in a tertiary hospital which was admitting both covid and non-covid patients during the time of this study. All elderly patients admitted with COVID 19 disease in Covid ward and covid ICU (Intensive care unit) were included in the study. Their Demographic details, duration of illness, vital parameters, oxygen saturation, partial pressure of arterial oxygen compared to fraction of inspired oxygen (PaO2-FiO2 ratio) were recorded and also relevant investigations such as complete blood count, kidney function tests, liver function tests, arterial blood gases, chest X-rayand ECG (Electrocardiogram),CT scan of the brain, CSF(cerebrospinal fluid) studies and other tests where relevant were recorded. Inflammatory markers such as C-Reactive Protein (CRP), Ferritin, D-Dimer and Chest CT scan were noted. Clinical profiles and outcomes were noted till discharge or death. RESULTS: Among 231 patients that were included in this study, 81(35%) were female and 150 (65%) were male. Ninety-two patients died (39.8%) while 139 patients (60.2%) survived in our study. Majority of our patients (211;91.3%) presented in category E(pneumonia with respiratory failure) or category F(pneumonia with respiratory failure and multiorgan dysfunction syndrome). Factors which had a major impact on mortality were- a low PaO2-FiO2 ratio on admission, high C-Reactive Protein (CRP) levels, high d-dimer levels, a finding of bilateral ground glass opacities on x-ray, and need for invasive ventilation on admission. CONCLUSIONS: Elderly remain vulnerable to severe consequences of COVID-19 infection owing to the increasing comorbidities and immunosenescence in them. Prolonged oxygen therapy and intensive respiratory rehabilitation are the mainstays of effective management. Given the constant threat of mutating virus, masking, maintaining hand sanitization, vaccination and also caring for our elders while still maintaining social distance are our best bet against a fatal third wave.
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COVID-19 , Insuficiência Respiratória , Idoso , Proteína C-Reativa , Feminino , Humanos , Índia/epidemiologia , Masculino , Oxigênio , Respiração Artificial , SARS-CoV-2 , Centros de Atenção TerciáriaRESUMO
BACKGROUND: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm. METHOD: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26. RESULTS: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation. CONCLUSION: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.
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Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19 , Síndrome da Liberação de Citocina , Hipóxia , Interleucina-6/antagonistas & inibidores , Pneumonia Viral , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/terapia , Ensaios de Uso Compassivo/estatística & dados numéricos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Feminino , Humanos , Hipóxia/etiologia , Hipóxia/terapia , Índia/epidemiologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Respiração Artificial/métodos , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: With a rapidly rising geriatric population, the magnitude of elderly patients requiring intensive care is a major cause of concern. Data on critically ill geriatric patients is scarce, especially in developing countries. AIM AND OBJECTIVE: The aim of the study is to identify the etiology, clinical profile, and outcome in elderly patients admitted to the intensive care unit (ICU) and to predict their survival using the sequential organ failure assessment (SOFA) score. MATERIALS AND METHODS: A prospective observational study was performed over a period of 18 months with analysis of 100 patients admitted to the ICU, above the age of 60 years, with multi-organ dysfunction. The outcome of discharge or death was studied using the SOFA score on admission, on day 2, and the delta SOFA score. RESULTS: In this study of 100 patients, 88% of patients were in the 60-70 years age-group. The number of male and female patients was equal. Seventy percent of patients had comorbidities, of which hypertension was most common. The two most common etiologies were acute febrile illness and pneumonia. The use of mechanical ventilation, inotropic support, and serum creatinine has a significant association with the outcome. The SOFA score at admission did not have a significant association, but the score at 48 hours and delta SOFA score co-related with the outcome of the patients. Sixty-four patients got discharged; thus, there was a survival rate of 64%. CONCLUSION: The SOFA score at 48 hours is the most sensitive predictor of outcome, followed closely by the delta SOFA score, as compared to the SOFA score on admission, for critically ill elderly patients. There is a significant association of use of mechanical ventilation, inotropic support, and serum creatinine with the outcome. HOW TO CITE THIS ARTICLE: Chopra S, Pednekar S, Karnik ND, Londhe C, Pandey D. A Study of the Outcome of Critically Ill Elderly Patients in a Tertiary Care Hospital Using SOFA Score. Indian J Crit Care Med 2021;25(6):655-659.
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RATIONALE: Chronic low-grade inflammation is proposed as the keystone in pathogenesis of metabolic syndrome. The inflammatory biomarker Procalcitonin which is produced by adipose tissue, can serve as a biomarker for insulin resistant state present in metabolic syndrome. OBJECTIVES: To evaluate the association of plasma Procalcitonin (PCT) with components of metabolic syndrome (abdominal obesity, dyslipidemia, hypertension, and hyperglycemia) and with insulin resistance as compared to healthy controls. DESIGN: In this case-control study Plasma Procalcitonin was measured in patients with metabolic syndrome and compared to healthy controls. Its association was investigated with insulin resistance, individual components of metabolic syndrome, cardiovascular complications and microalbuminuria. RESULTS: Plasma Procalcitonin was significantly higher (mean 0.55 ± 0.60 ng/ ml, Median 0.156 ng/ml) in 53 patients with metabolic syndrome (n = 53) as compared to 26 healthy controls (p < 0.001). PCT significantly correlated with level of Insulin Resistance (p< 0.01), Waist Circumference, S. Triglycerides, S. VLDL (p < 0.05), fasting blood glucose (p < 0.01) and inversely with S.HDL (p< 0.05). PCT was significantly higher in patients with cardiovascular complication (n=16/53, z = -7.137) and in those with microalbuminuria (n=18/53, z = - 7.265) as compared to cases without complications. CONCLUSION: Raised plasma procalcitonin levels in the normal range are associated with insulin resistance and components of the metabolic syndrome (abdominal obesity, hypertriglyceridemia, high VLDL, low HDL and hyperglycemia), suggesting its role as a promising biomarker.
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Biomarcadores/sangue , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Pró-Calcitonina/sangue , Glicemia , Índice de Massa Corporal , Estudos de Casos e Controles , Humanos , Índia , ObesidadeAssuntos
Doenças Ósseas Metabólicas , Idoso , Densidade Óssea , Humanos , Fatores de Risco , UltrassonografiaRESUMO
Integrins are critical for platelet adhesion and aggregation during arterial thrombosis and hemostasis. Although the platelet-specific αIIbß3 integrin is known to be crucial for these processes, the in vivo role of ß1 integrins is a matter of debate. Here we demonstrate that mice expressing reduced levels of ß1 integrins or an activation-deficient ß1 integrin show strongly reduced platelet adhesion to collagen in vitro and in a carotis ligation model in vivo. Interestingly, hypomorphic mice expressing only 3% of ß1 integrins on platelets show normal bleeding times despite reduced platelet adhesion. The residual 3% of ß1 integrins are able to trigger intracellular signals driving Rac-1-dependent granule release required for platelet aggregation and hemostasis. Our findings support a model, in which platelet ß1 integrins serve as an important signaling receptor rather than an adhesion receptor in vivo and therefore promote ß1 integrins as a promising and so far clinically unemployed antithrombotic target.
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Plaquetas/metabolismo , Hemostasia/fisiologia , Integrina beta1/metabolismo , Vesículas Secretórias/metabolismo , Transdução de Sinais/fisiologia , Actinas/metabolismo , Animais , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Integrina beta1/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuropeptídeos/metabolismo , Adesividade Plaquetária/fisiologia , Ligação Proteica/fisiologia , Trombose/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
We present the case of 36 yrs old female who presented with acute onset quadriparesis who was subsequently diagnosed to have Sjogrens syndrome with distal RTA with hypothyroidism.
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Acidose Tubular Renal/etiologia , Síndrome de Sjogren/diagnóstico , Adulto , Feminino , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnóstico , Humanos , Hipotireoidismo/etiologia , Quadriplegia/etiologia , Síndrome de Sjogren/complicaçõesRESUMO
In platelets stimulated by thrombin to secrete and aggregate, cofilin is rapidly dephosphorylated leading to its activation. Cofilin by severing existing actin filaments and stimulating F-actin polymerization on newly created barbed ends dynamizes the actin cytoskeleton. We previously found that cofilin dephosphorylation is Ca(2+)-dependent and occurs upstream of degranulation in stimulated platelets. We report now in thrombin-stimulated platelets that Rac1 and class II PAKs (PAK4/5/6) were rapidly (within 5 seconds) activated, whereas PAK1/2 (class I PAKs) phosphorylation was slower. The Rac1-specific inhibitor NSC23766 blocked phosphorylation of class II PAKs, but not PAK1/2. Moreover, inhibition of the Ca(2+)/calmodulin-dependent phosphatase calcineurin inhibited Rac1 activation and class II PAKs phosphorylation. Prevention of Rac1 activation by calcineurin inhibition or NSC23766 also blocked cofilin dephosphorylation and platelet granule secretion indicating that a calcineurin/Rac1/class II PAKs pathway regulates cofilin dephosphorylation leading to secretion. We further found that PI3-kinases were activated downstream of Rac1, but were not involved in regulating cofilin dephosphorylation and secretion in thrombin-stimulated platelets. Our study unravels a Ca(2+)-dependent pathway of secretion in stimulated platelets as a signaling pathway linking Rac1 activation to actin dynamics: calcineurin-->Rac1-->class II PAKs-->cofilin activation. We further demonstrate that this pathway is separate and independent of the protein kinase C (PKC) pathway mediating secretion.
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Fatores de Despolimerização de Actina/metabolismo , Plaquetas/metabolismo , Transdução de Sinais , Trombina/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Aminoquinolinas/farmacologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/classificação , Isoenzimas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ativação Plaquetária/efeitos dos fármacos , Proteína Quinase C/metabolismo , Pirimidinas/farmacologia , Quinases Ativadas por p21/classificação , Quinases Ativadas por p21/metabolismo , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidoresRESUMO
Dyskeratosis Congenita (DKC) is a rare progressive bone marrow disorder associated with multi-systemic involvement. It is also characterized by triad of abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Liver cirrhosis and portal hypertension are said to be uncommon among these patients. We hereby report a case of an adult male who presented with pancytopenia, abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Skin biopsies along with clinical features confirmed the case. Imaging studies were reported as suggestive of and portal hypertension. Liver biopsy done but non-conclusive. Patient's one son and one daughter also had similar skin pigmentation.
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Disceratose Congênita/complicações , Disceratose Congênita/diagnóstico , Hipertensão Portal/complicações , Veias Jugulares/diagnóstico por imagem , Adulto , Biópsia , Humanos , Hipertensão Portal/diagnóstico , Leucoplasia Oral/complicações , Leucoplasia Oral/patologia , Fígado/patologia , Masculino , Doenças da Unha/complicações , Pancitopenia/complicações , Pele/patologia , UltrassonografiaRESUMO
Here we report a case of VACTERL ASSOCIATION in a twenty three years old married female patient primigravida with 3 months of amenorrhea admitted with history of fever and gastroenteritis along with congenital developmental defects such as scoliosis (V), small ventricular septal defect (C), right sided hemifacial dysmorphic features (right mandibular hypoplasia), small sized right sided kidney (R), bilateral hypoplastic thumb (L). For the diagnosis of VACTERL atleast three out of seven anomalies should be present while our patient had four anomalies.
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Anormalidades Múltiplas/diagnóstico , Cardiopatias Congênitas/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Complicações na Gravidez/diagnóstico , Amenorreia/etiologia , Canal Anal/anormalidades , Canal Anal/patologia , Ecocardiografia , Eletrocardiografia , Esôfago/anormalidades , Esôfago/patologia , Feminino , Cardiopatias Congênitas/patologia , Humanos , Rim/anormalidades , Rim/patologia , Deformidades Congênitas dos Membros/patologia , Gravidez , Complicações na Gravidez/patologia , Segundo Trimestre da Gravidez , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Traqueia/anormalidades , Traqueia/patologia , Resultado do Tratamento , Adulto JovemRESUMO
The synthesis of Cox1, the conserved catalytic-core subunit of Complex IV, a multisubunit machinery of the mitochondrial oxidative phosphorylation (OXPHOS) system under environmental stress, has not been sufficiently addressed. In this study, we show that the putative YihA superfamily GTPase, Mrx8, is a bona fide mitochondrial protein required for Cox1 translation initiation and elongation during suboptimal growth condition at 16°C. Mrx8 was found in a complex with mitochondrial ribosomes, consistent with a role in protein synthesis. Cells expressing mutant Mrx8 predicted to be defective in guanine nucleotide binding and hydrolysis were compromised for robust cellular respiration. We show that the requirement of Pet309 and Mss51 for cellular respiration is not bypassed by overexpression of Mrx8 and vice versa. Consistently the ribosomal association of Mss51 is independent of Mrx8. Significantly, we find that GTPBP8, the human orthologue, complements the loss of cellular respiration in Δmrx8 cells and GTPBP8 localizes to the mitochondria in mammalian cells. This strongly suggests a universal role of the MRX8 family of proteins in regulating mitochondrial function.
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Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Regulação Fúngica da Expressão Gênica/genética , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Ribossomos Mitocondriais/metabolismo , Fosforilação Oxidativa , Biossíntese de Proteínas , RNA Fúngico/metabolismo , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Saccharomyces cerevisiae/metabolismo , Temperatura , Fatores de Transcrição/metabolismoRESUMO
Replication competent vesicular stomatitis virus (VSV) is the basis of a vaccine against Ebola and VSV strains are developed as oncolytic viruses. Both functions depend on the ability of VSV to induce adequate amounts of interferon-α/ß. It is therefore important to understand how VSV triggers interferon responses. VSV activates innate immunity via retinoic acid-inducible gene I (RIG-I), a sensor for viral RNA. Our results show that VSV needs to replicate for a robust interferon response. Analysis of RIG-I-associated RNA identified a copy-back defective-interfering (DI) genome and full-length viral genomes as main trigger of RIG-I. VSV stocks depleted of DI genomes lost most of their interferon-stimulating activity. The remaining full-length genome and leader-N-read-through sequences, however, still triggered RIG-I. Awareness for DI genomes as trigger of innate immune responses will help to standardize DI genome content and to purposefully deplete or use DI genomes as natural adjuvants in VSV-based therapeutics.
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Proteína DEAD-box 58/metabolismo , Genoma Viral , Mutação , Receptores Imunológicos/metabolismo , Estomatite Vesicular/metabolismo , Estomatite Vesicular/virologia , Vírus da Estomatite Vesicular Indiana/fisiologia , Replicação Viral , Animais , Linhagem Celular , Genoma Viral/genética , Genoma Viral/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunomodulação , RNA Viral/genética , RNA Viral/imunologiaRESUMO
CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor-ß (TGF-ß). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-ß receptor 2 (DNR) can simultaneously shield them from TGF-ß. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-ß shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.
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Neoplasias , Humanos , Neoplasias/terapia , Linfócitos T Reguladores , Fator de Crescimento Transformador beta/farmacologiaRESUMO
BACKGROUND: Platelet activation requires rapid remodeling of the actin cytoskeleton which is regulated by small GTP-binding proteins. By using the Rac1-specific inhibitor NSC23766, we have recently found that Rac1 is a central component of a signaling pathway that regulates dephosphorylation and activation of the actin-dynamising protein cofilin, dense and α-granule secretion, and subsequent aggregation of thrombin-stimulated washed platelets. OBJECTIVES: To study whether NSC23766 inhibits stimulus-induced platelet secretion and aggregation in blood. METHODS: Human platelet aggregation and ATP-secretion were measured in hirudin-anticoagulated blood and platelet-rich plasma (PRP) by using multiple electrode aggregometry and the Lumi-aggregometer. Platelet P-selectin expression was quantified by flow cytometry. RESULTS: NSC23766 (300 µM) inhibited TRAP-, collagen-, atherosclerotic plaque-, and ADP-induced platelet aggregation in blood by 95.1%, 93.4%, 92.6%, and 70%, respectively. The IC50 values for inhibition of TRAP-, collagen-, and atherosclerotic plaque-, were 50 ± 18 µM, 64 ± 35 µM, and 50 ± 30 µM NSC23766 (mean ± SD, n = 3-7), respectively. In blood containing RGDS to block integrin αIIbß3-mediated platelet aggregation, NSC23766 (300 µM) completely inhibited P-selectin expression and reduced ATP-secretion after TRAP and collagen stimulation by 73% and 85%, respectively. In ADP-stimulated PRP, NSC23766 almost completely inhibited P-selectin expression, in contrast to aspirin, which was ineffective. Moreover, NSC23766 (300 µM) decreased plaque-stimulated platelet adhesion/aggregate formation under arterial flow conditions (1500s-1) by 72%. CONCLUSIONS: Rac1-mediated signaling plays a central role in secretion-dependent platelet aggregation in blood stimulated by a wide array of platelet agonists including atherosclerotic plaque. By specifically inhibiting platelet secretion, the pharmacological targeting of Rac1 could be an interesting approach in the development of future antiplatelet drugs.
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Trifosfato de Adenosina/metabolismo , Placa Aterosclerótica/patologia , Agregação Plaquetária/efeitos dos fármacos , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/metabolismo , Fosfatase Ácida/metabolismo , Difosfato de Adenosina/farmacologia , Aminoquinolinas/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Colágeno/farmacologia , Humanos , Isoenzimas/metabolismo , Selectina-P/metabolismo , Plasma Rico em Plaquetas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fosfatase Ácida Resistente a Tartarato , Trombose/patologia , Trombose/fisiopatologiaRESUMO
Nephrotic syndrome, though common in children, association of it with Gitelman's syndrome (GS) is a rare occurrence. Very few cases have been reported in the medical literature so far. Here we report a case of nephrotic syndrome with frequent relapses and remissions on intermittent steroid and diuretic therapy. Patient was restarted on steroids and frusemide. Puffiness of face, bipedal edema and oliguria improved but patient developed tingling numbness in both limbs, perioral numbness and carpopedal spasm. On investigation she was found to have proteinuria, metabolic alkalosis, hypokalemia, hypocalcemia, hypomagnesemia and hyperreninemia with normal blood pressure.
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Síndrome de Gitelman/complicações , Síndrome Nefrótica/complicações , Proteinúria/complicações , Alcalose/complicações , Alcalose/tratamento farmacológico , Tratamento Farmacológico , Feminino , Síndrome de Gitelman/tratamento farmacológico , Humanos , Hipocalcemia/complicações , Hipocalcemia/tratamento farmacológico , Hipopotassemia/complicações , Hipopotassemia/tratamento farmacológico , Magnésio/sangue , Síndrome Nefrótica/tratamento farmacológico , Proteinúria/tratamento farmacológico , Renina/sangue , Síndrome , Tetania/complicações , Resultado do Tratamento , Adulto JovemRESUMO
The work includes evaluation of elastic constants of wurtzite Boron nitride (w-BN) at different particle-size (5-40â¯nm) and pressure (0-60â¯GPa) at 300â¯K using potential model approach. Size and pressure dependent thermo-physical and ultrasonic parameters are also calculated using evaluated elastic constants. It is found that the elastic constants, ultrasonic velocities and Debye temperature of nanostructured w-BN enhance with increase in pressure and reduction in particle size. The size variation of thermal relaxation time resembles the dependency of thermal conductivity with size. The thermal conductivity of nanostructured w-BN is found to increase with reduction in nanoparticle size.
RESUMO
Neuronal growth cone filopodia contain guidance receptors and contribute to axon guidance; however, the mechanism by which the guidance cue netrin increases filopodia density is unknown. Here, we demonstrate that TRIM9, an E3 ubiquitin ligase that localizes to filopodia tips and binds the netrin receptor DCC, interacts with and ubiquitinates the barbed-end polymerase VASP to modulate filopodial stability during netrin-dependent axon guidance. Studies with murine Trim9(+/+) and Trim9(-/-) cortical neurons, along with a non-ubiquitinatable VASP mutant, demonstrate that TRIM9-mediated ubiquitination of VASP reduces VASP filopodial tip localization, VASP dynamics at tips, and filopodial stability. Upon netrin treatment, VASP is deubiquitinated, which promotes VASP tip localization and filopodial stability. Trim9 deletion induces axon guidance defects in vitro and in vivo, whereas a gradient of deubiquitinase inhibition promotes axon turning in vitro. We conclude that a gradient of TRIM9-mediated ubiquitination of VASP creates a filopodial stability gradient during axon turning.