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BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
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Neuropatias Amiloides Familiares/terapia , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/sangue , Neuropatias Amiloides Familiares/complicações , Progressão da Doença , Método Duplo-Cego , Edema/induzido quimicamente , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Infusões Intravenosas/efeitos adversos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Polineuropatias/etiologia , Polineuropatias/terapia , Pré-Albumina/análise , Pré-Albumina/genética , Qualidade de Vida , RNA Interferente Pequeno/efeitos adversos , Índice de Gravidade de Doença , Teste de CaminhadaRESUMO
BACKGROUND: The diagnosis and follow-up of stone forming patients is usually performed by analysis of 24-h urine samples. However, crystallization risk varies throughout the day, being higher at night. The main objective of this study is to evaluate the urinary crystallization risk in adults and children by calculating risk indexes based on different collection periods. METHODS: The study included 149 adults (82 healthy and 67 stone-formers) and 108 children (87 healthy and 21 stone-formers). 24-h urine was collected, divided into 12-h daytime sample (8 am to 8 pm), and 12-h overnight sample (8 pm to 8 am next morning). Solute concentrations, the calcium to citrate ratio (Ca/Cit), and the ion activity product of calcium oxalate (AP[CaOx]) and calcium phosphate (AP[CaP]) were calculated in each 12-h sample and in overall 24-h urine. Assessments were also related to stone type. RESULTS: Ca/Cit and AP(CaOx) were significantly higher in stone forming patients than in healthy subjects. The 12-h overnight samples had the highest values for both risk indexes, confirming a greater risk for crystallization at night. The AP(CaP) index was significantly higher in patients with pure hydroxyapatite stones than healthy controls, but was not significantly different between stone-formers overall and healthy controls. CONCLUSIONS: The calculation of risk indexes is a simple method that clinicians can use to estimate crystallization risk. For this purpose, the use of 12-h overnight urine may be a reliable alternative to 24-h collections.
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Cálculos Urinários/diagnóstico , Coleta de Urina/métodos , Adulto , Cálcio/urina , Oxalato de Cálcio/urina , Fosfatos de Cálcio/urina , Criança , Ácido Cítrico/urina , Cristalização , Humanos , Fatores de Risco , Fatores de Tempo , Urinálise/métodos , Cálculos Urinários/químicaRESUMO
PURPOSE OF REVIEW: These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene. RECENT FINDINGS: The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP. SUMMARY: Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP.
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Neuropatias Amiloides Familiares , Gerenciamento Clínico , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/terapia , Doenças Assintomáticas/epidemiologia , Progressão da Doença , Europa (Continente)/epidemiologia , Testes Genéticos , HumanosRESUMO
OBJECTIVE: The aim of this study was to evaluate the relationship between physiological levels of myo-inositol hexaphosphate (phytate) and cardiovascular (CV) calcification in patients with chronic kidney disease (CKD). DESIGN AND METHODS: This was a prospective cross-sectional study conducted from December 2012 to June 2013. SUBJECTS: Sixty-nine consecutive patients with CKD who were not undergoing renal replacement therapy. INTERVENTION: All subjects were given lateral lumbar X-rays to quantify abdominal aortic calcification (AAC). Clinical laboratory analyses and phytate food frequency questionnaires were also performed. MAIN OUTCOME MEASURE: Phytate urinary excretion, estimated phytate consumption (based on food frequency questionnaire) and AAC score. Patients were divided into two groups based on median abdominal aortic calcification (AAC) score: no/mild AAC (AAC ≤ 6, n = 35) and moderate/severe AAC (AAC > 6, n = 34). RESULTS: Patients with no/mild AAC were younger, had lower pulse pressure, greater dietary intake of phytate, greater urinary phytate and the prevalence of prior CV disease was significantly lower compared to patients with moderate/severe AAC. Among the top 10 phytate-rich foods, lentil consumption was significantly greater in patients with no/mild AAC than in those with moderate/severe AAC. Multivariate logistic regression analysis indicated that age, prior CV disease, urinary phytate (or lentil consumption) were independently associated to AAC. CONCLUSION: Our results suggest that adequate consumption of phytate can prevent AAC in patients with CKD. Further prospective studies must be performed to elucidate the benefits of a phytate-rich diet and the associated risk of phosphorus bioavailability in these patients.
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Aorta Abdominal/patologia , Dieta , Ácido Fítico/administração & dosagem , Insuficiência Renal Crônica/patologia , Calcificação Vascular/patologia , Idoso , Aorta Abdominal/diagnóstico por imagem , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Fítico/urina , Prevalência , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Resultado do Tratamento , Calcificação Vascular/diagnóstico por imagem , Circunferência da CinturaRESUMO
Chronic kidney disease-associated pruritus (CKD-aP) is one of the most common and disabling comorbidities in patients with advanced CKD. In addition, it is associated with an increased risk of mortality, poorer quality of life, sleep disorders, mental health disorders, and increased use of health care resources. The clinical presentation of CKD-aP is very heterogeneous, making it difficult to diagnose and treat. Currently, there are no national guidelines on the management of CKD-aP. The aim of this document is to provide national consensus recommendations for the diagnostic and therapeutic management of CKD-aP. The document was prepared in three phases: a diagnostic and therapeutic management algorithm was proposed by a small group of nephrology specialists; the proposal was validated by a larger group of nephrologists; and a second validation by a multidisciplinary group that also included dermatology specialists. The diagnostic and therapeutic management algorithm attempts to cover the current need of a lack of specific guidelines for the adequate management of CKD-aP. At the same time, it introduces the use of difelikefalin, the first and only drug specifically approved for CKD-aP, with a good safety and efficacy profile.
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Defined as the unpleasant sensation that causes the desire to scratch, pruritus is the most common skin symptom associated with uremia and appears in almost half of patients with advanced chronic kidney disease (CKD). Beyond its direct impact on quality of life, CKD-associated pruritus (CKD-aP) is an independent predictor of mortality that also has a synergistic effect with other quality of life-related symptoms, such as insomnia, depression, and anxiety. Although different mechanisms have been proposed to explain the origin of Pa-ERC, its etiopathogenesis is still not fully understood. Since new therapeutic targets have been identified and several clinical trials have recently shown promising results, our current understanding of the interrelationships has expanded significantly and the pathophysiological mechanisms underlying CKD-aP are now considered to be multifactorial. The potential triggers of pruritus in patients with CKD are discussed in this review, including hypotheses about skin xerosis, accumulation of uremic toxins, dysregulation of the immune system and systemic inflammation, uremic neuropathy, and imbalances in the endogenous opioid system. Other non-uremic causes of pruritus are also discussed, with the aim of guiding the physicians to apply an adequate aetiopathogenic approach to CKD-aP in their day-to-day clinical practice.
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Insuficiência Renal Crônica , Uremia , Humanos , Qualidade de Vida , Prurido/etiologia , Insuficiência Renal Crônica/complicações , Uremia/complicações , Uremia/terapiaRESUMO
INTRODUCTION: Pruritus associated with chronic kidney disease is defined as the sensation of itching, in people with chronic kidney disease, in a one area or all over the body that causes the need to scratch, after having ruled out other dermatological or systemic causes. It is an old and known problem whose prevalence has been able to decrease with the improvement of dialytic techniques but which still persists and is underdiagnosed. OBJECTIVES: The objective of this study was to analyse the current perception of nephrologists about this problem that influences the quality of life of people with chronic kidney disease through a survey. RESULTS: 135 nephrologists, most of them engaged in haemodialysis, participated. 86% considered that pruritus associated with chronic kidney disease is still a problem today that affects the quality of life. Most nephrologists believe that the main pathophysiological cause is uremic toxins (60%) and only 16% believe that it is due to the dysregulation of the opioid system/endorphins-dynorphins. Only 16% comment that the prevalence of pruritus in their centre is greater than 20%. 40% believe that the diagnosis is made because it is manifested by the patient and only 27% because it is asked by the doctor. Moreover, it is not usual to use scales to measure it or the codification in the medical records. The main treatment used is antihistamines (96%), followed by moisturizers/anaesthetics (93%) and modification of the dialysis regimen (70%). CONCLUSIONS: Pruritus associated with chronic kidney disease is still a current problem, it is underdiagnosed, not codified and with a lack of indicated, effective and safe treatments. Nephrologists do not know its real prevalence and the different pathophysiological mechanisms involved in its development. Many therapeutic options are used with very variable results, ignoring their efficacy and applicability at the present time. The new emerging kappa-opioid-receptor agonist agents offer us an opportunity to reevaluate this age-old problem and improve the quality of life for our patients with chronic kidney disease.
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Nefrologistas , Insuficiência Renal Crônica , Humanos , Qualidade de Vida , Analgésicos Opioides/uso terapêutico , Insuficiência Renal Crônica/complicações , Prurido/etiologia , PercepçãoRESUMO
There is an unmet need to create consensus documents on the management of cardiorenal patients since, due to the aging of the population and the rise of both pathologies, these patients are becoming more prevalent in daily clinical practice. Chronic kidney disease coexists in up to 40%-50% of patients with chronic heart failure cases. There have yet to be consensus documents on how to approach palliative care in cardiorenal patients. There are guidelines for patients with heart failure and chronic kidney disease separately, but they do not specifically address patients with concomitant heart failure and kidney disease. For this reason, our document includes experts from different specialties, who will not only address the justification of palliative care in cardiorenal patients but also how to identify this patient profile, the shared planning of their care, as well as knowledge of their trajectory and the palliative patient management both in the drugs that will help us control symptoms and in advanced measures. Dialysis and its different types will also be addressed, as palliative measures and when the decision to continue or not perform them could be considered. Finally, the psychosocial approach and adapted pharmacotherapy will be discussed.
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Diabetic kidney disease (DKD) is the most frequent cause of kidney failure (KF). There are large variations in the incidence rates of kidney replacement therapy (KRT). Late referral to nephrology services has been associated with an increased risk of adverse outcomes. In many countries, when patients reach severely reduced glomerular filtration rate (GFR), they are managed by multidisciplinary teams led by nephrologists. In these clinics, efforts will continue to halt chronic kidney disease (CKD) progression and to prevent cardiovascular mortality and morbidity. In patients with diabetes and severely reduced GFR and KF, treating hyperglycemia is a challenge, since some drugs are contraindicated and most of them require dose adjustments. Even more, a decision-making process will help in deciding whether the patient would prefer comprehensive conservative care or KRT. On many occasions, this decision will be conditioned by diabetes mellitus itself. Effective education should cover the necessary information for the patient and family to answer these questions: 1. Should I go for KRT or not? 2. If the answer is KRT, dialysis and/or transplantation? 3. Dialysis at home or in center? 4. If dialysis at home, peritoneal dialysis or home hemodialysis? 5. If transplantation is desired, discuss the options of whether the donation would be from a living or deceased donor. This review addresses the determinant factors with an impact on DKD, aiming to shed light on the specific needs that arise in the management and recommendations on how to achieve a comprehensive approach to the diabetic patient with chronic kidney disease.
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Invasive pneumococcal disease (IPD) presents high mortality in the population at risk. The aim of this work is to know the evolution, clinical and microbiological characteristics of IPD in the adult population of Majorca, since the introduction of a public funded program for pneumococcal conjugate vaccine (PCV-13) in the pediatric population in the Balearic Islands in 2016. For this purpose, a retrospective multicenter study was carried out in which all episodes of IPD in adult patients from the four hospitals of the public health system of Majorca were included, comparing the periods between 2012 and 2015 and between 2016 and 2019. Clinical variables, serotypes and antibiotic sensitivity were collected. There were 498 cases of IPD; 56.8% were male with a mean age of 67 (standard deviation: 16). Most infections were bacterial pneumonias (73.7%). Of the total cases, 264 (53%) presented complications. Of the 498 cases, 351 strains were obtained, of which 145 (41.3%) belong to vaccinal serotypes (included in the PCV-13 vaccine) and 206 (58.7%) to non-vaccinal serotypes (not included in the PCV-13 vaccine). The percentage of IPD caused by vaccinal serotypes was lower in the second period (47.8% vs. 34.5%; p = 0.012).
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INTRODUCTION: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). METHODS: We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. RESULTS: A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48-2.20). No relevant safety issues were identified. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.
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BACKGROUND: Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup. RESULTS: Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months. CONCLUSIONS: Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.
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Neuropatias Amiloides Familiares , Pré-Albumina , Neuropatias Amiloides Familiares/tratamento farmacológico , Humanos , Pré-Albumina/genética , Qualidade de Vida , RNA Interferente PequenoRESUMO
Progress in transplantation means the process of procuring both human organ and tissues has become a daily challenge. Considering that tissues are usually procured from organ donors who have suffered brain death or after controlled cardiac death, the tissue procurement is done mainly in major hospitals. With the aim of highlighting the potential role of regional hospitals in tissue donation, a prospective descriptive study was carried out of all the patients who died at the Regional Hospital of Inca in Mallorca (Spain) from January 2013 to August 2018. To ensure an early detection of all possible tissue donors, the hospital has implemented a computerized alert system that is activated immediately after a patient dies. This strategy has proven to be very useful as in the analyzed period, the hospital had an average of 280 donors per million population, which is one of the highest rates of cornea donation among the Spanish hospitals. Our data and experience show the important role of regional hospitals in tissue donation and the value of implementing screening programs and early selection of potential tissue donors.
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Hospitais Comunitários , Doadores de Tecidos/provisão & distribuição , Doadores de Tecidos/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/organização & administração , Obtenção de Tecidos e Órgãos/estatística & dados numéricos , Feminino , Hospitais Comunitários/estatística & dados numéricos , Humanos , Masculino , Estudos Prospectivos , EspanhaRESUMO
The aim of this study of patients with chronic kidney disease (CKD) is to assess the safety of daily consumption of walnuts on the physiological levels of phosphorous, potassium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), and to assess the short-term benefits of this intervention on risk factors associated with cardiovascular events. This led us to perform a prospective, randomized, crossover, pilot clinical trial examined 13 patients with CKD. Subjects were randomly assigned to a diet of 30 g of walnuts per day or the control diet. After 30 days, each group was given a 30-day washout period, and then switched to the alternate diet for 30 days. Urinary and serum levels of phosphorous and potassium, multiple vascular risk factors, and urinary inositol phosphates (InsPs) were measured at baseline and at the end of the intervention period. Our results showed that the walnut dietary supplement led to reduced blood pressure, LDL cholesterol, and albumin excretion, but had no effect on the physiological levels of phosphorous, potassium, PTH, and FGF23. This is the first report to show that daily consumption of walnuts by patients with CKD does not alter their physiological levels of phosphorous, potassium, PTH, and FGF23 when included in a sodium-, protein-, phosphate-, and potassium-controlled diet, and it could be an effective strategy for reducing cardiovascular risk in patients with CKD.
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Dieta , Juglans , Nozes , Insuficiência Renal Crônica , Idoso , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/prevenção & controle , Estudos Cross-Over , Dieta/efeitos adversos , Dieta/métodos , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Fosfatos de Inositol/urina , Masculino , Hormônio Paratireóideo/sangue , Fósforo/sangue , Fósforo/urina , Projetos Piloto , Potássio/sangue , Potássio/urina , Estudos Prospectivos , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/fisiopatologia , Fatores de RiscoRESUMO
INTRODUCTION AND OBJECTIVES: Cardiac involvement determines prognosis and treatment options in transthyretin-familial amyloidosis. Cardiac magnetic resonance T1 mapping techniques are useful to assess myocardial extracellular volume. This study hypothesized that myocardial extracellular volume allows identification of amyloidotic cardiomyopathy and correlates with the degree of neurological impairment in transthyretin-familial amyloidosis. METHODS: A total of 31 transthyretin-familial amyloidosis patients (19 mean age, 49 ± 12 years; 26 with the Val30Met mutation) underwent a T1 mapping cardiac magnetic resonance study and a neurological evaluation with Neuropathy Impairment Score of the Lower Limb score, Norfolk Quality of Life questionnaire, and Karnofsky index. RESULTS: Five patients had cardiac amyloidosis (all confirmed by 99mTc-DPD scintigraphy). Mean extracellular volume was increased in patients with cardiac amyloidosis (0.490 ± 0.131 vs 0.289 ± 0.035; P = .026). Extracellular volume correlated with age (R = 0.467; P = .008), N-terminal pro-B-type natriuretic peptide (RS = 0.846; P < .001), maximum wall thickness (R = 0.621; P < .001), left ventricular mass index (R = 0.685; P < .001), left ventricular ejection fraction (R = -0.378; P = .036), Neuropathy Impairment Score of the Lower Limb (RS = 0.604; P = .001), Norfolk Quality of Life questionnaire (RS = 0.529; P = .003) and Karnofsky index (RS= -0.517; P = .004). A cutoff value of extracellular volume of 0.357 was diagnostic of cardiac amyloidosis with 100% sensitivity and specificity (P < .001). Extracellular volume and N-terminal pro-B-type natriuretic peptide were the only cardiac parameters that significantly correlated with neurologic scores. CONCLUSIONS: Extracellular volume quantification allows identification of cardiac amyloidosis and correlates with the degree of neurological impairment in transthyretin-familial amyloidosis. This noninvasive technique could be a useful tool for early diagnosis of cardiac amyloidosis and to track cardiac and extracardiac amyloid disease.
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Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Doenças do Sistema Nervoso/complicações , Adulto , Idoso , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/genética , Volume Cardíaco/fisiologia , Cardiomiopatias/complicações , Cardiomiopatias/genética , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doenças do Sistema Nervoso/genética , Variações Dependentes do Observador , Fatores de RiscoRESUMO
Water used to prepare haemodialysis fluid is not sterile, and its microbiological control is important for the prevention of haemodialysis-associated illness. Bacterial populations inhabiting a distribution system for haemodialysis water were studied over an 18-month period. 203 planktonic bacteria isolated on R2A medium were identified by restriction analysis and sequencing of 16S rRNA gene. A diverse bacterial community was detected, containing predominantly Gram-negative members of the Alphaproteobacteria and Betaproteobacteria, as well as representatives of the genus Mycobacterium. Ecological and clinical consequences are discussed: bacteria from the genera Novosphingobium, Pseudomonas and Sphingomonas have been described in the build-up of biofilms, and others like Acinetobacter, Mycobacterium or Brevibacterium may represent a health risk to patients under haemodialysis treatment.
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Bactérias/genética , Soluções para Hemodiálise/análise , Filogenia , Microbiologia da Água , Sequência de Bases , Análise por Conglomerados , Contagem de Colônia Microbiana , Impressões Digitais de DNA , Primers do DNA , Dados de Sequência Molecular , RNA Ribossômico 16S/genética , Análise de Sequência de DNARESUMO
BACKGROUND: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). METHODS: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). RESULTS: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). CONCLUSIONS: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. TRIAL REGISTRATION NUMBER: NCT01617967 .