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1.
Amino Acids ; 2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33788002

RESUMEN

Trimethyllysine (TML) is involved in the generation of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO) by gut microbiota. In clinical studies, elevated TML levels predicted major adverse cardiovascular events (MACE) in patients with acute or stable coronary artery disease (CAD). In contrast to cardiovascular patients, the role of TML in patients with acute cerebral ischemia is unknown. Here, we evaluated circulating TML levels in 374 stroke patients from the prospective biomarkers in stroke (MARK-STROKE) study. Compared with 167 matched healthy controls, acute ischemic stroke patients had lower median TML plasma concentrations, i.e. 0.71 vs. 0.47 µmol/L (p < 0.001) and this difference persisted after adjusting for age and sex. TML plasma concentrations were associated with age, serum creatinine, glucose, cholesterol and lysine. Patients with prevalent arterial hypertension, atrial fibrillation or a history of myocardial infarction had increased TML levels, but this observation was not independent of age, sex and GFR. In 274 patients, follow-up data were available. During a median follow-up of 284 [25th-75th percentile: 198, 431] days, TML was not associated with incident MACE (stroke, myocardial infarction, death). In summary, our data suggests a different role of TML in acute ischemic stroke compared with CAD patients.

2.
Parkinsonism Relat Disord ; 85: 5-10, 2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33636481

RESUMEN

OBJECTIVES: In prospective cohort studies different blood lipid fractions have been identified as risk factors of Parkinson's disease (PD). However, data relating lipoproteins to disease phenotypes and progression in advanced PD patients are sparse. Therefore, we assessed the most common lipoproteins in a case-control design and evaluated their associations with motor and cognitive function and decline in PD patients. METHODS: Triglycerides, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein a (Lp(a)) were analyzed in 294 PD patients of the MARK-PD study cohort and 588 controls matched for age, sex and cardiovascular risk factors. In PD patients, motor (MDS-UPDRS III, Hoehn-Yahr stage) and cognitive function (MoCA) were examined. In a sub-cohort (n = 98 patients), baseline lipid levels were correlated with motor and cognitive disease progression during a follow-up period of 523 ± 199 days. RESULTS: At baseline, HDL-C levels were lower in PD patients compared to matched controls after adjustment. We observed a very weak association of Lp(a) levels with UDPRS III scores. In cross-sectional analyses, no other lipid fraction revealed a significant and consistent association with motor or cognitive function. During follow-up, no lipid fraction level was associated with motor or cognitive progression. CONCLUSION: In advanced PD, there is no strong and consistent association of lipid levels with motor or cognitive function and decline.

3.
PLoS Pathog ; 17(2): e1009304, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33544760

RESUMEN

S. epidermidis is a substantial component of the human skin microbiota, but also one of the major causes of nosocomial infection in the context of implanted medical devices. We here aimed to advance the understanding of S. epidermidis genotypes and phenotypes conducive to infection establishment. Furthermore, we investigate the adaptation of individual clonal lines to the infection lifestyle based on the detailed analysis of individual S. epidermidis populations of 23 patients suffering from prosthetic joint infection. Analysis of invasive and colonizing S. epidermidis provided evidence that invasive S. epidermidis are characterized by infection-supporting phenotypes (e.g. increased biofilm formation, growth in nutrient poor media and antibiotic resistance), as well as specific genetic traits. The discriminating gene loci were almost exclusively assigned to the mobilome. Here, in addition to IS256 and SCCmec, chromosomally integrated phages was identified for the first time. These phenotypic and genotypic features were more likely present in isolates belonging to sequence type (ST) 2. By comparing seven patient-matched nasal and invasive S. epidermidis isolates belonging to identical genetic lineages, infection-associated phenotypic and genotypic changes were documented. Besides increased biofilm production, the invasive isolates were characterized by better growth in nutrient-poor media and reduced hemolysis. By examining several colonies grown in parallel from each infection, evidence for genetic within-host population heterogeneity was obtained. Importantly, subpopulations carrying IS insertions in agrC, mutations in the acetate kinase (AckA) and deletions in the SCCmec element emerged in several infections. In summary, these results shed light on the multifactorial processes of infection adaptation and demonstrate how S. epidermidis is able to flexibly repurpose and edit factors important for colonization to facilitate survival in hostile infection environments.

4.
J Am Heart Assoc ; 10(3): e017822, 2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33496189

RESUMEN

Background Prospective longitudinal follow-up of left ventricular ejection fraction (LVEF) trajectories after acute cardiac decompensation of heart failure is lacking. We investigated changes in LVEF and covariates at 6-months' follow-up in patients with a predischarge LVEF ≤40%, and determined predictors and prognostic implications of LVEF changes through 18-months' follow-up. Methods and Results Interdisciplinary Network Heart Failure program participants (n=633) were categorized into subgroups based on LVEF at 6-months' follow-up: normalized LVEF (>50%; heart failure with normalized ejection fraction, n=147); midrange LVEF (41%-50%; heart failure with midrange ejection fraction, n=195), or persistently reduced LVEF (≤40%; heart failure with persistently reduced LVEF , n=291). All received guideline-directed medical therapies. At 6-months' follow-up, compared with patients with heart failure with persistently reduced LVEF, heart failure with normalized LVEF or heart failure with midrange LVEF subgroups showed greater reductions in LV end-diastolic/end-systolic diameters (both P<0.001), and left atrial systolic diameter (P=0.002), more increased septal/posterior end-diastolic wall-thickness (both P<0.001), and significantly greater improvement in diastolic function, biomarkers, symptoms, and health status. Heart failure duration <1 year, female sex, higher predischarge blood pressure, and baseline LVEF were independent predictors of LVEF improvement. Mortality and event-free survival rates were lower in patients with heart failure with normalized LVEF (P=0.002). Overall, LVEF increased further at 18-months' follow-up (P<0.001), while LV end-diastolic diameter decreased (P=0.048). However, LVEF worsened (P=0.002) and LV end-diastolic diameter increased (P=0.047) in patients with heart failure with normalized LVEF hospitalized between 6-months' follow-up and 18-months' follow-up. Conclusions Six-month survivors of acute cardiac decompensation for systolic heart failure showed variable LVEF trajectories, with >50% showing improvements by ≥1 LVEF category. LVEF changes correlated with various parameters, suggesting multilevel reverse remodeling, were predictable from several baseline characteristics, and were associated with clinical outcomes at 18-months' follow-up. Repeat hospitalizations were associated with attenuation of reverse remodeling. Registration URL: https://www.controlled-trials.com; Unique identifier: ISRCTN23325295.

5.
Lancet Digit Health ; 2(1): e16-e24, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-33328035

RESUMEN

BACKGROUND: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial showed that, compared with usual care, a structured remote patient management (RPM) intervention done over 12-months reduced the percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause death. The aim of the study was to evaluate whether this clinical benefit seen for the RPM group during the initial 12 month follow-up of the TIM-HF2 trial would be sustained 1 year after stopping the RPM intervention. METHODS: TIM-HF2 was a prospective, randomised, multicentre trial done in 43 hospitals, 60 cardiology practices, and 87 general practitioners in Germany. Patients with heart failure, New York Heart Association functional class II or III, and who had been hospitalised for heart failure within 12 months before randomisation were randomly assigned to either the RPM intervention or usual care. At the final study visit (main trial), the RPM intervention was stopped and the 1 year extended follow-up period started, which lasted 1 year. The primary outcome was percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause mortality. Analyses were done using the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01878630. FINDINGS: Between Aug 13, 2013, and May 12, 2017, 1538 patients were enrolled (765 to the remote patient management group and 773 to the usual care group) in the main trial. 671 of 765 patients in the remote patient management group and 673 of 773 in the usual care group completed the main trial and started the extended follow-up period up to 1 year later. In the extended follow-up period, the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality did not differ significantly between groups weighted mean 5·95% [95% CI 4·59-7·31] in the RPM group vs 6·64% [95% CI 5·19-8·08] in the usual care group [rate ratio 0·79; 95% CI 0·78-1·21]). However, when data from the main trial and the extended follow-up period were combined, the percentage of days lost due to unplanned cardiovascular hospitalisation or all-cause death was significantly less in patients allocated to the RPM group (382 [50%] of 765; weighted mean 9·28%; 95% CI 7·76-10·81) than in the UC group (398 [51%] of 773; 11·78%; 95% CI 10·08-13·49; ratio of weighted average 0·79; 95% CI 0·62-1·00; p=0·0486). INTERPRETATION: The positive effect of our RPM intervention on morbidity and mortality over the course of the main trial was no longer observed 1 year after stopping the RPM intervention. However, because the TIM-HF2 trial was not powered to show significance during the extended follow-up period, our results are exploratory and require further research. FUNDING: German Federal Ministry of Education and Research.


Asunto(s)
Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/terapia , Telemedicina , Privación de Tratamiento , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Insuficiencia Cardíaca/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Morbilidad , Estudios Prospectivos , Factores de Tiempo
6.
Artículo en Inglés | MEDLINE | ID: mdl-32978686

RESUMEN

PURPOSE: Dysphagia is common in patients with Parkinson's disease (PD) and often leads to pneumonia, malnutrition, and reduced quality of life. This study investigates the ability of the Eating Assessment Tool-10 (EAT-10), an established, easy self-administered screening tool, to detect aspiration in PD patients. This study aims to validate the ability of the EAT-10 to detect FEES-proven aspiration in patients with PD. METHODS: In a controlled prospective cross-sectional study, a total of 50 PD patients completed the EAT-10 and, subsequently, were examined by Flexible Endoscopic Evaluation of Swallowing (FEES) to determine the swallowing status. The results were rated through the Penetration-Aspiration Scale (PAS) and data were analyzed retrospectively. RESULTS: PAS and EAT-10 did not correlate significantly. Selected items of the EAT-10 could not predict aspiration or residues. 19 (38%) out of 50 patients with either penetration or aspiration were not detected by the EAT-10. The diagnostic accuracy was established at only a sufficient level (AUC 0.65). An optimal cut-off value of ≥ 6 presented a sensitivity of 58% and specificity of 82%. CONCLUSIONS: The EAT-10 is not suited for the detection of penetration and aspiration in PD patients. Therefore, it cannot be used as a screening method in this patient population. There is still a need for a valid, simple, and efficient screening tool to assist physicians in their daily diagnostics and to avoid clinical complications.

7.
Arch Gynecol Obstet ; 301(6): 1503-1512, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32322982

RESUMEN

PURPOSE: Management of high-grade cervical intraepithelial neoplasia [CIN grade 2 or 3 (CIN2-3)] diagnosed during pregnancy is controversial. Monitoring with colposcopy and cytology every 8-12 weeks is advised by the most current guidelines. STUDY DESIGN: This study analyzes the course of disease in pregnant women with abnormal cytologies or clinically suspicious cervixes. RESULTS: In total, 139 pregnant women, at a median age of 31 years (range 19-49), treated at the Colposcopy Unit of the University Medical Center Hamburg-Eppendorf between 2011 and 2017 were identified. During pregnancy, at least one biopsy was performed on 70.5% of patients. In 84.7% of cases, CIN2-3 (CIN2 n = 14 (14.3%), CIN3 n = 69 (70.4%)) was detected, 7.1% (n = 7) of women were diagnosed with CIN1, while no dysplasia was found in 8.2% (n = 8) of cases. No interventions were necessary during pregnancy. Despite explicit invitation, only 72.3% of women with CIN2-3 attended postpartal consultations. While 61.7% showed persistent lesions, 5% were diagnosed with CIN1 and 33.3% with complete remission. During pregnancy, 68.7% of women with prepartal CIN2-3 were tested for HPV infection. Later, 49.1% were followed up postpartally by means of HPV testing and histology. HPV clearance was observed in 36.4% of women with complete histological remission. Postpartum conization was performed on 44.6% of patients with prepartal CIN2-3 diagnosis. CIN2-3 was histologically confirmed in 97.3% cases. Progression from persistent CIN3 to microinvasive carcinoma was observed in a single case. CONCLUSIONS: High-grade CIN lesions, diagnosed during pregnancy, show a high rate of regression postpartum; whereas, progression to carcinoma is rare. Close and continuous monitoring rarely has any therapeutic consequences. Compliance for postpartal follow-up needs to be improved.


Asunto(s)
Neoplasia Intraepitelial Cervical/diagnóstico , Adulto , Neoplasia Intraepitelial Cervical/patología , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo , Adulto Joven
8.
Sci Rep ; 10(1): 2024, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32029783

RESUMEN

The transmembrane protein claudin-1 is a major component of epidermal tight junctions (TJs), which create a dynamic paracellular barrier in the epidermis. Claudin-1 downregulation has been linked to atopic dermatitis (AD) pathogenesis but variable levels of claudin-1 have also been observed in healthy skin. To elucidate the impact of different levels of claudin-1 in healthy and diseased skin we determined claudin-1 levels in AD patients and controls and correlated them to TJ and skin barrier function. We observed a strikingly broad range of claudin-1 levels with stable TJ and overall skin barrier function in healthy and non-lesional skin. However, a significant decrease in TJ barrier function was detected in lesional AD skin where claudin-1 levels were further reduced. Investigations on reconstructed human epidermis expressing different levels of claudin-1 revealed that claudin-1 levels correlated with inside-out and outside-in barrier function, with a higher coherence for smaller molecular tracers. Claudin-1 decrease induced keratinocyte-autonomous IL-1ß expression and fostered inflammatory epidermal responses to non-pathogenic Staphylococci. In conclusion, claudin-1 decrease beyond a threshold level results in TJ and epidermal barrier function impairment and induces inflammation in human epidermis. Increasing claudin-1 levels might improve barrier function and decrease inflammation and therefore be a target for AD treatment.


Asunto(s)
Claudina-1/metabolismo , Dermatitis Atópica/inmunología , Epidermis/patología , Uniones Estrechas/patología , Adulto , Biopsia , Estudios de Casos y Controles , Células Cultivadas , Claudina-1/análisis , Claudina-1/genética , Dermatitis Atópica/microbiología , Dermatitis Atópica/patología , Regulación hacia Abajo , Epidermis/inmunología , Epidermis/microbiología , Femenino , Técnicas de Silenciamiento del Gen , Voluntarios Sanos , Humanos , Interleucina-1beta/metabolismo , Queratinocitos/inmunología , Queratinocitos/metabolismo , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Staphylococcus/inmunología , Staphylococcus/aislamiento & purificación , Pérdida Insensible de Agua/inmunología , Adulto Joven
9.
Neurol Sci ; 41(1): 149-153, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31482247

RESUMEN

BACKGROUND: Guanidino compounds, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine (hArg), have been associated with cardio- and cerebrovascular events and risk. We aimed to study if low hArg/ADMA and hArg/SDMA ratios are associated with mortality and outcome after stroke. METHODS: In two prospective cohorts of acute stroke patients from Germany and the UK, we analyzed hArg, ADMA, and SDMA to determine hArg/ADMA and hArg/SDMA ratios. The guanidino compound levels were associated with mortality, adverse events, and neurological impairment, i.e., National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). RESULTS: During 7.4 years, high hArg/ADMA and hArg/SDMA ratios were both associated with a reduction in all-cause mortality in patients with ischemic stroke in a UK stroke cohort (hArg/ADMA: hazard ratio (HR) 0.75 [95% confidence interval (CI) 0.62-0.92]; n = 394; P = 0.006; hArg/SDMA: HR 0.68 [0.54-0.85]; n = 394; P = 0.001). In a German stroke cohort, patients with high hArg/SDMA ratio experienced fewer adverse events compared with those with low hArg/SDMA ratios within 30 days after stroke (HR 0.73 [0.57-0.92]; n = 135; P = 0.009), whereas hArg/ADMA was not predictive. Furthermore, hArg/SDMA ratios inversely correlated with the degree of neurological impairment (NIHSS) (r = - 0.27; P = 0.001; n = 138). Lower hArg/SDMA ratios were also found in dependent (mRS 3-6) compared with independent patients (mRS < 3; P = 0.007; n = 138), whereas hArg/ADMA did not. CONCLUSION: These results from two prospective stroke studies reveal that hArg/SDMA ratio could prove a valuable blood-based biomarker to discriminate patients with poor short- and long-term outcome, increased neurological impairment, and severe disability after stroke.


Asunto(s)
Arginina/análogos & derivados , Homoarginina/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/mortalidad , Arginina/sangre , Biomarcadores/sangre , Estudios de Cohortes , Humanos , Estudios Prospectivos , Tasa de Supervivencia/tendencias , Resultado del Tratamiento
10.
Sleep Breath ; 23(4): 1315-1321, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31332621

RESUMEN

OBJECTIVES: Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder characterized by severe multi-systemic organ manifestations including obstructive sleep apnea syndrome (OSAS). Hematopoietic stem cell transplantation (HSCT) is the treatment of choice in severe MPS I (MPS IH, Hurler syndrome). However, the effect of HSCT on OSAS in MPS IH still remains unclear. The purpose of this study was to analyze respiratory patterns during sleep following HSCT in MPS IH children and to relate these findings to craniofacial abnormalities. METHODS: Overnight polysomnographies of nine MPS IH children (mean age: 8.2 years) previously treated with HSCT were retrospectively analyzed. Magnetic resonance images of the head were assessed with regard to soft and hard tissue abnormalities of the upper respiratory tract. RESULTS: The mean apnea hypopnea index (AHI) was 5.3 events/h (range, 0.3-12.2), and the majority of apnea/hypopneas were obstructive. Whereas two patients had severe OSAS (AHI > 10) and two moderate OSAS (5 > AHI < 10), five patients had no evidence of OSAS (AHI < 2.0). Donor cell chimerism was significantly lower in MPS IH patients with OSAS as compared to patients without OSAS (p < 0.001). The upper airway space and the maxilla were significantly smaller and the adenoids larger in MPS IH patients with OSAS as compared to those of non-OSAS patients. CONCLUSION: OSAS was only observed in MPS IH patients with graft failure or low donor cell chimerism. Conversely, successful HSCT seems to ameliorate adenoid hyperplasia and maxillary constriction in MPS IH patients and thereby minimizes the risk of OSAS at least at younger ages.

11.
J Neurol Sci ; 397: 156-161, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30640152

RESUMEN

INTRODUCTION: Guanidino compounds, including l-homoarginine (l-hArg), symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA) and l-arginine (l-Arg) are associated with mortality, fatal strokes, stroke incidence, and atherosclerosis. OBJECTIVES: We aimed to study the association of guanidino compounds (l-hArg/ADMA and l-hArg/SDMA) with stroke etiology, internal carotid artery (ICA) stenosis and CHA2DS2-VASc score in patients with cerebrovascular disease. METHODS: We analyzed l-hArg, SDMA, ADMA, l-Arg, and compound molar ratios, i.e. l-hArg/ADMA and l-hArg/SDMA, in 272 patients with cerebrovascular disease in a cross-sectional discovery cohort and two cross-sectional validation cohorts of acute stroke patients from Germany (n = 137) and UK (n = 394). The guanidino compound levels were compared with clinical, imaging, and ultrasound parameters. RESULTS: Low l-hArg/ADMA and l-hArg/SDMA molar ratios predicted territorial infarcts (OR 1.74; 95% CI 1.34-2.26 and OR 1.64; 95% CI 1.26-2.15, respectively) and were associated with stroke subtypes due to large vessel disease or cardio-embolism (OR 1.52; 95% CI 1.12-2.06 and OR 2.01; 95% CI 1.35-3.00, respectively) in meta-analysis of the discovery and validation cohort data. In line with these results, a low l-hArg/ADMA and l-hArg/SDMA molar ratio was found in patients with ICA stenosis (OR 0.73; 95% CI 0.55-0.97 and OR 0.69; 95% CI 0.50-0.94, respectively) in the discovery and validation cohort. Furthermore, guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) were strongly correlated with CHA2DS2-VASC score (p < .001) in all three cohorts. DISCUSSION: The results from these three cross-sectional studies reveal that guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) can discriminate stroke etiologies, predict ICA stenosis and estimate risk prediction in patients with cerebrovascular disease.


Asunto(s)
Arginina/análogos & derivados , Arginina/sangre , Isquemia Encefálica/sangre , Estenosis Carotídea/sangre , Homoarginina/sangre , Hemorragias Intracraneales/sangre , Accidente Cerebrovascular/sangre , Anciano , Biomarcadores/sangre , Isquemia Encefálica/diagnóstico por imagen , Arterias Carótidas/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Hemorragias Intracraneales/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Recurrencia , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología
12.
Crit Care ; 22(1): 216, 2018 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-30231905

RESUMEN

BACKGROUND: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular and immune function. NO is generated by nitric oxide synthases (NOS) from L-arginine. Cellular L-arginine uptake is inhibited by symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) is a competitive inhibitor of NOS. Increased inhibitor blood concentrations lead to reduce NO bioavailability. The aim of this study was to determine whether plasma concentrations of SDMA and ADMA are markers for sepsis survival. METHOD: This prospective, single center study involved 120 ICU patients with sepsis. Plasma SDMA and ADMA were measured on admission (day 1), day 3 and day 7 by mass spectrometry together with other laboratory markers. The sequential organ failure assessment (SOFA) score was used to evaluate sepsis severity. Survival was documented until day 28. Groups were compared using the Mann-Whitney U test, chi-squared test or non-parametric analysis of variance (ANOVA). Mortality was assessed using Kaplan-Meier curves and compared using the log-rank test. Specific risk groups were identified using a decision tree algorithm. RESULTS: Median plasma SDMA and ADMA levels were significantly higher in non-survivors than in survivors of sepsis: SDMA 1.14 vs. 0.82 µmol/L (P = 0.002) and ADMA 0.93 vs. 0.73 µmol/L (P = 0.016). ANOVA showed that increased plasma SDMA and ADMA concentrations were significantly associated with SOFA scores. The 28-day mortality was compared by chi-square test: for SDMA the mortality was 12% in the lower, 25% in the intermediate and 43% in the 75th percentile (P = 0.018); for ADMA the mortality was 18-20% in the lower and intermediate but 48% in the 75th percentile (P = 0.006). The highest mortality (61%) was found in patients with plasma SDMA > 1.34 together with ADMA levels > 0.97 µmol/L. CONCLUSIONS: Increased plasma concentrations of SDMA and ADMA are associated with sepsis severity. Therefore, our findings suggest reduced NO bioavailability in non-survivors of sepsis. One may use individual SDMA and ADMA levels to identify patients at risk. In view of the pathophysiological role of NO we conclude that the vascular system and immune response are most severely affected when SDMA and ADMA levels are high.


Asunto(s)
Arginina/análogos & derivados , Sepsis/sangre , Anciano , Análisis de Varianza , Arginina/análisis , Arginina/sangre , Biomarcadores/análisis , Biomarcadores/sangre , Femenino , Humanos , Unidades de Cuidados Intensivos/organización & administración , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Estudios Prospectivos , Sepsis/mortalidad , Análisis de Supervivencia
13.
Front Cardiovasc Med ; 5: 108, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30159316

RESUMEN

Background: Fabry disease (FD) is characterized by early development of vasculopathy and endothelial dysfunction. However, it is unclear whether these findings also play a pivotal role in cardiac manifestation. As Fabry cardiomyopathy (FC) is the leading cause of death in FD, we aimed to gather a better insight in pathological mechanisms of the disease. Methods: Serum samples were obtained from 17 healthy controls, 15 FD patients with and 7 without FC. FC was defined by LV wall thickening of >12 mm in cardiac magnetic resonance imaging and serum level of proBNP, high sensitive Troponin T (hsT), and globotriaosylsphingosine (lyso-GB3) were obtained. A multiplex ELISA-Assay for 23 different angiogenesis markers was performed in pooled samples. Markers showing significant differences among groups were further analyzed in single samples using specific Elisa antibody assays. L-homoarginine (hArg), L-arginine, asymmetric (ADMA), and symmetric Dimethylarginine (SDMA) were quantified by liquid chromatography-mass spectrometry. Results: Angiostatin and matrix metalloproteinase 9 (MMP-9) were elevated in FD patients compared to controls independently of the presence of FC (angiostatin: 98 ± 25 vs. 75 ± 15 ng/mL; p = 0.001; MMP-9: 8.0 ± 3.4 vs. 5.0 ± 2.4 µg/mL; p = 0.002). SDMA concentrations were highest in patients with FC (0.90 ± 0.64 µmol/l) compared to patients without (0.57 ± 0.10 µmol/l; p = 0.027) and vs. controls (0.58 ± 0.12 µmol/l; p = 0.006) and was positively correlated with indexed LV-mass (r = 0.61; p = 0.003), hsT (r = 0.56, p = 0.008), and lyso-Gb3 (r = 0.53, p = 0.013). Accordingly, the ratio of L-homoarginine to SDMA (hArg/SDMA) was lowest in patients with FC (2.63 ± 1.78) compared to controls (4.16 ± 1.44; p = 0.005). For L-arginine, hArg and ADMA no significant differences among groups could be detected, although a trend toward higher ADMA and lower hArg levels could be observed in the FC group. Furthermore, a significant relationship between kidney and cardiac function could be revealed (p = 0.045). Conclusion: Elevated MMP-9 and angiostatin levels suggest an increased extracellular matrix turnover in FD patients. Furthermore, endothelial dysfunction may also be involved in FC, as SDMA and hArg/SDMA are altered in these patients.

14.
Lancet Child Adolesc Health ; 2(8): 582-590, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30119717

RESUMEN

BACKGROUND: Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. METHODS: We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. FINDINGS: In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. INTERPRETATION: In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. FUNDING: EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.


Asunto(s)
Lipofuscinosis Ceroideas Neuronales/diagnóstico , Adolescente , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino
15.
Clin Res Cardiol ; 107(2): 130-137, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28965260

RESUMEN

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of sudden cardiac death (SCD) primarily due to ventricular arrhythmia (VA). In patients (pts.) with a high risk of SCD, the implantation of an intracardiac cardioverter defibrillator (ICD) is thus indicated. Previous studies suggest that a prolonged interval between the peak and the end of the T wave, T-peak to T-end (TpTe), is associated with an elevated risk of VA and SCD in various clinical settings. The aim of our study was to evaluate the association between TpTe and VA in HCM pts. with a previously implanted ICD. METHODS: In 40 HCM pts. (51.4 ± 16.4 years; 62.5% men), TpTe was measured using the baseline digital standard resting 12-lead ECG during sinus rhythm. VA was assessed by device follow-up. RESULTS: Within 41.8 ± 35.1 months, 7 (17.5%) pts. had VA leading to appropriate therapy (AT), 7 pts. (17.5%) had non-sustained VA, and 26 pts. (65.0%) had no VA. The maximum TpTe was significantly prolonged in pts. with VA leading to AT compared to pts. without VA (101.3 ± 19.6 vs. 79.9 ± 15.3 ms; p = 0.004). Maximum TpTe was associated with an elevated risk of VA leading to AT (hazard ratio per 10 ms increase 1.63; 95% CI 1.04-2.54; p = 0.031) and pts. with a maximum TpTe ≤ 78 ms were without any VA leading to AT during follow-up. There was no correlation of maximum TpTe to other clinical parameters in our patient cohort. CONCLUSION: A prolonged TpTe is associated with VA and AT in HCM. Our findings suggest that TpTe can possibly serve as a marker for ventricular arrhythmogenesis in pts. with HCM and assessment of TpTe might, therefore, optimize SCD risk stratification.


Asunto(s)
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/terapia , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Electrocardiografía , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca , Potenciales de Acción , Adulto , Anciano , Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/fisiopatología , Cardiomiopatía Hipertrófica/mortalidad , Cardiomiopatía Hipertrófica/fisiopatología , Supervivencia sin Enfermedad , Ecocardiografía , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Procesamiento de Señales Asistido por Computador , Factores de Tiempo , Resultado del Tratamiento
16.
Eur J Heart Fail ; 20(3): 536-544, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29193576

RESUMEN

AIMS: The SERVE-HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo-ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers. METHODS AND RESULTS: In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12-month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between-group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N-terminal pro B-type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between-group differences in changes in cardiac, renal and systemic inflammation biomarkers. CONCLUSION: In patients with systolic heart failure and CSA, addition of ASV to guideline-based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE-HF may not be related to adverse remodelling or worsening heart failure.


Asunto(s)
Insuficiencia Cardíaca Sistólica/complicaciones , Ventrículos Cardíacos/fisiopatología , Apnea Central del Sueño/terapia , Volumen Sistólico/fisiología , Función Ventricular Izquierda/fisiología , Anciano , Ecocardiografía , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca Sistólica/diagnóstico , Insuficiencia Cardíaca Sistólica/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Imagen por Resonancia Cinemagnética , Masculino , Respiración con Presión Positiva/métodos , Apnea Central del Sueño/complicaciones , Resultado del Tratamiento
17.
J Am Podiatr Med Assoc ; 107(5): 419-427, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28708428

RESUMEN

BACKGROUND: Measurement of the medial longitudinal foot arch in children is a controversial topic, as there are many different methods without a definite standard procedure. The purpose of this study was to 1) investigate intraday and interrater reliability regarding dynamic arch index and static arch height, 2) explore the correlation between both arch indices, and 3) examine the variation of the medial longitudinal arch at two different times of the day. METHODS: Eighty-six children (mean ± SD age, 8.9 ± 1.9 years) participated in the study. Dynamic footprint data were captured with a pedobarographic platform. For static arch measurements, a specially constructed caliper was used to assess heel-to-toe length and dorsum height. A mixed model was established to determine reliability and variation. RESULTS: Reliability was found to be excellent for the static arch height index in sitting (intraday, 0.90; interrater, 0.80) and standing positions (0.88 and 0.85) and for the dynamic arch index (both 1.00). There was poor correlation between static and dynamic assessment of the medial longitudinal arch (standing dynamic arch index, r = -0.138; sitting dynamic arch index, r = -0.070). Static measurements were found to be significantly influenced by the time of day (P < .001), whereas the dynamic arch index was unchanged (P = .845). This study revealed some further important findings. The static arch height index is influenced by gender (P = .004), whereas dynamic arch index is influenced by side (P = .011) and body mass index (P < .001). CONCLUSIONS: Dynamic and static foot measurements are reliable for medial longitudinal foot arch assessment in children. The variation of static arch measurements during the day has to be kept in mind. For clinical purposes, static and dynamic arch data should be interpreted separately.


Asunto(s)
Dermatoglifia , Pie/anatomía & histología , Soporte de Peso , Estatura , Peso Corporal , Niño , Intervalos de Confianza , Femenino , Voluntarios Sanos , Humanos , Masculino , Postura , Presión , Valores de Referencia , Reproducibilidad de los Resultados
18.
J Hypertens ; 35(10): 2053-2058, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28598953

RESUMEN

OBJECTIVE: Common genetic variants in the gene encoding uromodulin (UMOD) have been associated with renal function, blood pressure (BP) and hypertension. We investigated the associations between an important single nucleotide polymorphism (SNP) in UMOD, that is rs12917707-G>T, and estimated glomerular filtration rate (eGFR), BP and cardiac organ damage as determined by echocardiography in patients with arterial hypertension. METHODS: A cohort of 1218 treated high-risk patients (mean age 58.5 years, 83% men) with documented cardiovascular disease (81% with coronary heart disease) was analysed. RESULTS: The mean values for 24-h SBP and DBP were 124.7 ±â€Š14.7 and 73.9 ±â€Š9.4 mmHg; mean eGFR was 77.5 ±â€Š18.3 ml/min per 1.73 m, mean left ventricular ejection fraction was 59.3 ±â€Š9.9% and mean left ventricular mass index in men and women was 53.9 ±â€Š23.2 and 54.9 ±â€Š23.7 g/m with 50.4% of patients having left ventricular hypertrophy. A significant association between rs12917707 and eGFR was observed with T-allele carriers showing significantly higher eGFR values (+2.6 ml/min per 1.73 m, P = 0.006) than noncarriers. This SNP associated also with left atrial diameter (P = 0.007); homozygous carriers of the T-allele had smaller left atrial diameter (-1.5 mm) than other genotype groups (P = 0.040). No significant associations between rs12917707 and other cardiac or BP phenotypes were observed. CONCLUSIONS: These findings extend the previously documented role of UMOD for renal function also to treated high-risk patients with arterial hypertension and reveal a novel association with left atrial remodelling and thus a potential cardiorenal link modulated by UMOD.


Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Enfermedades Renales , Riñón/fisiología , Polimorfismo de Nucleótido Simple/genética , Uromodulina/genética , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Ecocardiografía , Femenino , Estudios de Asociación Genética , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Hipertensión/genética , Enfermedades Renales/complicaciones , Enfermedades Renales/epidemiología , Enfermedades Renales/genética , Pruebas de Función Renal , Masculino , Persona de Mediana Edad
19.
Pediatr Transplant ; 21(4)2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28205363

RESUMEN

While reduced HRQOL following isolated organ transplantation has been previously reported, there are no data in the context of children following CLKT. Twenty-three children who underwent CLKT at our institution were included in the study. The indication for CLKT was PH1 in 13 patients and ARPKD in 10 patients. Quantification of HRQOL was facilitated through the use of the PedsQL 4.0 Generic Core Scale. The results of the study were compared to healthy children and published data of children who had undergone LTx or KTx. The CLKT samples' child self-report showed good HRQOL. No statistically significant difference was found between the patients with PH1 and patients with ARPKD (P=.4). Compared to healthy children, a significant difference in the total scale score, the physical health score, and the school functioning was reported. HRQOL did not differ significantly when compared to patients following isolated LTx or KTx. To improve HRQOL after CLKT, a focus on patients' physical health, educational performances, and overall quality of life is crucial. Thus, coordinated medical care across disciplines and psychological and social support is essential to achieve this goal.


Asunto(s)
Indicadores de Salud , Hiperoxaluria Primaria/cirugía , Trasplante de Riñón , Trasplante de Hígado , Riñón Poliquístico Autosómico Recesivo/cirugía , Calidad de Vida , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Autoinforme , Resultado del Tratamiento
20.
Forensic Sci Int ; 271: 43-48, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28063329

RESUMEN

BACKGROUND: Ethyl glucuronide (EtG), a minor metabolite of ethanol, is used as a direct alcohol biomarker for the prolonged detection of ethanol consumption. Hair testing for EtG offers retrospective, long-term detection of ethanol exposition for several months and has gained practical importance in forensic and clinical toxicology. Since quantitative results of EtG hair testings are included in interpretations, a rugged quantitation of EtG in hair matrix is important. As generally known, sample preparation is critical in hair testing, and the scope of this study was on extraction of EtG from hair matrix. METHODS: The influence of extraction solvent, ultrasonication, incubation temperature, incubation time, solvent amount and hair particle size on quantitative results was investigated by a multifactorial experimental design using a validated analytical method and twelve different batches of authentic human hair material. Eight series of extraction experiments in a Plackett-Burman setup were carried out on each hair material with the studied factors at high or low levels. The effect of pulverization was further studied by two additional experimental series. Five independent samplings were performed for each run, resulting in a total number of 600 determinations. RESULTS: Considerable differences in quantitative EtG results were observed, concentrations above and below interpretative cut-offs were obtained from the same hair materials using different extraction conditions. Statistical analysis revealed extraction solvent and temperature as the most important experimental factors with significant influence on quantitative results. The impact of pulverization depended on other experimental factors and the different hair matrices themselves proved to be important predictors of extraction efficiency. CONCLUSIONS: A standardization of extraction procedures should be discussed, since it will probably reduce interlaboratory variabilities and improve the quality and acceptance of hair EtG analysis.


Asunto(s)
Glucuronatos/análisis , Cabello/química , Manejo de Especímenes/métodos , Alcoholismo/diagnóstico , Biomarcadores/análisis , Cromatografía Liquida , Humanos , Análisis Multivariante , Solventes , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem , Temperatura , Factores de Tiempo , Ondas Ultrasónicas
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