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1.
J Lipid Res ; : 100589, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38969064

RESUMO

BACKGROUND: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS: We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS: Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS: In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.

2.
Internist (Berl) ; 62(8): 827-840, 2021 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-34143250

RESUMO

Statins are among the most frequently prescribed drugs in Germany. Their benefits in lowering cardiovascular risk are beyond dispute. Nevertheless, many patients complain of side effects from statin therapy, including statin-associated muscle symptoms (SAMS) in particular. Despite their relative frequency, it is difficult to objectively diagnose them, as the time until appearance of first symptoms, the nature of the complaints and the severity of muscle problems vary widely. This narrative review summarizes the causes of SAMS as well as new possibilities regarding their diagnosis and therapy.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Alemanha , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Músculos
3.
Int J Obes (Lond) ; 44(5): 1119-1128, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31819201

RESUMO

BACKGROUND: Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome. METHODS: In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO2 conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO2 21%) conditions or hypoxia (n = 12; FiO2 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual V̇O2max. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues. RESULTS: The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISIClamp: 0.035 (IQR 0.016-0.075) vs. 0.037 (IQR 0.026-0.056) mg* kg-1 *min-1/(mU* l-1); p = 0.767). In contrast, ISIClamp improved during hypoxia training (0.028 (IQR 0.018-0.035) vs. 0.038 (IQR 0.024-0.060) mg * kg-1 *min-1/(mU *l-1); p < 0.05). Between group comparison of ISIClamp change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISIClamp during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISIClamp during hypoxic training. CONCLUSIONS: Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.


Assuntos
Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Síndrome Metabólica , Músculo Esquelético/metabolismo , Obesidade , Idoso , Humanos , Hipóxia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/terapia , Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue
4.
Clin Genet ; 98(5): 457-467, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32770674

RESUMO

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.


Assuntos
Apolipoproteína B-100/genética , LDL-Colesterol/genética , Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , LDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/patologia , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
5.
Neuroimage ; 184: 520-534, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253206

RESUMO

Although dietary decision-making is regulated by multiple interacting neural controllers, their impact on dietary treatment success in obesity has only been investigated individually. Here, we used fMRI to test how well interactions between the Pavlovian system (automatically triggering urges of consumption after food cue exposure) and the goal-directed system (considering long-term consequences of food decisions) predict future dietary success achieved in 39 months. Activity of the Pavlovian system was measured with a cue-reactivity task by comparing perception of food versus control pictures, activity of the goal-directed system with a food-specific delay discounting paradigm. Both tasks were applied in 30 individuals with obesity up to five times: Before a 12-week diet, immediately thereafter, and at three annual follow-up visits. Brain activity was analyzed in two steps. In the first, we searched for areas involved in Pavlovian processes and goal-directed control across the 39-month study period with voxel-wise linear mixed-effects (LME) analyses. In the second, we computed network parameters reflecting the covariation of longitudinal voxel activity (i.e. principal components) in the regions identified in the first step and used them to predict body mass changes across the 39 months with LME models. Network analyses testing the link of dietary success with activity of the individual systems as reference found a moderate negative link to Pavlovian activity primarily in left hippocampus and a moderate positive association to goal-directed activity primarily in right inferior parietal gyrus. A cross-paradigm network analysis that integrated activity measured in both tasks revealed a strong positive link for interactions between visual Pavlovian areas and goal-directed decision-making regions mainly located in right insular cortex. We conclude that adaptation of food cue processing resources to goal-directed control activity is an important prerequisite of sustained dietary weight loss, presumably since the latter activity can modulate Pavlovian urges triggered by frequent cue exposure in everyday life.


Assuntos
Encéfalo/fisiopatologia , Desvalorização pelo Atraso/fisiologia , Obesidade/dietoterapia , Obesidade/fisiopatologia , Adulto , Terapia Comportamental/métodos , Condicionamento Clássico , Dietoterapia/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento
6.
J Tissue Viability ; 28(4): 200-209, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31575473

RESUMO

BACKGROUND: Xerosis cutis of the feet is one of the most common skin conditions among type 2 diabetics. Whether skin dryness among diabetic patients is different from 'general' skin dryness is unclear. The overall aim was to compare the structure, function and molecular markers of dry and cracked foot skin between diabetics and non-diabetics. METHODS: The foot skin of 40 diabetics and 20 non-diabetics was evaluated. A clinical assessment of skin dryness was performed and transepidermal water loss, stratum corneum hydration, skin surface pH, epidermal thickness, skin roughness, elasticity and structural stiffness were measured. Ceramides, natural moisturizing factors, histamines, proteins and molecular markers of oxidative stress were analyzed based on a non-invasive sampling method for collection of surface biomarkers. RESULTS: The mean number of superficial fissures in the diabetic group was nearly three times higher than in the non-diabetic group (11.0 (SD 6.2) vs. 3.9 (SD 4.2)). The skin stiffness was higher in the diabetic group and the values of almost all molecular markers showed considerably higher values compared to non-diabetics. Malondialdehyde and glutathione were lower in the diabetic sample. CONCLUSIONS: The high number of superficial fissures may be based on an increased stiffness of dry diabetic foot skin combined with different concentrations of molecular markers in the stratum corneum compared to dry foot skin of non-diabetics.


Assuntos
Pé/irrigação sanguínea , Pé/fisiopatologia , Pele/fisiopatologia , Adulto , Idoso , Biomarcadores/análise , Diabetes Mellitus/fisiopatologia , Epiderme/metabolismo , Epiderme/microbiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia
7.
Depress Anxiety ; 34(11): 1040-1048, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28556577

RESUMO

BACKGROUND: Physical activity has shown to be effective in anxiety disorders. For specific phobia, no studies are available that systematically examined the effects of an aerobic exercise intervention on phobic fear within a randomized-controlled design. Therefore, we investigated the acute effect of a standardized aerobic training on clinical symptoms of dental phobia as well as on stress-related neurobiological markers. METHODS: Within a crossover design, 30 patients with dental phobia (mean age: 34.1 years; mean score of the Dental Anxiety Scale: 18.8) underwent two minor dental interventions separated by 7 days. Dental treatment was performed after 30 min of physical activity at either 20% VO2 max (control) or 70% VO2 max (intervention), respectively. To control for habituation, patients were randomly assigned to one of the two conditions prior to the first intervention. Moreover, saliva samples were collected at five times in order to determine changes in salivary cortisol (sC) and alpha-amylase (sAA) due to treatment. RESULTS: In comparison to baseline, aerobic exercise within 70% VO2 max significantly reduced clinical anxiety and sC concentrations before, during, and after the dental treatment. In contrast, the control condition led to decreased sAA levels at different time points of measurement. Habituation occurred at the second study day, independent of the order. CONCLUSIONS: Our study provides evidence for an effect of moderate-intense exercise on clinical symptoms and sC in patients with dental phobia. Therefore, acute aerobic exercise might be a simple and low-cost intervention to reduce disorder-specific phobic fear.


Assuntos
Ansiedade ao Tratamento Odontológico/fisiopatologia , Ansiedade ao Tratamento Odontológico/terapia , Exercício Físico/psicologia , Hidrocortisona/sangue , alfa-Amilases/sangue , Adulto , Nível de Alerta/fisiologia , Estudos Cross-Over , Ansiedade ao Tratamento Odontológico/psicologia , Medo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escala Visual Analógica , Adulto Jovem
8.
Clin Endocrinol (Oxf) ; 82(6): 838-43, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25640450

RESUMO

OBJECTIVE: Insulin resistance and subclinical inflammation are characteristics in the development of type 2 diabetes mellitus (T2DM). The adipokine chemerin has been associated with both factors. The aim of this study was to analyse whether chemerin predicts T2DM. DESIGN: Blood samples of 440 participants of the Metabolic-Syndrome Berlin-Potsdam (MesyBepo) follow-up study without diabetes at baseline were available for chemerin measurement. Mean follow-up of participants was 5·3 years. Glucose metabolism was analysed using oral glucose tolerance test including insulin measurements. Chemerin was measured using a commercially available ELISA. RESULTS: Thirty-five individuals developed T2DM during follow-up. Chemerin predicted incident T2DM (Chemerin 1. Tertile: reference, 2. Tertile: OR 2·33 [0·68-7·95]; Chemerin 3. Tertile: OR 3·42 [1·01-11·58] after adjustment for age, sex, BMI, follow-up time, HbA1c, HOMA-IR and WHR). In a secondary analysis, chemerin also predicted worsening of fasting glucose and HbA1c (adjusted for age, sex, BMI, time of follow-up, WHR, HDL cholesterol and triglycerides). CONCLUSIONS: Our data suggest that chemerin is a weak predictor of T2DM.


Assuntos
Quimiocinas/sangue , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Seguimentos , Alemanha , Teste de Tolerância a Glucose/métodos , Hemoglobinas Glicadas/análise , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico
9.
J Clin Lipidol ; 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38908966

RESUMO

BACKGROUND: Elevated lipoprotein(a) (Lp(a)) is an established risk factor for cardiovascular disease (CVD). To date, the only approved treatment to lower Lp(a) is lipoprotein apheresis (LA). Previous studies have demonstrated that LA is effective in reducing cardiovascular (CV) risk in patients with elevated low-density lipoprotein cholesterol (LDL-C) and/or Lp(a). Here we report our long-term experience with LA and its effectiveness in reducing CVD events in patients with elevated Lp(a). METHODS: This retrospective open-label, single-center study included 25 individuals with Lp(a) elevation >60 mg/dL and LDL-C < 2.59 mmol/L who had indication for LA. The primary endpoint of this study was the incidence of any CV event (determined by medical records) after initiation of LA. RESULTS: Mean LA treatment duration was 7.1 years (min-max: 1-19 years). Median Lp(a) was reduced from 95.0 to 31.1 mg/dL after LA (-67.3 %, p < 0.0001). Mean LDL-C was reduced from 1.85 to 0.76 mmol/L after LA (-58.9 %, p < 0.0001). Prior LA, 81 CV events occurred in total (0.87 events/patient/year). During LA, 49 CV events occurred in total (0.24 events/patient/year; -0.63, p = 0.001). Yearly major adverse cardiac event (MACE) rate was reduced from 0.34 to 0.006 (-0.33, p = 0.0002). Similar results were obtained when considering only individuals with baseline LDL-C below 1.42 mmol/L. CONCLUSION: In this observational study of a heterogeneous CV high-risk cohort with elevated Lp(a), LA reduced Lp(a) levels and was paralleled by a decrease in CV events and MACE. We recommend LA for patients with high Lp(a) who still have CV events despite optimal lipid-lowering medication and lifestyle changes.

10.
Diabetes Care ; 47(5): 798-802, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38277397

RESUMO

OBJECTIVE: Determining the cause of severe insulin resistance and early-onset diabetes in the case of a young woman in which a wide range of differential diagnoses did not apply. RESEARCH DESIGN AND METHODS: Diagnostic workup including medical history, physical examination, specialist consultations, imaging methods, laboratory assessment, and genetic testing carried out by next-generation panel sequencing. RESULTS: After ruling out several differential diagnoses, genetic testing revealed a previously unknown homozygous variant within the canonical splice site of intron 4 in the WRN gene classified as pathogenic. Thus, although not all cardinal clinical criteria according to existing guidelines had been met, the phenotype of our patient was attributed to Werner syndrome (WS), an autosomal-recessive inherited progeroid syndrome. CONCLUSIONS: WS, although rare, must be considered as a differential diagnosis in cases of severe insulin resistance. Moreover, recognized clinical criteria of WS may not lead to diagnosis in all cases.


Assuntos
Resistência à Insulina , Síndrome de Werner , Feminino , Humanos , Síndrome de Werner/diagnóstico , Síndrome de Werner/genética , Helicase da Síndrome de Werner/genética , Resistência à Insulina/genética , Mutação , Testes Genéticos
11.
Nat Commun ; 13(1): 5104, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36042189

RESUMO

A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.


Assuntos
COVID-19 , Síndrome de Fadiga Crônica , Adulto , Biomarcadores , COVID-19/complicações , COVID-19/epidemiologia , Canadá/epidemiologia , Síndrome de Fadiga Crônica/complicações , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/epidemiologia , Feminino , Alemanha/epidemiologia , Força da Mão , Humanos , Masculino , Pandemias , Estudos Prospectivos , Síndrome de COVID-19 Pós-Aguda
12.
Am J Cardiovasc Drugs ; 21(1): 83-92, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32514867

RESUMO

AIMS: Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs). OBJECTIVES: We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks. METHODS: In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68. RESULTS: At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were - 41.7% (alirocumab 75 mg Q2W), - 53.7% (alirocumab 150 mg Q2W), and - 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P < 0.0001). PCSK9i consistently improved levels of other lipoproteins throughout. Overall, 47.1% of patients reported adverse events at week 68. CONCLUSIONS: Consistent with clinical trial findings, alirocumab and evolocumab improved lipid levels in a real-world setting in patients with high baseline LDL-C levels despite receiving maximally tolerated LLTs. PCSK9i were generally well-tolerated.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Inibidores de PCSK9 , Anticorpos Monoclonais Humanizados/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Comorbidade , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lipídeos/sangue , Estudos Prospectivos
13.
Am J Physiol Endocrinol Metab ; 299(1): E126-30, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20424140

RESUMO

Fibroblast growth factor 21 (FGF-21), a novel metabolic factor in obesity and fasting metabolism, has been shown to be regulated by supraphysiological levels of free fatty acids (FFAs) under hyperinsulinemic conditions. Interestingly, it is still unclear whether the observed effects of FFAs on FGF-21 are relevant under physiological conditions, and the relative functions of FFAs and insulin within this context also need to be determined. Fourteen healthy men were studied in a randomized controlled crossover trial (RCT) using lipid heparin infusion (LHI) at a dose inducing physiological elevations of FFAs vs. saline heparin infusion. In a second randomized controlled trial, FGF-21 was analyzed in 14 patients with type 1 diabetes (6 men, 8 women) during continuous insulin supply vs. discontinued insulin infusion and subsequently increased lipolysis and ketosis. Circulating FGF-21 increased during physiologically elevated FFAs induced by LHI, which was accompanied by mild hyperinsulinemia. Interestingly, a mild elevation of FFAs resulting from complete insulin deficiency also increased FGF-21 levels. These results from two independent human RCTs suggest that FFAs increase circulating FGF-21, while insulin is only of minor importance under physiological conditions. This mechanism might explain the apparent paradox of increased FGF-21 levels in obesity, insulin resistance, and starvation.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Ácidos Graxos não Esterificados/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Insulina/administração & dosagem , Insulina/sangue , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Heparina/administração & dosagem , Humanos , Resistência à Insulina/fisiologia , Corpos Cetônicos/metabolismo , Corpos Cetônicos/urina , Masculino
14.
Neuroradiol J ; 33(5): 400-409, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32666872

RESUMO

PURPOSE: Obesity has become a major health problem and is associated with endocrine disorders and a disturbed hypothalamic-pituitary axis. The purpose of this study was to correlate pituitary gland volume determined by routine magnetic resonance imaging with patient characteristics, in particular body mass index and obesity. MATERIAL AND METHODS: A total of 144 'healthy' patients with normal findings in cerebral magnetic resonance imaging were retrospectively included. Pituitary gland volume was measured in postcontrast three-dimensional T1-weighted sequences. A polygonal three-dimensional region of interest covering the whole pituitary gland was assessed manually. Physical characteristics (gender, age, body height and body mass index) were correlated with pituitary gland volume. Multiple subgroup and regression analyses were performed. RESULTS: Pituitary gland volumes were significantly larger in females than in males (p<0.001) and young individuals (<35 years) versus middle-aged patients (35-47 years) (p=0.042). Obese patients (body mass index ≥30) had significantly larger pituitary gland volumes than overweight (250.05). Regression analysis showed that increased pituitary gland volume is associated with higher body mass index independent from gender, age and body height. CONCLUSION: Pituitary gland volume is increased in obese individuals and a high body mass index can be seen as an independent predictor of increased pituitary gland volume. Therefore, gland enlargement might be an imaging indicator of dysfunction in the hypothalamus-pituitary axis. Besides gender and age, body mass index should be considered by radiologists when diagnosing abnormal changes in pituitary gland volume.


Assuntos
Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Obesidade/complicações , Hipófise/diagnóstico por imagem , Adolescente , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Compostos Organometálicos , Estudos Retrospectivos , Fatores Sexuais
15.
Vascul Pharmacol ; 135: 106804, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32987194

RESUMO

BACKGROUND: Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-I) have been reported to cause a moderate increase in high-density lipoprotein (HDL) cholesterol in human studies. We thus evaluated the effect of two approved PCSK9-I on the concentration and lipid composition of HDL particle subclasses. SUBJECTS AND METHODS: 95 patients (62.8 ± 10.3 years old, 58% men), with or without statin and/or ezetimibe treatment and eligible for PCSK9-I therapy, received either evolocumab (140 mg) or alirocumab (75 or 150 mg). Their HDL particle profiles were measured by NMR spectroscopy at baseline and after 4 weeks of PCSK9-I treatment. RESULTS: PCSK9-I treatment increased the level of HDL-C by 7%. The level of medium-sized HDL particles (M-HDL-P) increased (+8%) while the level of XL-HDL-P decreased (-19%). The lipid core composition was altered in the smaller S- and M-HDL-P, with a reduction in triglycerides (TG) and an enrichment in cholesterol esters (CE), whereas the for the larger XL- and L-HDL-P the relative CE content decreased and the TG content increased. Ezetimibe therapy differentially impacted the HDL particle distribution, independently of statin use, with an increase in S-HDL-P in patients not receiving ezetimibe. CONCLUSIONS: As S- and M-HDL-P levels are inversely related to cardiovascular risk, PCSK9-I treatment may result in a more atheroprotective HDL particle profile, particularly in patients not concomitantly treated with ezetimibe.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Inibidores de PCSK9 , Inibidores de Serina Proteinase/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/etiologia , Biomarcadores/sangue , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/complicações , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Medição de Risco , Fatores de Risco , Inibidores de Serina Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
Clin Endocrinol (Oxf) ; 71(4): 507-11, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19751297

RESUMO

OBJECTIVE: Obesity and insulin resistance are associated with low adiponectin levels, although adiponectin is exclusively expressed in white adipose tissue. The mechanism beyond that paradox is not entirely clear, although insulin itself may reduce circulating adiponectin levels. However, obesity is also associated with hyperlipidaemia and the effects of free fatty acids (FFAs) and triglycerides (TG) on circulating adiponectin levels have not yet been investigated. MATERIALS AND METHODS: We analysed the effect of an acute and euglycaemic elevation of insulin on adiponectin oligomers in 23 healthy individuals. In a subgroup including 11 healthy men, FFAs and TG were acutely elevated by infusion of heparin/lipids over 120 min. Again the effect on circulating adiponectin and its oligomers was investigated. Adiponectin was determined by ELISA, oligomers were detected by nondenaturating Western blot. RESULTS: Acute hyperinsulinaemia resulted in a significant reduction of total adiponectin to 7.74 +/- 0.98 microg/ml (P = 0.004). High molecular weight (HMW) adiponectin did not change (0.80 +/- 0.12 to 0.81 +/- 0.14 microg/ml; P = 0.887), whereas MMW adiponectin decreased from 4.30 +/- 0.51 to 3.78 +/- 0.48 microg/ml (P = 0.005) and LMW adiponectin from 3.63 +/- 0.42 to 3.15 +/- 0.46 microg/ml (P = 0.048). Interestingly, heparin/lipid infusion also reduced circulating adiponectin levels (P = 0.001), which was primarily the result of reduced MMW adiponectin (P = 0.004), whereas LMW and HMW were not significantly affected. CONCLUSIONS: The presented data suggest that both, hyperinsulinaemia and hyperlipidaemia, may contribute to low adiponectin levels in states of obesity.


Assuntos
Adiponectina/sangue , Hiperinsulinismo/sangue , Hiperlipidemias/sangue , Adulto , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Lipídeos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Peso Molecular , Obesidade/sangue , Multimerização Proteica , Triglicerídeos/sangue
17.
Mol Genet Metab Rep ; 20: 100479, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31249784

RESUMO

We report on a case of very rare autosomal recessive cholesteryl ester storage disease due to lysosomal acid lipase deficiency (LALD). LALD is caused by mutations in the lysosomal acid lipase A (LIPA) gene resulting in cholesteryl ester accumulation in liver, spleen, and macrophages. It can lead to liver failure, accelerated atherosclerosis and premature death. Until recently, treatment options were limited to lipid-lowering medications to control dyslipidemia. Presently, a long-term enzyme replacement therapy with Sebelipase alfa, a recombinant human lysosomal acid lipase, is available for patients with LALD. Our patient's condition became conspicuous at the age of two due to a xanthogranuloma of the chin together with increased lipid levels, elevated liver enzymes and hepatomegaly. It took another five years until our patient was diagnosed with LALD after genetic testing. A bi-weekly therapy with intravenous Sebelipase alfa was started at the age of 26 years. It led to normalization of lipid levels, reduction of liver enzymes and beginning regression of hepatomegaly in the absence of adverse drug reactions after 46 infusions. Since LALD can take a fatal course even in patients with a long-term stable condition, it is essential to identify affected patients early and to treat them appropriately by enzyme replacement therapy. LALD should be suspected in patients with low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) in conjunction with elevated liver enzymes or hepatomegaly. A registry for LALD patients shall help to advance our understanding of the disease as well as improve patient care (NCT01633489).

18.
Sci Rep ; 9(1): 11995, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427613

RESUMO

Familial hypercholesterolemia (FH) is characterised by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and a substantial risk for cardiovascular disease. The autosomal-dominant FH is mostly caused by mutations in LDLR (low density lipoprotein receptor), APOB (apolipoprotein B), and PCSK9 (proprotein convertase subtilisin/kexin). Recently, STAP1 has been suggested as a fourth causative gene. We analyzed STAP1 in 75 hypercholesterolemic patients from Berlin, Germany, who are negative for mutations in canonical FH genes. In 10 patients with negative family history, we additionally screened for disease causing variants in LDLRAP1 (low density lipoprotein receptor adaptor protein 1), associated with autosomal-recessive hypercholesterolemia. We identified one STAP1 variant predicted to be disease causing. To evaluate association of serum lipid levels and STAP1 carrier status, we analyzed 20 individuals from a population based cohort, the Cooperative Health Research in South Tyrol (CHRIS) study, carrying rare STAP1 variants. Out of the same cohort we randomly selected 100 non-carriers as control. In the Berlin FH cohort STAP1 variants were rare. In the CHRIS cohort, we obtained no statistically significant differences between carriers and non-carriers of STAP1 variants with respect to lipid traits. Until such an association has been verified in more individuals with genetic variants in STAP1, we cannot estimate whether STAP1 generally is a causative gene for FH.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/etiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Estudos de Associação Genética/métodos , Humanos , Metabolismo dos Lipídeos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Análise de Sequência de DNA
19.
Metabolism ; 83: 60-67, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29360493

RESUMO

BACKGROUND: Lifestyle based weight loss interventions are hampered by long-term inefficacy. Prediction of individuals successfully reducing body weight would be highly desirable. Although sympathetic activity is known to contribute to energy homeostasis, its predictive role in body weight maintenance has not yet been addressed. OBJECTIVES: We investigated, whether weight regain could be modified by a weight maintenance intervention and analyzed the predictive role of weight loss-induced changes of the sympathetic system on long-term weight regain. DESIGN: 156 subjects (age > 18; BMI ≥ 27 kg/m2) participated in a 12-week weight reduction program. After weight loss (T0), 143 subjects (weight loss > 8%) were randomized to a 12-month lifestyle intervention or a control group. After 12 months (T12) no further intervention was performed until month 18 (T18). Weight regain at T18 (regainBMI) was the primary outcome. Evaluation of systemic and tissue specific estimates of sympathetic system was a pre-defined secondary outcome. RESULTS: BMI was reduced by 4.67 ±â€¯1.47 kg/m2 during the initial weight loss period. BMI maintained low in subjects of the intervention group until T12 (+0.07 ±â€¯2.98 kg/m2; p = 0.58 compared to T0), while control subjects regained +0.98 ±â€¯1.93 kg/m2 (p < 0.001 compared to T0). The intervention group regained more weight than controls after ceasing the intervention (1.17 ±â€¯1.34 vs. 0.57 ±â€¯0.93 kg/m2) until T18. Consequently, BMI was not different at T18 (33.49 (32.64; 34.33) vs. 34.18 (33.61; 34.75) kg/m2; p=0.17). Weight loss-induced modification of urinary metanephrine excretion independently predicted regainBMI (R2 = 0.138; p < 0.05). The lifestyle intervention did not modify the course of urinary metanephrines after initial weight loss. CONCLUSIONS: Our lifestyle intervention successfully maintained body weight during the intervention period. However, no long-term effect could be observed beyond the intervention period. Predictive sympathetic activity was not persistently modified by the intervention, which may partially explain the lack of long-term success of such interventions.


Assuntos
Terapia Comportamental , Manutenção do Peso Corporal/fisiologia , Dieta Redutora , Terapia por Exercício , Obesidade/terapia , Sistema Nervoso Simpático/fisiologia , Programas de Redução de Peso/métodos , Adulto , Terapia Combinada , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Obesidade/psicologia , Resultado do Tratamento , Redução de Peso/fisiologia
20.
Diabetes ; 55(1): 141-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16380487

RESUMO

Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism.


Assuntos
Adiponectina/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Adiponectina/líquido cefalorraquidiano , Adiponectina/farmacologia , Tecido Adiposo/metabolismo , Adulto , Idoso , Animais , Encéfalo/metabolismo , Células Endoteliais/efeitos dos fármacos , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Adiponectina , Receptores de Superfície Celular/metabolismo , Soro/metabolismo
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