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1.
J Orthop Surg Res ; 14(1): 367, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727136

RESUMO

BACKGROUND: There is still a challenge in discriminating between vertebral osteomyelitis and degenerative diseases of the spine. To this end, we determined the suitability of soluble urokinase-type plasminogen activator receptor (suPAR) and compared the diagnostic potential of suPAR to CRP. METHODS: Patients underwent surgical stabilization of the lumbar and/or thoracic spine with removal of one or more affected intervertebral discs, as therapy for vertebral osteomyelitis (n = 16) or for erosive osteochondrosis (control group, n = 20). In this prospective study, we evaluated the suPAR and CRP levels before (pre-OP) and after surgery (post-OP) on days 3-5, 6-11, 40-56, and 63-142. RESULTS: The suPAR levels in vertebral osteomyelitis patients were significantly higher than those from controls pre-OP, 3-5 days post-OP, and 6-11 days post-OP. Significantly higher CRP levels were observed in the vertebral osteomyelitis group than in the controls pre-OP and 6-11 days post-OP. Levels of suPAR and CRP correlated positively in all patients in the pre-OP period: r = 0.63 (95% CI: 0.37-0.79), p < 0.0001. The values for the area under the receiver operating characteristics curve (AUC) for pre-OP and the overall model post-OP were 0.88 (95% CI: 0.76-1.00) and 0.84 (95% CI: 0.71-0.97) for suPAR, 0.93 (95% CI: 0.85-1.00) and 0.77 (95% CI: 0.62-0.93) for CRP, and 0.98 (95% CI: 0.96-1.00) and 0.91 (95% CI: 0.82-1.00) for the combination of suPAR and CRP. The AUC for suPAR pre-OP revealed an optimum cut-off value, sensitivity, specificity, NPV, and PPV of 2.96 ng/mL, 0.69, 1.00, 0.80, and 1.00, respectively. For CRP, these values were 11.58 mg/L, 0.88, 0.90, 0.90, and 0.88, respectively. CONCLUSION: The present results show that CRP is more sensitive than suPAR whereas suPAR is more specific than CRP. Moreso, our study demonstrated that improvement in the diagnostic power for discrimination of vertebral osteomyelitis and degenerative diseases of the spine can be achieved by a combination of both suPAR and CRP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02554227, posted Sept. 18, 2015, and updated Aug. 13, 2019.

2.
Am J Med Genet A ; 179(12): 2474-2480, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31584751

RESUMO

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.

3.
Am J Hum Genet ; 104(6): 1223-1232, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130282

RESUMO

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

4.
Sci Rep ; 9(1): 3641, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842540

RESUMO

Cardiovascular risk rapidly increased following exposure to air pollution. Changes in human autonomic regulation have been implicated based on epidemiological associations between exposure estimates and indirect autonomic nervous system measurements. We conducted a mechanistic study to test the hypothesis that, in healthy older individuals, well-defined experimental exposure to ultrafine carbon particles (UFP) increases sympathetic nervous system activity and more so with added ozone (O3). Eighteen participants (age >50 years, 6 women) were exposed to filtered air (Air), UFP, and UFP + O3 combination for 3 hours during intermittent bicycle ergometer training in a randomized, crossover, double-blind fashion. Two hours following exposure, respiration, electrocardiogram, blood pressure, and muscle sympathetic nerve activity (MSNA) were recorded at supine rest, during deep breathing, and during a Valsalva manoeuvre. Catechols and inflammatory marker levels were measured in venous blood samples. Induced sputum was obtained 3.5 h after exposure. Combined exposure to UFP + O3 but not UFP alone, caused a significant increase in sputum neutrophils and circulating leucocytes. Norepinephrine was modestly increased while the ratio between plasma dihydroxyphenylglycol (DHPG) and norepinephrine levels, a marker for norepinephrine clearance, was reduced with UFP + O3. Resting MSNA was not different (47 ± 12 with Air, 47 ± 14 with UFP, and 45 ± 14 bursts/min with UFP + O3). Indices of parasympathetic heart rate control were unaffected by experimental air pollution. Our study suggests that combined exposure to modest UFP and O3 levels increases peripheral norepinephrine availability through decreased clearance rather than changes in central autonomic activity. Pulmonary inflammatory response may have perturbed pulmonary endothelial norepinephrine clearance.

5.
Genet Med ; 20(10): 1175-1185, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29469822

RESUMO

PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

6.
Am J Med Genet A ; 176(2): 470-476, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29271604

RESUMO

Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.

8.
Hypertension ; 67(3): 585-91, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26831195

RESUMO

Bilateral bipolar electric carotid sinus stimulation acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant arterial hypertension but is no longer available. The second-generation device uses a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We hypothesized that the second-generation device acutely lowers BP and MSNA in treatment-resistant hypertensive patients. Eighteen treatment-resistant hypertensive patients (9 women/9 men; 53±11 years; 33±5 kg/m(2)) on stable medications have been included in the study. We monitored finger and brachial BP, heart rate, and MSNA. Without stimulation, BP was 165±31/91±18 mm Hg, heart rate was 75±17 bpm, and MSNA was 48±14 bursts per minute. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited interindividually variable changes in systolic BP (-16.9±15.0 mm Hg; range, 0.0 to -40.8 mm Hg; P=0.002), heart rate (-3.6±3.6 bpm; P=0.004), and MSNA (-2.0±5.8 bursts per minute; P=0.375). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (systolic BP, -6.3±7.0 mm Hg; range, 2.8 to -14.5 mm Hg; P=0.028 and heart rate, -1.5±2.3 bpm; P=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) were correlated (r(2)=0.329; P=0.025). In our patient cohort, unilateral unipolar electric baroreflex stimulation acutely lowered BP. However, side effects may limit efficacy. The approach should be tested in a controlled comparative study.


Assuntos
Pressão Sanguínea/fisiologia , Seio Carotídeo/inervação , Resistência a Medicamentos , Estimulação Elétrica/métodos , Hipertensão/terapia , Sistema Nervoso Simpático/fisiopatologia , Vasodilatação/fisiologia , Anti-Hipertensivos/farmacologia , Barorreflexo/fisiologia , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/fisiopatologia
9.
J Am Heart Assoc ; 5(1)2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26764413

RESUMO

BACKGROUND: Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. METHODS AND RESULTS: We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. CONCLUSIONS: HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Benzazepinas/administração & dosagem , Relógios Biológicos/efeitos dos fármacos , Fármacos Cardiovasculares/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Nó Sinoatrial/efeitos dos fármacos , Adulto , Sistema Nervoso Autônomo/fisiologia , Benzazepinas/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/induzido quimicamente , Bradicardia/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Eletrocardiografia , Alemanha , Voluntários Saudáveis , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Ivabradina , Masculino , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/metabolismo , Músculo Esquelético/inervação , Canais de Potássio/metabolismo , Nó Sinoatrial/inervação , Nó Sinoatrial/metabolismo , Fatores de Tempo , Adulto Jovem
10.
PLoS One ; 10(10): e0139700, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26444874

RESUMO

The production and consumption of mare's milk in Europe has gained importance, mainly based on positive health effects and a lower allergenic potential as compared to cows' milk. The allergenicity of milk is to a certain extent affected by different genetic variants. In classical dairy species, much research has been conducted into the genetic variability of milk proteins, but the knowledge in horses is scarce. Here, we characterize two major forms of equine αS2-casein arising from genomic 1.3 kb in-frame deletion involving two coding exons, one of which represents an equid specific duplication. Findings at the DNA-level have been verified by cDNA sequencing from horse milk of mares with different genotypes. At the protein-level, we were able to show by SDS-page and in-gel digestion with subsequent LC-MS analysis that both proteins are actually expressed. The comparison with published sequences of other equids revealed that the deletion has probably occurred before the ancestor of present-day asses and zebras diverged from the horse lineage.


Assuntos
Caseínas/genética , Éxons/genética , Variação Genética/genética , Deleção de Sequência/genética , Alérgenos/genética , Sequência de Aminoácidos , Animais , DNA/genética , DNA Complementar/genética , Digestão/genética , Europa (Continente) , Feminino , Cavalos , Espectrometria de Massas , Leite/metabolismo , Proteínas do Leite/genética , Fases de Leitura/genética
11.
J Am Soc Hypertens ; 9(10): 794-801, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26324745

RESUMO

Patients with treatment-resistant arterial hypertension exhibited profound reductions in single sympathetic vasoconstrictor fiber firing rates after renal nerve ablation. In contrast, integrated multi-unit muscle sympathetic nerve activity (MSNA) changed little or not at all. We hypothesized that conventional MSNA analysis may have missed single fiber discharges, thus, obscuring sympathetic inhibition after renal denervation. We studied patients with difficult-to-control arterial hypertension (age 45-74 years) before, 6 (n = 11), and 12 months (n = 8) after renal nerve ablation. Electrocardiogram, respiration, brachial, and finger arterial blood pressure (BP), as well as the MSNA and raw MSNA signals were analyzed. We detected MSNA action-potential spikes using 2 stage kurtosis wavelet denoising techniques to assess mean, median, and maximum spike rates for each beat-to-beat interval. Supine heart rate and systolic BP did not change at 6 (ΔHR: -2 ± 3 bpm; ΔSBP: 2 ± 9 mm Hg) or at 12 months (ΔHR: -1 ± 3 mm Hg, ΔSBP: -1 ± 9 mm Hg) after renal nerve ablation. Mean burst frequency and mean spike frequency at baseline were 34 ± 3 bursts per minute and 8 ± 1 spikes per second. Both measurements did not change at 6 months (-1.4 ± 3.6 bursts/minute; -0.6 ± 1.4 spikes/second) or at 12 months (-2.5 ± 4.0 bursts/minute; -2.0 ± 1.6 spikes/second) after renal nerve ablation. After renal nerve ablation, BP decreased in 3 of 11 patients. BP and MSNA spike frequency changes were not correlated (slope = -0.06; P = .369). Spike rate analysis of multi-unit MSNA neurograms further suggests that profound sympathetic inhibition is not a consistent finding after renal nerve ablation.


Assuntos
Potenciais de Ação/fisiologia , Ablação por Cateter/métodos , Hipertensão/cirurgia , Rim/inervação , Rim/cirurgia , Sistema Nervoso Simpático/cirurgia , Idoso , Pressão Sanguínea/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Fibras Nervosas/fisiologia , Neurônios Eferentes/fisiologia , Simpatectomia , Sistema Nervoso Simpático/fisiopatologia
12.
J Am Soc Hypertens ; 9(4): 293-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25816714

RESUMO

Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applanation tonometry. These pilot study findings suggest that impedance cardiography combined with thigh oscillometry provides comparable results. Intra- and inter-observer variability was tested by two observers in two subjects. We instrumented 41 patients and 12 healthy normotensive controls for impedance cardiography and consecutive applanation tonometry and compared methods using the Bland-Altman method. Observer variability for the impedance-thigh cuff method (range, 3.61%-7.77%) was comparable with the tonometric method (range, 2.93%-7.37%). Comparison of the two methods based on the Bland-Altman plot revealed a good agreement between methods. The bias between impedance and tonometric measurements was -0.28 ± 0.37 m/s. Both measurements were significantly correlated (r(2) = 0.94; P < .0001; slope = 1.038).Impedance cardiography combined with thigh oscillometry is an easy to use approach which, in addition to providing hemodynamic information, yields aPWV measurements comparable to applanation tonometry. Following full validation according to current guidelines, the methodology could prove useful in cardiovascular risk stratification.


Assuntos
Aorta/fisiopatologia , Cardiografia de Impedância , Manometria , Análise de Onda de Pulso , Adulto , Estudos de Casos e Controles , Eletrocardiografia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Oscilometria , Projetos Piloto
17.
Auton Neurosci ; 172(1-2): 31-6, 2012 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-23146623

RESUMO

Treatment resistant arterial hypertension is commonly defined as blood pressure that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes. The sympathetic nervous system promotes arterial hypertension and cardiovascular as well as renal damage, thus, providing a logical treatment target in these patients. Recent physiological studies suggest that baroreflex mechanisms contribute to long-term control of sympathetic activity and blood pressure providing an impetus for the development of electrical carotid sinus stimulators. The concept behind electrical stimulation of baroreceptors or baroreflex afferent nerves is that the stimulus is sensed by the brain as blood pressure increase. Then, baroreflex efferent structures are adjusted to counteract the perceived blood pressure increase. Electrical stimulators directly activating afferent baroreflex nerves were developed years earlier but failed for technical reasons. Recently, a novel implantable device was developed that produces an electrical field stimulation of the carotid sinus wall. Carefully conducted experiments in dogs provided important insight in mechanisms mediating the depressor response to electrical carotid sinus stimulation. Moreover, these studies showed that the treatment success may depend on the underlying pathophysiology of the hypertension. Clinical studies suggest that electrical carotid sinus stimulation attenuates sympathetic activation of vasculature, heart, and kidney while augmenting cardiac vagal regulation, thus lowering blood pressure. Yet, not all patients respond to treatment. Additional clinical trials are required. Patients equipped with an electrical carotid sinus stimulator provide a unique opportunity gaining insight in human baroreflex physiology.


Assuntos
Barorreflexo , Seio Carotídeo/inervação , Terapia por Estimulação Elétrica , Hipertensão/terapia , Animais , Anti-Hipertensivos/uso terapêutico , Artérias/efeitos dos fármacos , Artérias/inervação , Artérias/fisiopatologia , Barorreflexo/efeitos dos fármacos , Seio Carotídeo/fisiopatologia , Resistência a Medicamentos , Terapia por Estimulação Elétrica/métodos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia
18.
Hypertension ; 60(6): 1485-90, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23045466

RESUMO

Endovascular renal nerve ablation has been developed to treat resistant hypertension. In addition to lowering efferent renal sympathetic activation, the intervention may attenuate central sympathetic outflow through decreased renal afferent nerve traffic, as evidenced by a recent case report. We tested the hypothesis in 12 nonpreselected patients with difficult-to-control hypertension (aged 45-74 years) admitted for renal nerve ablation. All patients received ≥ 3 antihypertensive medications at full doses, including a diuretic. Electrocardiogram, respiration, brachial and finger arterial blood pressure, and muscle sympathetic nerve activity were recorded before and 3 to 6 months after renal nerve ablation. Heart rate and blood pressure variability were analyzed in the time and frequency domain. Pharmacological baroreflex slopes were determined using the modified Oxford bolus technique. Resting heart rate was 61 ± 3 bpm before and 58 ± 2 bpm after ablation (P = 0.4). Supine blood pressure was 157 ± 7/85 ± 4 mm Hg before and 157 ± 6/85 ± 4 mm Hg after ablation (P = 1.0). Renal nerve ablation did not change resting muscle sympathetic nerve activity (before, 34 ± 2 bursts per minute; after, 32 ± 3 bursts per minute P = 0.6), heart rate variability, or blood pressure variability. Pharmacological baroreflex control of heart rate and muscle sympathetic nerve activity did not change. We conclude that reduced central sympathetic inhibition may be the exception rather than the rule after renal nerve ablation in unselected patients with difficult-to-control arterial hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Ablação por Cateter , Hipertensão/cirurgia , Rim/inervação , Simpatectomia , Sistema Nervoso Simpático/cirurgia , Idoso , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema Nervoso Simpático/fisiopatologia , Resultado do Tratamento
19.
Hypertension ; 60(3): 849-55, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22824986

RESUMO

The superior clinical outcome of new continuous-flow left ventricular assist devices (LVADs) challenges the physiological dogma that cardiovascular autonomic homeostasis requires pulsatile blood flow and pressure. We tested the hypothesis that continuous-flow LVADs impair baroreflex control of sympathetic nerve traffic, thus further exacerbating sympathetic excitation. We included 9 male heart failure patients (26-61 years; 18.9-28.3 kg/m(2)) implanted with a continuous-flow LVAD. We recorded ECG, respiration, finger blood pressure, brachial blood pressure, and muscle sympathetic nerve activity. After baseline measurements had been taken, patients underwent autonomic function testing including deep breathing, a Valsalva maneuver, and 15° head-up tilt. Finally, we increased the LVAD speed in 7 patients. Spontaneous sympathetic baroreflex sensitivity was analyzed. Brachial blood pressure was 99±4 mm Hg with 14±2 mm Hg finger pulse pressure. Muscle sympathetic nerve activity bursts showed a normal morphology, were linked to the cardiac cycle, and were suppressed during blood pressure increases. Mean burst frequency was lower compared with age- and body mass index-matched controls in 2 patients, slightly increased in 4 patients, and increased in 2 patients (P=0.11). Muscle sympathetic nerve activity burst latency and the median values of the burst amplitude distribution were similar between groups. Muscle sympathetic nerve activity increased 4±1 bursts per minute with head-up tilt (P<0.0003) and decreased 3±4 bursts per minute (P<0.031) when LVAD speed was raised. The mean sympathetic baroreflex slope was -3.75±0.79%/mm Hg in patients and -3.80±0.55%/mm Hg in controls. We conclude that low pulse pressure levels are sufficient to restrain sympathetic nervous system activity through baroreflex mechanisms.


Assuntos
Barorreflexo/fisiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Coração Auxiliar , Adulto , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Respiração , Sistema Nervoso Simpático/fisiologia
20.
Curr Alzheimer Res ; 9(4): 507-15, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22372439

RESUMO

Autobiographical memory (AM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.


Assuntos
Doença de Alzheimer/complicações , Disfunção Cognitiva/complicações , Hipocampo/patologia , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Memória Episódica , Idoso , Doença de Alzheimer/patologia , Análise de Variância , Distribuição de Qui-Quadrado , Disfunção Cognitiva/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica
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