RESUMO
After a fall a 52-year-old female patient suffered an unstable fracture of lumbar vertebral body 3 and a stable fracture of thoracic vertebral body 12 without neurological deficits. In addition to the balloon kyphoplasty of thoracic vertebral body 12, percutaneous fixator internal instrumentation of lumbar vertebral bodies 2-4 was carried out with cement-augmented pedicle screws. Cement leakage into the inferior vena cava occurred. After the onset of detachment of the cement parts, we decided on an endovascular removal using the sling technique. The postinterventional course was uncomplicated.
Assuntos
Embolia , Cifoplastia , Parafusos Pediculares , Fraturas da Coluna Vertebral , Cimentos Ósseos/efeitos adversos , Feminino , Humanos , Cifoplastia/efeitos adversos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Pessoa de Meia-Idade , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Vértebras TorácicasAssuntos
Comportamento Cooperativo , Hipertensão Pulmonar/tratamento farmacológico , Comunicação Interdisciplinar , Terapia de Alvo Molecular/métodos , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Terapia Combinada , Aprovação de Drogas , Quimioterapia Combinada , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Medicina Baseada em Evidências , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. OBJECTIVE: To perform an individual patient data meta-analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. METHODS: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once-daily) and UFH (5000 IU subcutaneous two- or three-times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. RESULTS: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51-0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17-0.85) at day 15. RR for total VTE in stroke and non-stroke patients was 0.59 (95% CI 0.47-0.74) and 0.87 (95% CI 0.51-1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53-2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64-1.08), compared with UFH. CONCLUSIONS: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all-cause mortality.
Assuntos
Anticoagulantes/farmacologia , Enoxaparina/farmacologia , Heparina/farmacologia , Tromboembolia Venosa/prevenção & controle , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Método Duplo-Cego , Enoxaparina/administração & dosagem , Enoxaparina/efeitos adversos , Feminino , França/epidemiologia , Hemorragia/etiologia , Heparina/administração & dosagem , Heparina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do Tratamento , Tromboembolia Venosa/mortalidadeRESUMO
The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more frequent forms of PH such as PH due to left heart disease. Despite the lack of data, targeted PAH treatments are increasingly being used for PH associated with left heart disease. This development is of concern. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease, so that it may be speculated whether selected patients may benefit from targeted PH therapy. It that sense, the practical implementation of the European Guidelines in Germany requires the consideration of several specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to PH due to left heart disease. This commentary summarizes the results and recommendations of this working group.
Assuntos
Insuficiência Cardíaca/complicações , Hipertensão Pulmonar/etiologia , Disfunção Ventricular Esquerda/complicações , Alemanha , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/terapia , Prognóstico , Análise de Sobrevida , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/terapiaRESUMO
BACKGROUND: Increased end-tidal oxygen (ET-O(2)) and decreased end-tidal carbon dioxide (ET-CO(2)) gas tensions are noninvasively measurable correlates of ventilatory inefficiency, leading to increased ventilatory requirements relative to gas exchange among patients with chronic heart failure (CHF). We investigated the prognostic value of ET-O(2) and ET-CO(2) as predictors of CHF mortality. METHODS: We measured resting ET-O(2) and ET-CO(2) electrochemically in 134 patients with symptomatic CHF in the supine position. We used Kaplan-Meier analysis, Cox proportional hazard models, and receiver operating characteristic curves to test our hypothesis. RESULTS: At a median follow-up of 16.5 months, 32 patients had died. ET-O(2) levels were increased (P = .001) and ET-CO(2) levels decreased (P = .002) with increased New York Heart Association class (I-IV). Survivors showed lower ET-O(2) (121 vs 118 mm Hg; P = .021) and higher ET-CO(2) (33.2 vs 32.1 mm Hg; P = .032) levels than nonsurvivors. Patients with ET-O(2) values ≥121 mm Hg and/or ET-CO(2) values <31 mm Hg had an increased risk of death with hazard ratios of 2.93 (95% confidence interval [CI], 1.43-6.01) and 2.47 (95% CI, 1.23-4.97), respectively. Kaplan-Meier estimates for follow-up mortality with ET-O(2) ≥121 mm Hg and/or ET-CO(2) <31 mm Hg were 83.8% (vs 60.1%; P = .0014) and 80.3% (vs 60.2%; P = .0061), respectively. Areas under the receiver operating characteristic curves for prediction of death with ET-O(2) and ET-CO(2) were both significant and similar to that of echocardiographic left ventricular function. CONCLUSIONS: In CHF, high levels of ET-O(2) and low levels of ET-CO(2) are associated with increased mortality. We suggest that the measurements may be useful prognostic markers for risk stratification.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Alvéolos Pulmonares/fisiopatologia , Idoso , Dióxido de Carbono/análise , Doença Crônica , Ecocardiografia , Feminino , Volume Expiratório Forçado , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/fisiopatologia , Oxigênio/análise , Prognóstico , Modelos de Riscos Proporcionais , Decúbito Dorsal , Volume de Ventilação Pulmonar/fisiologia , Disfunção Ventricular Esquerda/fisiopatologiaAssuntos
Anemia Falciforme , Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/epidemiologia , Comorbidade , Diagnóstico Diferencial , Alemanha/epidemiologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Prevalência , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: An adapted system of 'Diagnosis Related Groups' (DRG's) will be introduced for Germany at the beginning of 2003. This article focuses on the structure of the Australian DRG system (AR-DRG 4.1) regarding the diseases of the cardiovascular system and corresponding cost weights in Germany (G-DRG 1.0). METHODS: Cardiac diagnoses, procedures and cost weights (with a different base rate) were compared between the Australian and German DRG's. RESULTS: Categories and procedures for diagnostics and therapies are shown regarding coronary interventions, electrophysiological strategies including implantation of pacemakers and cardioverter/ defibrillators, hybrid treatment modalities, transcatheter closure of interatrial/-ventricular communications as well as interventions during intensive care treatment.
Assuntos
Doenças Cardiovasculares/economia , Grupos Diagnósticos Relacionados/economia , Angioplastia Coronária com Balão/economia , Austrália , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Ablação por Cateter/economia , Controle de Custos , Custos e Análise de Custo , Desfibriladores Implantáveis/economia , Tabela de Remuneração de Serviços , Honorários Médicos , Alemanha , Implante de Prótese de Valva Cardíaca/economia , Custos Hospitalares , Humanos , Tempo de Internação/economia , Marca-Passo Artificial/economia , Stents/economiaRESUMO
We report a case of symptomatic Torsades de pointes due to QTc prolongation by Mibefradil, which potentially explains unexpected deaths related to this drug. Multiple episodes of Torsades de pointes were documented in a 76-year-old woman with significant QTc prolongation of 0.53 s. After discontinuation of Mibefradil QTc intervals normalized and no further ventricular tachyarrythmias were observed. We conclude that Mibefradil can cause QTc prolongation and life threatening ventricular dysrhythmias.
Assuntos
Bloqueadores dos Canais de Cálcio/efeitos adversos , Mibefradil/efeitos adversos , Torsades de Pointes/induzido quimicamente , Idoso , Angina Pectoris/complicações , Angina Pectoris/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Síndrome do QT Longo/complicações , Mibefradil/uso terapêutico , Taquicardia Ventricular/induzido quimicamenteRESUMO
BACKGROUND: Progressive remodeling and dilation of cardiac chambers is responsible in part for myocardial dysfunction in chronic heart failure. Preclinical studies with suitable animal models indicate that a passive cardiac constraint device can promote reverse remodeling, with improvement in cardiac function. We hypothesize that such a device could provide benefit for stable heart failure patients in New York Heart Association (NYHA) class II and III. METHODS AND RESULTS: From April 1999 to March 2000, 27 patients received Acorn's Cardiac Support Device (CSD) during an initial safety/feasibility study. In 11 patients, the only surgical measure was CSD placement. Most patients suffered from idiopathic cardiomyopathy; 4 were in NYHA class II, one was in class II/III, and 6 were in class III. All were stable on intensive medical treatment. The CSD, a textile polyester device, was fitted snugly around the heart during surgery. All patients survived surgery and recovered smoothly. Three months after surgery, 56% of patients were in NYHA class I, 33% were in class II, and 11% were in class II/III. Echocardiography showed an improvement in left ventricular ejection fraction from an average of 22% to 28% and 33% at 3 and 6 months, respectively. Simultaneously, the left ventricular end-diastolic dimension decreased from 74 mm to 68 mm and 65 mm, respectively. Mitral valve regurgitation (on a scale of 0 to 4+) decreased from 1.3 to 0.7 by 3 months. Quality-of-life indices correlated with the apparent reversal of ventricular remodeling. Preoperative cardiac medications remained virtually unchanged after implant. CONCLUSIONS: In the short- and intermediate-term, CSD implantation seems to ameliorate symptoms and improve cardiac and functional performance in heart failure patients. Worldwide randomized trials are currently underway.
Assuntos
Procedimentos Cirúrgicos Cardíacos/instrumentação , Cardiomiopatias/cirurgia , Coração Auxiliar , Telas Cirúrgicas , Remodelação Ventricular , Adulto , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico por imagem , Doença Crônica , Segurança de Equipamentos , Teste de Esforço , Estudos de Viabilidade , Feminino , Seguimentos , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/diagnóstico por imagem , Qualidade de Vida , Indução de Remissão , Índice de Gravidade de Doença , Volume Sistólico , Taxa de Sobrevida , Resultado do Tratamento , UltrassonografiaAssuntos
Doenças Cardiovasculares/diagnóstico , Técnicas de Diagnóstico Cardiovascular , Angina Pectoris/etiologia , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/fisiopatologia , Contraindicações , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia , Teste de Esforço , Humanos , Valor Preditivo dos Testes , Ventriculografia com Radionuclídeos , EspirometriaRESUMO
The Cardiac Support Device (CSD), a preformed-knitted polyester device surgically placed over the cardiac ventricles, prevents left ventricular (LV) remodeling and improves LV ejection fraction (EF) in dogs with heart failure (HF). This study was designed to examine the safety of the CSD in patients with advanced HF. As of December 31, 1999, the CSD was implanted into 22 patients with myocardial disease. Ten patients had concomitant mitral valve repair, two patients had valve replacement (one patient aortic and one patient mitral), one patient had LV assist device (LVAD) placement, and eight patients received only the CSD. The CSD was placed while on bypass with the heart beating, attached to the epicardium groove, and tailored anteriorly to snugly fit the ventricles. There were no intraoperative deaths or complications. Two patients died early from non-CSD-related causes 4 and 23 days postoperatively; one late death occurred. Of the remaining 19 patients, none had any CSD-related adverse events during an average 3.5 +/- 0.4 month follow-up. All patients had completed 3-month follow-up. No patients had evidence of constrictive and/or restrictive physiology. Mitral valve regurgitation (MVR) improved in all patients. [table: see text] Initial findings indicate that the CSD is safe and improves heart failure symptoms and LV function. Additional studies and longer follow-up are needed to confirm these results.
Assuntos
Segurança de Equipamentos , Insuficiência Cardíaca/terapia , Coração Auxiliar , Adulto , Idoso , Estudos de Viabilidade , Feminino , Seguimentos , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/terapia , Fatores de Risco , Resultado do TratamentoRESUMO
Acquired muscular ventricular septal defects (MVSD) after myocardial infarction (MI) can lead to right heart failure and cardiogenic shock with high mortality. Early surgical therapy is often difficult to perform but can reduce the mortality. The closure of congenital septal defects is performed with high safety. Therefore, the interventional closure of an acquired post-MI VSD might be feasible and of potential benefit. To date, experiences with closure of post-MI MVSDs are minimal. We report on two patients with post-MI VSD.
Assuntos
Cateterismo Cardíaco , Cardiomiopatias/etiologia , Embolização Terapêutica , Septos Cardíacos , Infarto do Miocárdio/complicações , Idoso , Embolização Terapêutica/instrumentação , Embolização Terapêutica/métodos , Desenho de Equipamento , Feminino , Humanos , Próteses e ImplantesRESUMO
OBJECTIVES: We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin. BACKGROUND: Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure. METHODS: A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements. RESULTS: The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages. CONCLUSIONS: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.
Assuntos
Cardiotônicos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/administração & dosagem , Piridazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator Natriurético Atrial/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , SimendanaRESUMO
BACKGROUND: Impairment of ventilatory efficiency in congestive heart failure (CHF) correlates well with symptomatology and contributes importantly to dyspnea. METHODS AND RESULTS: We investigated 142 CHF patients (mean NYHA class, 2.6; mean maximum oxygen consumption [VO(2)max], 15.3 mL O(2) x kg(-1) x min(-1); mean left ventricular ejection fraction [LVEF], 27%). Patients were compared with 101 healthy control subjects. Cardiopulmonary exercise testing was performed, and ventilatory efficiency was defined as the slope of the linear relationship of V(CO(2)) and ventilation (VE). Results are presented in percent of age- and sex-adjusted mean values. Forty-four events (37 deaths and 7 instances of heart transplantation, cardiomyoplasty, or left ventricular assist device implantation) occurred. Among VO(2)max, NYHA class, LVEF, total lung capacity, and age, the most powerful predictor of event-free survival was the VE versus V(CO(2)) slope; patients with a slope =130% of age- and sex-adjusted normal values had a significantly better 1-year event-free survival (88.3%) than patients with a slope >130% (54.7%; P<0.001). CONCLUSIONS: The VE versus V(CO(2)) slope is an excellent prognostic parameter. It is easier to obtain than parameters of maximal exercise capacity and is of higher prognostic importance than VO(2)max.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Respiração , Adulto , Idoso , Teste de Esforço , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Oxigênio/sangue , Resistência Física , Prognóstico , Modelos de Riscos Proporcionais , Análise de SobrevidaRESUMO
BACKGROUND: The continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH. METHODS AND RESULTS: In 11 patients with PPH, we performed 2 consecutive cardiopulmonary exercise tests before and after the inhalation of 17 microgram of iloprost. Patients had marked pulmonary hypertension (mean pulmonary artery pressure 65 mm Hg), and inhalation resulted in a decrease in pulmonary vascular resistance (1509 versus 1175 dyne. s(-1). cm(-5), P<0.05). Arterial blood gases remained unchanged (PaO(2) 69.3 versus 66.8 mm Hg; PaCO(2) 29.6 versus 28.8 mm Hg). Iloprost significantly (P<0.05) improved exercise duration (379 versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL. kg(-1). min(-1)), VE-versus-V CO(2) slope (58 versus 51.4). CONCLUSIONS: The present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Iloprosta/administração & dosagem , Resistência Física/efeitos dos fármacos , Respiração/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Administração por Inalação , Adulto , Teste de Esforço , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Iloprosta/uso terapêutico , Pulmão/fisiopatologia , Pessoa de Meia-Idade , Vasodilatadores/uso terapêuticoRESUMO
STUDY OBJECTIVES: Diffusion impairment and reduced performance in cardiopulmonary exercise testing (CPX) have been found in patients after heart transplantation. The pathogenesis of these abnormalities is unclear. In particular, the contribution of pulmonary interstitial changes has not yet been verified. DESIGN: We analyzed pulmonary function tests, high-resolution CT (HRCT), echocardiography, left heart catheterization, and CPX in transplanted patients. PATIENTS: Forty long-term survivors were studied at a median of 47 months (range, 12 to 89 months) after heart transplantation. RESULTS: Diffusion was impaired in 40% (transfer factor for carbon monoxide) or 82.5% (carbon monoxide transfer coefficient) of the patients. Diffusion impairment was caused by a decreased diffusing capacity of the alveolar capillary membrane in 89% and/or by a decreased blood volume of the alveolar capillaries in 46% of cases. In five patients (12.5%), CT revealed interstitial lung changes. These patients did not have different values of diffusion capacity. Maximal oxygen uptake and ventilatory efficiency during exercise (minute ventilation/carbon dioxide output slope) were impaired in 92% and 46% of the cases, respectively. CONCLUSIONS: Our data show that the diffusion abnormalities are caused by an impaired diffusion status of the alveolar capillary membrane. Interstitial changes detectable in HRCT were found not to be involved in this process. The reduced performance in CPX in our long-term survivors is caused by pulmonary perfusion abnormalities and low tidal volume, which is due to the deconditioning of respiratory muscle, rather than by interstitial changes or diffusion abnormalities.