Prophylactic effect of angiotensin receptor blockers in children with genetic aortopathies: the early bird catches the worm.

AIMS: In genetic aortopathies (GA) particular attention is paid to aortic root dilatation which has an impact on morbidity and mortality. This study focuses on the effects of therapy with angiotensin-II-receptor-blockers (ARB) or beta-blockers (BB) on aortic root growth and the question which therapy should be initiated at which dosage and at what age. METHODS: Since 1998 we diagnosed 208 patients with GA (170 FBN-1). 81 patients between 5 months and 18 years receiving either ARB or BB therapy were included. We retrospectively analyzed the progression of the dilatation of Sinus Valsalva aortae (SV) using calculated z-scores before and after therapy initiation and compared BB and ARB treatment. RESULTS: Both ARB and BB (p < 0.05) therapy showed significant improvement in aortic root growth, while the effect is significantly more pronounced in ARB (p < 0.01) independent of age and genetic cause. A detailed comparison of the two drug groups showed a more sustained effect in limiting the progression of the dilatation of the aortic root in patients treated with ARB. Progression of dilatation of the SV was significantly lower in children treated with ARBs compared to BB (delta z-score, p < 0.05). In addition, ARBs were better tolerated and had a significantly lower discontinuation rate (3%) compared to BB (50%) (p < 0.01). Independently of age at initiation all children and adolescents were able to reach the target dose under ARB. CONCLUSION: We demonstrated a significant change in both treatment options, with the effect of ARB being more pronounced while being better tolerated throughout the treatment period.

Rescue Nuss procedure for inferior vena cava compression syndrome following posterior scoliosis surgery in Marfan syndrome.

PURPOSE: Scoliosis surgery in Marfan syndrome is common, even in the presence of a funnel chest. However, to date, no case has been reported with acute intra-/postoperative decompensation caused by vena cava compression following posterior spinal derotation and fusion. METHODS: A 15-year-old male patient with Marfan syndrome, a funnel chest and severe scoliosis was treated with surgery for the spinal deformity. Intraoperatively, the patient developed a clinically relevant compression of the inferior vena cava with severe circular depression. Postoperatively, a cava compression syndrome with severe pleural effusion, ascites and enormous swelling of the lower limbs was developed. A conservative treatment of the symptoms, consisting of thoracic drainage and negative fluid balance, failed. Subsequently, the patient was transferred to pediatric intensive care unit for further treatment. Echocardiography and a CT scan demonstrated cava compression syndrome. A rescue Nuss procedure of the funnel chest deformity was performed since conservative treatment failed. The clinical course proceeded without complications and with a decrease in clinical symptoms of inferior inflow congestion. The patient was discharged after almost 3 weeks. CONCLUSION: The problem of congenital stenosis of the inferior vena cava in Marfan syndrome has not yet been investigated. In the case of simultaneously existing funnel chest and scoliosis in Marfan syndrome, an interdisciplinary discussion is required to decide whether a repair of the funnel chest should be performed first in order to prevent a clinically relevant compression syndrome. For the detection of a preoperatively relevant stenosis of the inferior vena cava, an MRI or thoracic/abdominal CT should be used preoperatively.

Risk assessment and prevention of pressure ulcers: a clinical practice guideline from the American College of Physicians

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations based on the comparative effectiveness of risk assessment scales and preventive interventions for pressure ulcers. METHODS: This guideline is based on published literature on this topic that was identified by using MEDLINE (1946 through February 2014), CINAHL (1998 through February 2014), the Cochrane Library, clinical trials registries, and reference lists. Searches were limited to English-language publications. The outcomes evaluated for this guideline include pressure ulcer incidence and severity, resource use, diagnostic accuracy, measures of risk, and harms. This guideline grades the quality of evidence and strength of recommendations by using ACP's clinical practice guidelines grading system. The target audience for this guideline includes all clinicians, and the target patient population is patients at risk for pressure ulcers. RECOMMENDATION 1: ACP recommends that clinicians should perform a risk assessment to identify patients who are at risk of developing pressure ulcers. (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 2: ACP recommends that clinicians should choose advanced static mattresses or advanced static overlays in patients who are at an increased risk of developing pressure ulcers. (Grade: strong recommendation, moderate-quality evidence). RECOMMENDATION 3: ACP recommends against using alternating-air mattresses or alternating-air overlays in patients who are at an increased risk of developing pressure ulcers. (Grade: weak recommendation, moderate-quality evidence).(AU)

Systemic lupus erythematosus presenting as acute adrenal insufficiency: a rare clinical presentation.

Systemic lupus erythematosus is a complex autoimmune disease with multisystem involvement with varied presentation. Autoimmune adrenal disease, on the other hand, can be associated with other autoimmune diseases. Adrenal insufficiency as a presenting feature of Systemic lupus erythematosus is a rare occurrence. We hereby report a case of a 20 year-old female who presented to us in an acute hypoadrenal state and was found to have Systemic lupus erythematosus with renal involvement. Patient was successfully managed with steroids and improved clinically.

Pediatric patients with Marfan syndrome: frequency of dural ectasia and its correlation with common cardiovascular manifestations.

PURPOSE: Marfan syndrome (MFS) is a genetic disorder of the connective tissue. Aortic root dilation is a main criterion of the Ghent Nosology. Dural ectasia and the presence of mitral valve prolapse (MVP) contribute to its systemic score. The purpose of this study was to investigate the frequency of dural ectasia and its correlation with cardiovascular manifestations in a pediatric study population. PATIENTS AND METHODS: 119 pediatric patients with confirmed or suspected MFS were examined in the local Marfan Clinic. 31 children with MFS who underwent magnetic resonance imaging (MRI) were included. Each patient was evaluated according to the Ghent nosology. Echocardiography was used to measure the aortic root diameter and assess the presence of MVP and mitral regurgitation. Z-scores were calculated for the evaluation of the aortic root diameters. MRI was performed to determine the dural sac ratio (DSR). RESULTS: The prevalence of dural ectasia was 90.3 %, of aortic root dilation 32.2 %, of MVP 64.5 % and of mitral regurgitation 51.6 %. DSR at L5 correlated with the intraindividual z-scores (slope, 3.62 ±â€Š1.5 [0.56; 6.68]; r = 0.17; p = 0.02; F = 5.84). Z-scores ≥ 2 were accompanied by dural ectasia in 100 %, MVP in 95 % and mitral regurgitation in 100 % of cases. MVP was accompanied by mitral regurgitation in 70 % of cases. CONCLUSION: As the examined cardiac manifestations show a coincidence with dural ectasia in 95 - 100 % of cases, MRI for diagnostic dural sac imaging should be reserved for MFS suspicions with the absence of those manifestations in order to establish the diagnosis according to the Ghent criteria. Thus, the present study supports the recent downgrading of dural ectasia to a contributor to the systemic score.

Comprehensive analysis of dural ectasia in 150 patients with a causative FBN1 mutation.

The purpose of this study was to perform a comprehensive study of dural ectasia (DE) related to FBN1 mutations. We performed a database analysis of two German metropolitan regions of 150 patients (68 men, 82 women; mean age 35 ± 16 years). All patients had a FBN1 mutation and underwent dural magnetic resonance imaging. Age was <16 years in 20, 16-25 in 27, 26-35 in 67, and >35 in 36 patients. Prevalence of dural ectasia was 89% with criteria of Oosterhof and Habermann, 83% with Fattori, 78% with Lundby, and 59% with Ahn. DE was less frequent in patients <16 years with Ahn and Fattori. DE related to skeletal manifestations with all criteria, to aortic Z-scores and mitral valve prolapse with criteria of Habermann and Lundby, and to age with criteria of Fattori. The Fattori-grade of DE increased with age, aortic Z-scores, and skeletal score points. There was no consistent relationship of DE with any type of FBN1 mutation. DE is frequent in patients with FBN1 mutations irrespective of age and its severity increases during life. Criteria of Oosterhof and Habermann yielded most consistent diagnostic results. DE relates to skeletal involvement, aortic Z-scores, and mitral valve prolapse.

Dural ectasia in Loeys-Dietz syndrome: comprehensive study of 30 patients with a TGFBR1 or TGFBR2 mutation.

The purpose of this study was to assess the frequency, severity, and clinical associations of dural ectasia (DE) in Loeys-Dietz syndrome (LDS). Database analysis of three German metropolitan regions identified 30 patients with LDS and TGFBR1 mutation in 6 and a TGFBR2 mutation in 24 individuals (17 men; mean age: 31 ± 19 years), as well as 60 age and sex-matched control patients with Marfan syndrome carrying a FBN1 mutation. DE was present in 22 patients with LDS (73%), and it related to skeletal score points (p = 0.008), non-skeletal score points (p < 0.001), and to the presence of ≥7 systemic score points (p = 0.010). Similarly, the severity of DE was related to body height (p = 0.010) and non-skeletal score points (p = 0.004). Frequency (p = 0.131) and severity of DE (p = 0.567) was similar in LDS and Marfan syndrome. DE is a manifestation of LDS that occurs with similar frequency and severity as in Marfan syndrome. Severity of DE may serve as a marker of the overall connective tissue disease severity. LDS may be considered in patients with DE.

Emphysematous pyelonephritis: Outcome with conservative management.

Emphysematous pyelonephritis is a life-threatening condition characterized by necrotising gas forming infection of the renal parenchyma. We describe eight patients seen over a period of 2 years, 62.5% males and 37.5% females with age range between 21 and 65 years. About 75% patients had diabetes mellitus. Six patients were managed conservatively. One patient required nephrectomy with percutaneous drainage and one patient died without surgical intervention.

CHOP THERAPY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS.

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival. The redox state can be imaged by the redox scanner that collects the fluorescence signals from both the oxidized-flavoproteins (Fp) and the reduced form of nicotinamide adenine dinucleotide (NADH) in snap-frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses. Here, with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B-cell lymphoma cell line (DLCL2). The mice were treated with CHOP therapy, i.e., cyclophosphamide (C) + hydroxydoxorubicin (H) + Oncovin (O) + prednisone (P) with CHO administration on day 1 and prednisone administration on days 1-5. The Fp content of the treated group was significantly decreased (p = 0.033) on day 5, and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group (p = 0.048). The decrease of the Fp heterogeneity (measured by the mean standard deviation) had a border-line statistical significance (p = 0.071). The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

Cardiac characterization of 16 patients with large NF1 gene deletions.

The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age- and sex-matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p < 0.001) and increased intraventricular diastolic septal thickness (p = 0.001) compared with a healthy reference population without NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

A simple clinical model to estimate the probability of Marfan syndrome.

BACKGROUND: Marfan syndrome is a heritable connective tissue disease. Definitive diagnosis is complex, and requires sequencing of a large gene, FBN1. AIM: We aimed to develop a simple model to estimate the pre-test probability of Marfan syndrome. DESIGN: Prospective cross-sectional study. METHODS: We applied diagnostic standards for definitive diagnosis or exclusion of Marfan syndrome in 329 consecutive persons. In 208 persons with random assignment to our derivation group, we performed multivariate logistic regression to assess 14 clinical variables for inclusion in a prediction model with derivation of score points from the estimated coefficients. We created cut-offs to classify low, moderate and high probability of Marfan syndrome. For validation, we applied the model to the remaining 121 persons. RESULTS: We identified seven variables for inclusion in the final model, where we assigned four score points to ectopia lentis, two points to a family history of Marfan syndrome, and one point to previous thoracic aortic surgery, to pectus excavatum, to a wrist and thumb sign, to previous pneumothorax, and to skin striae. In the derivation group 12, 42 and 92% of persons with low (≤1 point), moderate (>1-3.5 points) or high pre-test probability (>3.5 points) had Marfan syndrome, compared to 12, 57 and 91%, respectively, in the validation group. Positive likelihood ratios were 13.96 and 8.54 in the high probability group of the derivation and validation group, respectively. CONCLUSION: A simple prediction model provides evidence for Marfan syndrome. This model can be used to identify patients who require definitive diagnostic work-up.

Aortic arch repair: let it beat!

Objective aortic arch repair (AAR) on the beating heart may reduce cross-clamping times and offer improved postoperative cardiac function.Methods A single-center review of all patients (n = 24) who underwent surgical AAR during biventricular repair between 01/2006 and 01/2008 was done. All patients were operated on under cardiopulmonary bypass (CPB) with antegrade cerebral perfusion (ACP). During AAR, 13 patients (group 1) received cardioplegic arrest, and were compared to 11 patients (group 2) who underwent a beating-heart modification with selective myocardial perfusion. Seventeen patients had additional intracardiac lesions and underwent simultaneous correction during the procedure.Results Durations of CPB, AAR and ACP did not differ statistically between groups. Cardioplegic arrest time was significantly lower in group 1 (34 ± 13 vs. 76 ± 11 min, p = 0.02) and resulted in a subsequent reduction of myocardial ischemic damage as borne out by lower postoperative levels of troponin T and CK-MB (2.5 ± 0.7 vs. 7.1 ± 1.4 ng/mL, p = 0.02; 68.7 ± 11.5 vs. 149.1 ± 27.2 U/l, p = 0.03). We observed an enhanced patient recovery with shorter inotropic and ventilatory support times (p < 0.05).Conclusion Pediatric aortic arch correction on a CPB beating heart with selective myocardial perfusion is technically feasible and safe. The reduction of the myocardial ischemic time is effective and results in less myocardial damage.

Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome.

Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.

Dural ectasia in individuals with Marfan-like features but exclusion of mutations in the genes FBN1, TGFBR1 and TGFBR2.

Mutations in the genes FBN1, TGFBR1, and TGFBR2 can result in heritable connective tissue disorders comprising the Marfan syndrome and the Loeys-Dietz syndrome. Dural ectasia is a characteristic manifestation of both syndromes. However, dural ectasia has not yet been investigated in connective tissue disorders that are unrelated to mutations in the FBN1, TGFBR1 or TGFBR2 genes. Here, we assessed dural ectasia in 33 individuals both with typical manifestations of heritable connective tissue disease and in whom mutations in all three genes had been excluded. We identified 19 individuals with dural ectasia (58%), who exhibited major skeletal manifestations of the Marfan syndrome more frequently than the remaining 14 persons without dural ectasia (p = 0.06). Moreover, only persons with dural ectasia fulfilled clinical criteria of the Marfan syndrome (p = 0.01). Conversely, aortic aneurysm (12 patients; p = 0.8), aortic dissection (five patients; p = 0.1), spontaneous dissection of the carotid arteries (five patients; p = 1), and mitral valve prolapse (13 patients; p = 0.4) were similarly frequent irrespective of dural ectasia. We conclude that dural ectasia is a marker for connective tissue disease which coincides with skeletal rather than with cardiovascular manifestations, and which may involve currently uncharacterized pathogenetic mechanisms and syndromes.

Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: do we need genetics for clinical decisions?

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

The Norwood procedure - does the type of shunt determine outcome?

BACKGROUND: Stage I palliation of hypoplastic left heart syndrome (HLHS) and its variants is usually performed by a Norwood operation. The management of pulmonary blood flow during this procedure remains controversial. The RV-to-PA conduit (RVPAC) has been proposed as the better alternative compared to a systemic-to-pulmonary shunt (SPS). METHODS: A retrospective single center chart review of consecutive patients who underwent a Norwood I procedure between 01/1997 and 09/2006 was performed. All patients were operated in deep hypothermia, with or without circulatory arrest, using different shunt modifications according to surgeon's preference. Patients were divided into two groups depending on surgical management for pulmonary blood flow (modified BT shunt [BT] and non-valved RVPAC [Sano]). RESULTS: Fifty-four patients were included in the study (BT: 31 patients vs. Sano: 23 patients). Diastolic blood pressure during the first 24 hours postoperatively was significantly lower in the BT group (BT: 38.6 +/- 6.9 mmHg vs. Sano: 42.4 +/- 7.2 mmHg; P < 0.01) with a trend towards a higher systolic blood pressure (BT: 74.1 +/- 13.5 mmHg vs. Sano: 69.8 +/- 12.1 mmHg; P = 0.08). Mean circulatory arrest time in the BT group was significantly longer compared to the Sano patients (BT: 41 +/- 21 min vs. Sano: 25 +/- 23 min; P < 0.01). The mean hospital stay was 18.5 days for BT patients and 20 days for Sano patients ( P = 0.45). Early mortality for the total cohort was 14.8 % (n = 8) (BT 19.4 % [n = 6] vs. Sano 8.7 % [n = 2]; P = 0.12). There was no significant difference in inter-stage mortality between the two groups (BT: 18.2 % vs. Sano: 21.1 %; P = 0.47). CONCLUSION: The results for both established surgical methods (BT and Sano) for the palliation of HLHS and its variants have improved over time and are reaching acceptable early mortality rates. There was a trend towards a favorable early outcome for Sano patients, which did not reach statistical significance in this study due to the low patient numbers.

Utility of N-terminal brain natriuretic peptide plasma concentrations in comparison to lactate and troponin in children with congenital heart disease following open-heart surgery.

We conducted a prospective study in a pediatric cardiac intensive care unit in order to determine the diagnostic value of N-terminal brain natriuretic peptide (N-BNP) plasma concentration in the perioperative care of children with congenital heart disease (CHD). N-BNP plasma concentrations were determined by using a validated enzyme immunoassay. We measured N-BNP the day before surgery and up to 15 days postoperatively in 23 children (age range, 0.25-11 years) undergoing cardiac surgery due to various CHDs. Supply and duration of catecholamines, vasodilators, and respiratory therapy were determined and correlated to N-BNP. In addition, troponin T (TnT) and arterial Lactat (aL) concentrations were measured simultaneously. We found a significant correlation between preoperative and maximal N-BNP levels and dosage of vasodilators (r = 0.41, p < 0.02 and r = 0.83, p < 0.01, respectively). Maximal TnT and aL levels were not correlated to dosage of vasodilators. The dosage and duration of catecholamines, the duration of respiratory therapy, and the plasma concentration of TnT and aL were not correlated to pre- or perioperative N-BNP. Maximal TnT and aL levels were correlated to duration (r = 0.53, p < 0.01 and r = 0.48, p < 0.02) and dosage (r = 0.52, p < 0.02 and r = 0.60, p < 0.01) of catecholamines and duration of respiratory therapy (r = 0.57, p < 0.01 and r = 0.50, p < 0.02). As recent studies show, N-BNP appears to be a powerful neurohumoral indicator of ventricular function and prognosis for guiding therapy in the outpatient department or for discriminating cardiac from noncardiac symptoms. In contrast, the value of N-BNP for guiding perioperative therapy in pediatric cardiac intensive care units is limited.

Plasma concentrations of N-terminal brain natriuretic peptide in healthy children, adolescents, and young adults: effect of age and gender.

Children with congenital heart disease need adequate diagnostic classification regarding their cardiovascular status (CVS). N-terminal brain natriuretic peptide (N-BNP) plasma concentration indicates dysfunction of the cardiovascular system and guides decisions concerning treatment and prognosis. Reference values are established for adults, with age-dependent increasing values and higher values in women. To avoid misclassification concerning the CVS, a large group of healthy children and adolescents can be used show the relationship between gender, age, and N-BNP and these can serve as reference values. N-BNP was measured in 434 healthy subjects (240 female and 194 male) with ages ranging from 0 to 32 years without any cardiovascular disease or renal or hepatic impairment. Measurements were performed with an electrochemiluminescence immunoassay from Roche Diagnostics. Mean N-BNP decreased from 12.6 fmol/ml (0-9 years; n = 79) to 9.41 fmol/ml (10-14 years; n = 154) and in adolescents from 6.1 (15-19 years; n = 99) to 4.8 fmol/ml (> 19 years; n = 102) in adults (p < 0.05). Mean N-BNP concerning gender did not differ in any age group younger than 19 years. In contrast, the adult female group had 78% higher N-BNP compared to the male group (p < 0.05). There was a significant peak in N-BNP at the age of 12-14 years. This study shows that reference values for N-BNP differed profoundly in children compared to adults and were up to 260% higher in children without any gender difference. Therefore, these reference values will help to avoid CVS misclassification in children for the biomarker N-BNP.

Incidence of traumatic injection neuropathy among children in Pakistan.

We used acute flaccid paralysis surveillance data collected between 1 January 2001 and 31 December 2003 from the Pakistan Polio Eradication Initiative to describe the epidemiological characteristics and disease burden of traumatic injection neuropathy among children aged under 15 years. Of the 5627 acute flaccid paralysis cases reported, 456 were identified as traumatic injection neuropathy by case review. The condition was more common in younger children who were also more likely to have persistent paralysis. We estimate that the annual incidence of traumatic injection neuropathy rate in Pakistan is 7.1 per 1 000 000 in children under 3 years old.