Ischemic stroke and rhabdomyolysis in a 15-year-old girl with paraganglioma due to an SDHB exon 6 (Q214X) mutation.

BACKGROUND: We report a 15-year-old girl with a recent diagnosis of type 2 diabetes mellitus who presented in malignant hypertensive crisis (BP 210/120 mm Hg). Abdominal CT showed an 8.2 x 4.7 x 7.0 cm mass in the region of the organ of Zuckerkandl. MIBG scan showed a single paraganglioma without metastatic foci. Plasma total metanephrines were 232,176.4 pmol/l [263-1052] with normetanephrine predominance. Pre-operative course was complicated by ischemic stroke in the left MCA and right thalamic regions, acute renal failure, rhabdomyolysis and congestive heart failure. She required massive doses of propranolol, phenoxybenzamine, doxazosin and metyrosine prior to surgery. RESULTS: Pathology showed a Zellballen pattern, negative tumor margins and benign para-aortic lymph nodes. Mutation analysis of the succinate dehydrogenase type B (SDHB) gene revealed a heterozygous change of C to T at position 640 in exon 6 (Q214X) predicting an amino acid change to a stop codon. CONCLUSION: We report a severe clinical phenotype in a patient with a paraganglioma affecting multiple organ systems, due to an SDHB mutation. SDHB mutation warrants close follow up and investigation of the family due to high malignant potential and risk of familial occurrence.

Non-alcoholic fatty liver disease pathogenesis: the present and the future.

Non-alcoholic fatty liver disease is the clinical hepatic expression of metabolic syndrome. The prevalence of non-alcoholic fatty liver disease is around 20-30%, and with a rapid increase in the metabolic risk factors in the general population, non-alcoholic fatty liver disease has become the most common cause of liver disease worldwide. A fraction (20-30%) of non-alcoholic fatty liver disease patients develop a potentially progressive hepatic disorder, namely non-alcoholic steatohepatitis, leading to end-stage liver disease. The pathogenesis of non-alcoholic fatty liver disease is not entirely understood, and even if insulin resistance is a major pathogenetic key, many other factors are implicated in both liver fat accumulation and disease progression to non-alcoholic steatohepatitis. In this review we aim to examine the literature, principally concerning human non-alcoholic fatty liver disease pathogenesis, and to identify the newest, most promising clinical and basic research data.

Nutritional morbidity in survivors of congenital diaphragmatic hernia.

PURPOSE: The purpose of this report is to detail the nutritional sequelae seen in survivors of congenital diaphragmatic hernia (CDH) followed in a multidisciplinary clinic. METHODS: Data on 121 surviving CDH patients seen between 1990 and 2000 were collected. Regression analysis was used to determine the impact of factors such as Apgar score, birth weight, extracorporeal membrane oxygenation (ECMO), and patch repair on outcomes associated with nutritional morbidity. RESULTS: There were 100 left and 21 right CDH defects. Mean birth weight and 5-minute Apgar score were 3.1 kg (+/-0.8) and 6.8(+/-2), respectively. Extracorporeal membrane oxygenation was required in 43 (36%) patients and patch repair in 39 (32%). A gastrostomy was required in 39 (32%) patients and a fundoplication in 23 (19%) patients. The side of the defect did not affect the frequency of these procedures. Fifty-six percent of patients were below the 25th percentile for weight during most of their first year. Regression analysis found that duration of ventilation (P <.001) and the presence of a patch repair (P =.03) were independent variables predictive of failure to thrive thereby requiring a gastrostomy tube. Patch repair also was predictive of need for subsequent fundoplication caused by gastroesophageal reflux (P <.001). Twenty-nine patients (24%) had severe oral aversion. Risk factors were prolonged ventilation (P =.001) and oxygen requirement at discharge (P =.015). Two thirds of these patients subsequently improved. CONCLUSIONS: Nutritional problems continue to be a source of morbidity for survivors of CDH, particularly in the first year of life. Not surprisingly, patients who had prolonged intubation and prosthetic material at the gastroesophageal junction fared worse. Despite aggressive nutritional management, 56% of the population remained below the twenty-fifth percentile for weight. These data show the need for careful nutritional assessment in all CDH patients, especially those at high risk for malnutrition.

Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic.

BACKGROUND/PURPOSE: In 1990, the authors began a multidisciplinary follow-up clinic for congenital diaphragmatic hernia (CDH) patients. Although the nonpulmonary complications associated with CDH have been reported previously from this clinic, the purpose of this report is to detail the pulmonary outcome in survivors of CDH with severe pulmonary hypoplasia. METHODS: Between 1990 and 1999, one hundred patients were seen in the clinic. Before hospital discharge, all patients had baseline tests performed, which were repeated per protocol at clinic during follow-up. The data were analyzed by regression analysis to identify and determine the impact of factors on outcomes associated with the long-term pulmonary morbidity. RESULTS: The average birth weight was 3.16 kg (+/-0.7) with a mean Apgar score of 7 (+/- 2) at 5 minutes. Forty-one patients had an antenatal diagnosis performed. Extracorporeal membrane oxygenation (ECMO) was utilized in 29 patients, and a patch repair was required in 32, whereas 16 patients received both. Average time to extubation was 20.7 (+/- 20) days and mean time to discharge was 59.7 (+/- 61) days. Regression analysis showed that both the need for ECMO and a patch repair were independent predictors of delay in extubation (P <. 001, R(2) = 36%), and delay in discharge from the hospital (P =.001, R(2) = 29%). ECMO also was significantly correlated with the need for diuretics at discharge (P <.001, R(2) = 18%), and with the presence of left-right mismatch (P =.009, R(2) = 9%) and V/Q mismatch (P =.005, R(2) = 11%) on subsequent pulmonary ventilation-perfusion examinations. Sixteen patients required O(2) at discharge, and diuretics were necessary in 43 patients. Seventeen patients at discharge required bronchodilators, and during the first year an additional 36 required at least transient therapy. Similarly, 6 patients at discharge required steroids, and an additional 35 patients required at least transient therapy during the first year. Chest x-rays, although frequently abnormal, had little correlation with clinical outcome, but did influence medical therapy. V/Q scans had limited utility in patient management, and the presence of V/Q mismatch was not highly specific for future obstructive airway disease. Nevertheless, V/Q mismatch was sensitive for obstructive airway disease assessed by spirometry. Twenty-five patients over 5 years of age performed pulmonary function tests (PFTs), which showed 72% normal PFT results and 28% with evidence of obstructive airway disease. Before January 1997, 2 of 8 patients who required urgent treatment in the emergency department (ED) were admitted to the intensive care unit (ICU) secondary to acute respiratory distress. After the implementation of respiratory syncytial viral prophylaxis in January 1997, 8 patients were treated in the ED for acute respiratory distress, but none required admission to the ICU. CONCLUSIONS: Pulmonary problems continue to be a source of morbidity for survivors of CDH long after discharge. The need for ECMO and the presence of a patch repair are both predictive of more significant morbidity, but the data clearly show that non-ECMO CDH survivors also require frequent attention to pulmonary issues beyond the neonatal period. These data show the need for long-term follow-up of CDH patients preferably with a multidisciplinary team approach.

Stretch-induced upregulation of VEGF gene expression in murine pulmonary culture: a role for angiogenesis in lung development.

BACKGROUND/PURPOSE: The authors' have shown pulmonary alveolarization (capillary and alveolar growth) both after fetal tracheal occlusion and postnatal pulmonary distension. The trophic and developmental mechanisms responsible for this growth remain largely unknown; however, experimental systems have defined an enhanced expression of angiogenic proteins in response to tissue stretch. The authors hypothesize that the stimulation of pulmonary alveolarization after stretch is secondary to upregulation of the potent endothelial cell mitogen vascular endothelial growth factor (VEGF) and that the endothelial cell represents the central stimulus of parenchymal growth. METHODS: A mixed primary pulmonary cell culture obtained by enzymatic digestion of fetal, neonatal, and adult mouse lung was plated on Bioflex elastomer bottom plates, grown to confluence, rendered quiescent, and subjected to continuous cycles of stretch-relaxation with nonstretched cells as controls. Cells were harvested at time-points 0, 30 minutes, 2 hours, 4 hours, 8 hours, and 24 hours. RNA was extracted and VEGF gene expression analyzed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Similar cell groups were harvested, processed, and analyzed utilizing Western Blot techniques. VEGF PCR of mRNA isolated from fetal sheep subjected to surgical creation of diaphragmatic hernia both with (DH-TL) and without (DH) tracheal ligation also was analyzed. RESULTS: VEGF mRNA isoforms 120, 164, and 188 showed increased expression in all stretched groups, which was noted by 30 minutes with maximal expression seen at 2 to 4 hours and a return to baseline expression by 24 hours. VEGF protein was similarly elevated in all stretched cell groups. In preliminary studies, DH/TL sheep showed upregulation of VEGF compared with DH sheep alone. CONCLUSIONS: These data show in an in vitro system that "pulmonary stretch" upregulates VEGF mRNA and protein expression supporting the role of angiogenesis in the stretch-induced pulmonary alveolarization. The authors speculate that such angiogenic activity is a rate-limiting factor in stimulating alveolar epithelial development, and as a treatment modality, therapeutic angiogenesis may provide a noninvasive method with which to treat pulmonary hypoplasia.

Congenital diaphragmatic hernia: where are we and where do we go from here?

The infant born with congenital diphragmatic hernia (CDH) remains one of the most complex patients to manage. Pulmonary hypoplasia and immaturity of the CDH lung are well recognized as the definitive limitation leading to the high mortality rates. Based on the knowledge that CDH is more a physiological disease than a surgical disease, we have shifted our management strategy from immediate repair to delayed repair and stabilization. The associated pulmonary hypertension and right-to-left shunt are common and rarely the cause of death and as such may be largely ignored. Extracorporeal membrane oxygen has been shown to salvage some of the most severely affected neonates. Other advanced and experimental respiratory therapies merit investigation in properly conducted prospective randomized multi-center trials. Survivors of CDH have predictable pulmonary, gastrointestinal and nutritional problems which, when identified and treated early, are correctable. CDH survival is close to 90% at most advanced centers. Uniform standards for CDH management do not exist however. Therefore a minimal set of practice standards should be developed from evidenced-based scientific review.

Time to first shock in implantable cardioverter defibrillator (ICD) patients with Chagas cardiomyopathy.

UNLABELLED: The time to first ICD shock has been extensively studied in patients with coronary artery disease (CAD). However, there are no published data on ICD shocks in patients with Chagas cardiomyopathy (ChC). The occurrence of the first appropriate ICD shock during the first 6 months of follow-up in 20 patients with ChC (group 1) and 35 CAD patients (group 2) was analyzed retrospectively. All patients had received a third-generation pectoral ICD for ventricular tachycardia or fibrillation (VT/VF). Indications for ICD implantation were refractoriness to drug therapy or noninducibility of VT/VF at EPS in cardiac arrest survivors. RESULTS: The mean age, left ventricular ejection fraction (LVEF), and sex in groups I and II were 57.4 +/- 7 years versus 64 +/- 9 (P < 0.01), 30.9% +/- 10% versus 32.9% +/- 10% (P = NS), and 10 men versus 31 women (P < 0.005), respectively. Six months after ICD implantation, 85% (17/20) group I patients received appropriate ICD shocks versus 51% (18/35) in group 2, a statistically significant difference (P < 0.02, RR: 1.65, OR: 5.35). CONCLUSIONS: The incidence of appropriate ICD shocks within the first 6 months postimplantation was significantly higher in ChC patients than in CAD patients. ChC patients were younger and more often women than CAD patients.

Implantable cardioverter defibrillators in patients with Chagas' disease: are they different from patients with coronary disease?

Chagas' disease is a parasitic affliction, endemic to certain regions of South America, which may lead to a chronic dilated nonischemic cardiomyopathy. Ten Chagasic patients were compared to 18 coronary patients undergoing transvenous ICD implantation for ventricular tachycardia (VT), ventricular fibrillation (VF), or aborted cardiac arrest. Indications for ICD implantation were either drug intolerance or refractoriness, or no inducible tachyarrhythmia at EPS. There were no statistically significant differences between the Chagas and coronary artery disease groups with respect to age (60.2 vs 62.6 yrs), NYHA Class II (50% vs 62%), ejection fraction (31.1% vs 29.7%), and incidence of cardiac arrest (20% vs 33%), respectively. The following ICD implant and long-term follow-up variables were compared between the two groups: pacing threshold (0.94 V vs 0.95 V), defibrillation threshold (19.5 J vs 19.6 J), number of VT episodes (414 vs 435), number of spontaneous VT terminations (86 vs 187), percent efficacy of antitachycardia pacing (93.9% vs 92.1%), and total number of shocks (112 vs 145). These differences were not statistically significant. We conclude that patients with Chagas' disease, compared with coronary artery disease patients, have similar clinical characteristics leading to ICD implantation. Furthermore, no differences were found with respect to ICD and long-term follow-up characteristics between the two groups.

[Tilt test for the evaluation of syncope of unknown origin]. / Tilt test para la evaluación del síncope de origen desconocido.

UNLABELLED: The aim of this study was to evaluate the usefulness of head up tilt testing in patients with syncope of unknown origin. Between January 1994 and September 1995, 93 patients were referred for tilt table assessment due to recurrent syncope of uncertain etiology. There were 42 men (mean age 59 years). Thirty healthy volunteers served as a control group. The specific protocol used involved an initial period of supine rest for 15'. Baseline blood pressure (BP) and heart rate (HR) were recorded. This was followed by a tilt to 80 degrees for 30', BP and HR were measured every minute during the procedure. The test was considered positive when symptoms appeared associated with one of the following responses: systolic BP decreased more than 30 mmHg (vasodepressor), bradicardia or asystolia for up to 3" (cardioinhibitory) or mixed. RESULTS: The tilt test was positive in 31 of 93 patients (33%). Seventeen patients (55%) had a vasodepressor response, 3 patients (9%) a cardioinhibitory response and 11 patients (36%) mixed responses. The clinical manifestations were 62% near syncope, 19% syncope and the other patients presented dypsnea or dizziness. The symptoms disappeared promptly after adopting the supine position. None of the 30 healthy volunteers developed symptoms. We conclude that head up tilt test is a safe and effective method for identifying a neurocardiogenic origin in a syncope of uncertain etiology.

Results of delivered therapy for VT or VF in patients with third-generation implantable cardioverter defibrillators.

Third-generation implantable cardioverter defibrillators (ICDs) offer tiered therapy and can provide significant advantage in the management of patients with life-threatening arrhythmias. Three different types of ICDs were implanted in 21 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia presentation was VT (76%), VF (10%), or both (14%). The mean left ventricular ejection fraction for the group was 32.4 +/- 7%. No surgical mortality occurred. Prior to discharge individual EPS determined the final programmed settings of the ICDs. During a mean follow-up of 13 +/- 1.4 months (range 2-20) the overall patient survival was 85.7%. No sudden arrhythmic or cardiac death occurred. Twenty of 21 patients (95%) received therapy by their device. In 14 patients (67%) antitachycardia pacing (ATP) was programmed "on," 13 of which was self-adaptative autodecremental mode. There were 247 VT episodes, 231 of which were subjected to ATP with 97% success and 3% acceleration or failure. Low energy shocks reverted all other VT episodes. VF episodes were successfully reverted by a single shock (93%), two shocks (6%), or three shocks (1%). We conclude that ATP therapy of VT is successful in the large majority of episodes with rare failures, and that VF episodes are generally terminated by a single ICD shock.

Urine collection from disposable diapers in premature infants: biochemical analysis.

Urine collection for analysis is commonly done in premature infants in sterile adhesive bags. Leakage due to poor adherence of the bag and irritation of the skin are frequent drawbacks with this technique. Urine retrieved from the fiber padding of disposable diapers has been shown to be reliable for biochemical analysis. However, the previous studies were done under laboratory conditions and the volume of urine used was much larger than a premature infant may void at one time. The purpose of this study was to determine the reliability of urine collected from disposable diapers for biochemical analysis in premature infants in the intensive care nursery.

Changing trends in therapy delivery with a third generation noncommitted implantable defibrillator: results of a large single center clinical trial.

Thirty-four patients underwent implantation of a third generation ICD, the 4210 ATP, for sudden cardiac death or ventricular tachycardia. This device incorporates significant telemetry logs as well as a detailed analysis of each arrhythmia episode detected. During the period of clinical follow-up, a mean of 12.2 months, a total of 26,569 VT or VF detections were made. The vast majority of these were either due to atrial fibrillation, nonsustained VT, or "noise" detection, and only 6% led to device therapy. ATP was successful in 86.3% of episodes, with 3.5% accelerations and 2.4% failure of ATP trains. The majority of inappropriate therapy episodes were clustered in seven patients, and all were easily diagnosed with the aid of the extensive telemetry logs and sense histories. Of five late deaths, three were from congestive heart failure, one from cerebrovascular accident, and one unknown. These data reveal that this "tiered" therapy noncommitted ICD performs to expectations; the stored data is of significant value in diagnosing the cause of ICD therapy. In addition, ATP is an effective modality for termination of VT.

Electrophysiologic-structural correlations in chagasic aneurysms causing malignant arrhythmias.

We studied the structure and ultrastructure of three chagasic aneurysms, the excision of which abolished malignant arrhythmias. Chronic recurrent ventricular tachycardia often occurs in patients with chagasic aneurysms, and ventricular mapping indicates that these arrhythmias originate in regions adjacent to those aneurysms. In our patients, ventricular tachycardia had been refractory to medical treatment. During surgery, epicardial and endocardial mapping showed abnormal potentials. Sutures were placed in the areas of resection, their sizes approximating those of earliest activation so that these sites could be identified. The myocardium showed chronic inflammatory reaction, myocytolysis and fibrosis. The presence of "islets" was common (normal, "early" damaged or "established" necrotic myocytes surrounded by fibrous tissue). The "early" lesions were predominant at the previously identified areas of arrhythmogenic activity. The ultrastructural studies showed hypertrophy of myocytes and partial or complete loss of myofibrils, swelling of mitochondria and disruption of mitochondrial cristae, accumulation of lipofuscin granules, and intracellular oedema. A most striking alteration was the thickening of the basement membranes of myocytes and vascular endothelial and smooth muscle cells. The interlaced fronts of respectively healthy (fast conducting) and "early" damaged (slow conducting) myocytes seen in serial sectioning produced an ideal configuration for reentry circuits. The final proof that the arrhythmias originated in these endocardial regions was their abolition by resection of the aneurysm.