Pulmonary Hypertension in Congenital Heart Disease: Irreversible Vascular Changes in Young Infants

Among 280 infants under 1 year of age with congenital heart disease autopsied at the University of Colorado Health Sciences Center between 1959 and 1978, there were six instances of grade IV¹ pulmonary artery hypertension. Five were patients with ventricular septal defect (four associated with other cardiovascular malformations). The sixth was a patient with atrioventricular canal. The youngest was 2¹/₂ months of age. Advanced degrees of pulmonary hypertensive arteriopathy (grade IV or more) have been said to be rare in infants, especially under the age of 1 year. The fact that all of these cases occurred within the last few years of the study suggests the possibility of improved supportive care leading to the prolonged survival of infants who might otherwise have died prior to developing severe disease. In addition, the role of altitude in accelerating the arteriopathy must be considered in the present series. In any case, this unexpected increase in the frequency of severe pulmonary hypertensive arteriopathy should stimulate consideration of early surgical correction of the underlying cardiovascular malformation, especially in areas of relatively high altitude.     

Bcl-6 p53 mutations in lymphomas carrying the bcl-2/Jh rearrangement

BACKGROUND AND OBJECTIVES: The t(14;18)(q32;q21) chromosomal translocation is the hallmark of follicular lymphomas (FL). The translocation induces the overexpression of the Bcl-2 protein and prolongs the survival of clonogenic cells. Tumor cells may acquire additional molecular alterations that may be associated with histologic progression or with chemo-resistance. DESIGN AND METHODS: We analyzed the distribution and association of bcl-6 and p53 mutations in 55 consecutive bcl-2/Jh+ lymphoma samples derived from 43 patients obtained at the time of diagnosis and, in 5 of these patients, during follow-up. A total of 29 bcl-6 point mutations were detected in seventeen patients (40%) associated with major or minor breakpoints of the bcl-2/Jh fusion gene. In seven cases a p53 mutation was detected. Three cases corresponded to FL with the minor breakpoint in the bcl-2 gene and these patients had a favorable clinical evolution, whereas the 4 patients with p53 mutations and the major breakpoint had a bad clinical outcome with morphologic transformation to high-grade lymphoma in three cases. The sequential analysis of 5 patients showed a different timing in the acquisition of mutations: one patient showed bcl-6 and p53 mutations at diagnosis, another patient showed bcl-6 mutations at diagnosis and acquired a p53 mutation later whereas the third patient had a p53 mutation before the appearance of the bcl-6 mutation. RESULTS: We did not find significant differences in survival between patients with FL who showed exclusively bcl-6 mutations and those without bcl-6 mutations, but those patients with a high International Progostic Index score and p53 mutations showed the lowest overall survival (p = 0.002). INTERPRETATION AND CONCLUSIONS: These findings suggest that bcl-2/Jh lymphomas show molecular heterogeneity and that bcl-6 and p53 mutations may be acquired during the evolution of such lymphomas. Bcl-6 mutations, by themselves, do not seem to be associated with a bad prognosis. Rearrangements at the minor bcl-2 locus may have a different molecular evolution.     

Glomerulonephritis in Behçet’s Disease: Report of Seven Cases and Review of the Literature

Despite being recognised much more frequently than in the past, renal involvement has not previously been regarded as a feature of Behcet's disease (BD). In this study we aimed to assess the frequency of renal involvement in BD by performing urinalyses of 674 consecutive BD patients; we also retrospectively evaluated the charts of 4212 BD patients for the incidence of glomerulonephritis (GN). Urinary abnormalities (proteinuria and/or haematuria) were present in 10.8%; and during a period of 23 years GN was detected by renal biopsy in seven (0.16%) BD patients. Two patients with GN were lost to follow-up; end-stage renal failure developed in only one patient, and she underwent renal transplantation. We were unable to determine any pathognomonic feature that was predictive of renal involvement. Although males tend to have a more serious clinical course of BD the incidences of urinary abnormalities and GN were similar in both sexes in our series. According to our results, we can conclude that urinary abnormalities are more frequent in BD; however, serious renal lesions develop in only very few of these patients.     

A new model for prenatal brain damage. I. GABAA receptor activation induces cell death in developing rat hippocampus

Premature infants are at exceptionally high risk for hypoxic-ischemic insults and other traumatic events that result in permanent brain damage. However, no current models adequately mimic these events. An emerging concept is that the major excitatory drive in immature neurons is derived from depolarizing responses following activation of the gamma-aminobutyric acid (GABA)(A) receptor, resulting in the opening of voltage-sensitive calcium channels. While calcium-mediated signal transduction is trophic in developing neurons, excessive calcium entry is a major mediator of excitotoxicity. We report that exogenous activation of GABA(A) receptors by muscimol in newborn rats increases cell death in the hippocampus. The effects are region specific, persistent, and greater in males. Muscimol-induced damage is prevented by pretreatment with diltiazem, an L-type voltage-sensitive calcium channel blocker. Results using hippocampal cultures parallel those observed in vivo, indicating that the effects are mediated directly in the hippocampus. Existing models of pediatric hypoxic-ischemic brain damage focus on the effects of glutamate in the postnatal day 7 rat, because it is considered analogous to the newborn human. This makes the newborn rat analogous to the late gestational human. Ischemia in newborn rats induces GABA release and we propose that treatment with muscimol mimics the cell death cascade induced by hypoxia-ischemia in premature human infants.     

A novel model for prenatal brain damage. II. Long-term deficits in hippocampal cell number and hippocampal-dependent behavior following neonatal GABAA receptor activation

Premature infants are at especially high risk for asphyxia, seizures, and other conditions that cause hypoxia-ischemia. These events result in abnormal brain pathology and behavioral deficits that persist throughout adolescence and into adulthood. Current rodent models of human infant hypoxic-ischemic brain damage have focused on exogenous glutamate receptor agonist exposure in the postnatal day 7 rat. While this model is considered analogous to the newborn human, no adequate models for preterm infant brain damage have been developed. Recent work from our lab has proposed a potential model for preterm infant brain damage in which neonatal rats are treated with exogenous muscimol, the selective gamma-aminobutyric acid(A) (GABA(A)) receptor agonist, on postnatal days 0 and 1. In the companion paper to this one (Exp. Neurol., in press), we report fewer neurons in the hippocampal formation on postnatal day 7 (6 days after treatment), but the persistence of these anatomical deficits, and potential resultant behavioral dysfunctions, were not investigated. In the current experiment, we documented that muscimol exposure on postnatal days 0 and 1 leads to fewer neurons in the male and female rat hippocampus (CA1, CA2/3, and dentate gyrus) on postnatal day 21. Also, neonatal muscimol exposed males and females displayed deficits on hippocampal-dependent learning tasks such as a preweanling version of the Morris water maze task and the open field task. We conclude that exposure to exogenous GABA(A) receptor activation over the first 2 days of postnatal life, a model for preterm infant hypoxic injury, produces anatomical and behavioral deficits observed into adolescence.     

Direct ethanol metabolite ethyl glucuronide. Its value as alcohol intake and recurrence marker, methods of detection and prospects

In clinical as well as in forensic practice biological state markers of high sensitivity and specificity capable of monitoring alcohol consumption of those in treatment for alcohol dependence or poly-drug abusers are required. The known markers cannot be considered satisfactory in respect of these parameters. Furthermore, they do not cover the entire time axis for alcohol consumption. These traditional markers are often influenced besides by alcohol, by age, gender and various of substances and non-alcohol-associated diseases. Ethyl glucuronide (EtG) is a non volatile, water soluble, stable upon storage, direct metabolite of ethanol with a molecular weight of 222 g/mol that was determined by our group in more than 1200 samples of body fluids, tissues and hair from over 200 patients, almost 200 drivers and postmortem with different GC/MS and ESI-LC/MS-MS methods using deuterium-labelled EtG as internal standard. With its specific time frame of detection intermediate between short-term and long-term markers and a particularly high sensitivity and specificity, ethyl glucuronide is a promising marker of alcohol consumption in general that can be detected for an extended time period after the complete elimination of alcohol from the body (up tp 80 h) and a marker for relapse control enabling the therapist to intervene at an early stage of relapsing behaviour. The complementary use of EtG together with other upcoming markers of alcohol consumption like phosphatidyl ethanol should lead to an improvement in treatment outcome, quality of life and cost reduction.     

Arterial remodelling in Fabry disease

Aim : The enzymatic defect in Fabry disease results in the slow systemic deposition of uncleaved glycosphingolipids in the lysosomes of vascular endothelium and smooth muscle cells, leading to ischaemic strokes, cardiomyopathy and renal failure. Whereas it is known that Fabry disease affects small blood vessels, little is known about its effects on peripheral large arteries. We therefore set out to compare parameters of arterial wall structure and function in a cohort of patients with Fabry disease and an age-matched control group. Methods : Large artery phenotype was non-invasively investigated in 21 hemizygous patients with Fabry disease and 24 age-matched male controls. Common carotid and radial artery diameter, intima-media thickness (IMT) and distensibility were determined with high-definition echotracking systems and aplanation tonometry. Results : Patients with Fabry disease had a significant twofold increase in radial artery IMT and distensibility, independent of body surface area, age and mean blood pressure. In both groups, older age at the time of examination was significantly associated with larger radial artery IMT. The relationship between age and radial IMT was 2.3-fold higher in patients with Fabry disease than in controls ( p > 0.01). Carotid IMT was mildly but significantly increased in patients with Fabry disease (+18%), whereas distensibility was unchanged.
Conclusion : This study presents evidence of a major increase in arterial wall thickness and distensibility, measurable at the site of a medium-sized artery, in a cohort of patients with classic Fabry disease.