A novel mutation of the fibrillin-1 gene in a newborn with severe Marfan syndrome.

Marfan syndrome in the neonatal age represents a severe early and commonly lethal manifestation of Marfan syndrome, which is caused by mutations in the gene encoding fibrillin-1 (FBN1). Here, we report a newborn with severe Marfan syndrome and a novel mutation involving cysteine substitution within one of the epidermal growth factor-like domains of FBN1.

Bilateral semilunar valve dysplasia in a patient with inverted duplication 2p25-22.

Here we report a patient with partial trisomy 2p and congenital dysplasia of the semilunar valves. To our knowledge, this is the first case of 2p duplication with developmental defects of both semilunar valves and suggests that genes on this region contribute to the formation of the semilunar valves.

Giant coronary artery aneurysm formation following meningococcal septicaemia.

We report a case of coronary vasculitis with formation of giant coronary artery aneurysms in a child following meningococcal septicemia. We suggest that coronary vasculitis is a rare complication of meningococcal septicemia that should be included in the list of conditions known to elicit a Kawasaki-like inflammatory response.

Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.

Evaluation and treatment of syncope in infants.

Syncope in the infant and newborn occurs as a loss of consciousness due to a variety of etiologies. Because syncope at this age may be a harbinger of sudden infant death, the symptom provokes anxiety and challenges clinicians to identify those babies with an increased risk for life threatening events. Recently introduced diagnostic tests and advances in molecular biology offer promising potential, but the population at risk remains unknown. Controversy surrounds: many potential risk factors; the value of home monitoring; and appropriate preventive and therapeutic strategies. This article reviews the differential diagnosis of syncope in children less than 18 months of age, with particular attention to those diagnoses and problems specific to the evaluation and treatment in this age group. Recommendations are presented for an efficient evaluation, which must include a careful history, complete physical examination and thorough investigation of the family history and home environment. In addition, specific diagnostic tests and a practical approach to treatment are suggested.

p57Kip2 expression is enhanced during mid-cardiac murine development and is restricted to trabecular myocardium.

During embryonic development the heart is required to grow in size and cell number, undergo complex morphologic alterations, and function to circulate the blood. Between embryonic d 10.5 (E10.5) and E11.5, cardiac myocytes undergo rapid cell division, resulting in doubling of cardiac mass, while metabolic requirements are increased and contraction force is enhanced. Accelerated cardiomyocyte differentiation is accompanied by a significant increase in trabeculation of ventricular myocardium. Many single gene mutations in the mouse result in a "thinned myocardium" and embryonic lethality between E10.5 and E13.5 secondary to heart failure. This is the case in the Splotch mouse in which a mutation of the Pax3 gene results in neural crest and cardiac defects. Nevertheless, the molecular events governing these important developmental steps remain largely unknown. Here, we describe the use of suppression subtractive hybridization to identify mRNA transcripts whose expression is enhanced during this critical period in normal hearts. These genes encode functions related to maturation of the contractile apparatus, cardiomyocyte differentiation, altered cellular metabolism, and transcriptional regulation. One of the genes that we identified, p57Kip2, encodes a cyclin-dependent kinase inhibitor of the p21 family. We show that p57Kip2 is normally expressed in the inner trabecular layer of the developing heart. In Splotch embryos, expression of p57Kip2 is expanded to encompass the entire thickness of the myocardium. This result and further structural analysis suggests that the myocardial defect of Splotch embryos is associated with precocious cardiomyocyte differentiation.

Beneficial effects of C1 esterase inhibitor in murine traumatic shock.

Activation of the complement system is an integral part of the initiation and maintenance of the inflammatory process such as that occurring in traumatic shock, and is considered responsible for much of the trauma-induced microvascular injury. We investigated the effects of early complement blockade induced by a C1 esterase inhibitor (C1 INH) in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension and a 83.3% mortality rate with a mean survival time of 157.5 +/- 26 min. Accompanying these effects were significant endothelial dysfunction and elevated intestinal myeloperoxidase activity. Treatment with C1 INH 15 mg/kg administered intravenously 10 min post-trauma, increases survival rate to 66.7% (p < .05), and prolonged survival time to 248 +/- 27 min (p < .05). C1 INH significantly preserved the endothelium-dependent relaxation to acetylcholine and attenuated the increase in myeloperoxidase activity in C1 INH-treated rats compared with untreated trauma rats (p < .05). Our results suggest that complement activation plays an important role in tissue injury associated with trauma, and that its inhibition at an early step in the complement cascade through a C1 esterase inhibitor is beneficial in rats experiencing traumatic shock. The mechanisms of the protective effect of C1 INH involves preservation of vascular endothelial function and diminished neutrophil accumulation leading to reduced neutrophil-mediated tissue injury.

Effects of defibrotide on leukocyte-endothelial cell interaction in the rat mesenteric vascular bed: role of P-selectin.

The effects of defibrotide on leukocyte-endothelial cell interaction and P-selectin surface expression on the microvascular endothelium were investigated. Intravital microscopy was performed in the rat mesenteric microcirculation. The rat mesentery was superfused either with Krebs-Henseleit solution (i.e., control) or 50 microM NG nitro-L-arginine methyl ester (L-NAME). Defibrotide (40 mg/kg) was intravenously infused to control rats and to L-NAME superfused rats. P-selectin expression on mesenteric venules was also investigated by immunohistochemistry. L-NAME caused a significant, time-dependent increase in leukocyte rolling (13 +/- 5 to 101 +/- 18 cells/ min; p < 0.001) and adherence (1.6 +/- 0.7 to 12 +/- 2.5 cells/100 microns length of venule; p < 0.01) compared to control superfused rats. However, intravenous infusion of defibrotide (40 mg/kg) consistently decreased the L-NAME-induced leukocyte rolling (101 +/- 18 to 9.3 +/- 1.3 cells/min; p < 0.001) and adherence (12 +/- 2.5 to 1.9 +/- 1.1 cells/100 microns length of venule; p < 0.01). Exposure of rat mesentery to L-NAME consistently increased P-selectin surface expression (p < 0.01) on the vascular endothelium which was significantly attenuated by defibrotide (p < 0.05). In vivo administration of defibrotide can reduce leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. Since P-selectin was upregulated by the specific nitric oxide synthase inhibitor L-NAME, the present study also confirms the crucial role exerted by nitric oxide in attenuating leukocyte-endothelial cell interaction during various pathophysiological conditions.

Left intraventricular balloon pump optimization during intractable cardiac arrest.

This work aims to determine optimal balloon shape and volume during left intraventricular balloon pumping (IABP) in the fibrillating dog heart. A balloon volume equal to the left ventricular end-diastolic volume (LVEDV) maintained a higher systolic aortic pressure and flow (106.4 +/- 2.7 mmHg and 84.7 +/- 2.35 ml/kg/min, x +/- SEM, respectively) than a 25% smaller (97.8 +/- 3.3 mmHg, P = 0.002 and 63.7 +/- 4.1 ml/kg/min, P = 0.002, respectively) or a 25% larger balloon (87.4 +/- 2.3 mmHg, P = 0.002 and 70.9 +/- 3.4 ml/kg/min, P = 0.002, respectively). Among 5 different balloon shapes tested, a pear-shaped balloon inflated from the apex to the base of the left ventricle induced the highest (P varying from 0.042 to 0.01, compared to the remaining balloon shapes) systolic aortic pressure and flow (104.6 +/- 4.5 mmHg and 77.9 +/- 1.7 mg/kg/min, respectively). In conclusion, a pear shaped balloon, inflated to a volume equal to the LVEDV, from the apex to the base of the left ventricle, induced an optimal hemodynamic effect during LVBP.