Michael W. Vogel

Comparison of results and complications of surgical and amplatzer device closure of atrial septal defects

OBJECTIVES Results and complications of surgical versus transcatheter treatment of atrial septal defect in the current era are compared. METHODS All consecutive patients with a secundum atrial septal defect and a pulmonary/systemic flow ratio of 1.5:1 or more who presented between May 1997 and June 1998 were enrolled in this study. All patients except those who initially had defects not feasible for interventional occlusion were catheterized to allow interventional closure of the defects. All patients in whom interventional closure could not be performed underwent surgical closure. RESULTS Sixty-one patients underwent surgery at a median age of 20 years (0.5-74 years) and 61 had the defect closed with an Amplatzer device (AGA Medical Corporation, Golden Valley, Minn) at a median age of 12 years (0.8-77.7 years) (P >.2). Hospital stay in surgically treated patients was 8 days (6-19 days) versus 3 days (3-14 days) in interventionally treated patients (P <.001). Atrial septal defect and shunt sizes were larger in the surgical group ( P <.001). Closure rates in the 2 groups were identical (98%). One patient (68 years) in the surgical group had a perforated duodenal ulcer that necessitated an operation 8 days after closure of the atrial septal defect, and 1 (26 years) had an infected lateral thoracotomy wound necessitating plastic surgery. Embolization of the Amplatzer device to the left ventricle was observed in 1 patient (29 years). The device could be retrieved from the heart, but vascular surgery was required to extract it from the femoral artery. CONCLUSIONS As complete closure rates and complications are identical, but duration of hospital stay is shorter with less morbidity, we prefer implantation of an Amplatzer septal occluder to surgery wherever possible.

Prenatal Interaction of Mutant DISC1 and Immune Activation Produces Adult Psychopathology

BACKGROUND Gene-environment interactions (GEI) are involved in the pathogenesis of mental diseases. We evaluated interaction between mutant human disrupted-in-schizophrenia 1 (mhDISC1) and maternal immune activation implicated in schizophrenia and mood disorders. METHODS Pregnant mice were treated with saline or polyinosinic:polycytidylic acid at gestation day 9. Levels of inflammatory cytokines were measured in fetal and adult brains; expression of mhDISC1, endogenous DISC1, lissencephaly type 1, nuclear distribution protein nudE-like 1, glycoprotein 130, growth factor receptor-bound protein 2, and glycogen synthase kinase-3beta were assessed in cortical samples of newborn mice. Tissue content of monoamines, volumetric brain abnormalities, dendritic spine density in the hippocampus, and various domains of the mouse behavior repertoire were evaluated in adult male mice. RESULTS Prenatal interaction produced anxiety, depression-like responses, and altered social behavior that were accompanied by decreased reactivity of the hypothalamic-pituitary-adrenal axis, attenuated serotonin neurotransmission in the hippocampus, reduced enlargement of lateral ventricles, decreased volumes of amygdala and periaqueductal gray matter and density of spines on dendrites of granule cells of the hippocampus. Prenatal interaction modulated secretion of inflammatory cytokines in fetal brains, levels of mhDISC1, endogenous mouse DISC1, and glycogen synthase kinase-3beta. The behavioral effects of GEI were observed only if mhDISC1 was expressed throughout the life span. CONCLUSIONS Prenatal immune activation interacted with mhDISC1 to produce the neurobehavioral phenotypes that were not seen in untreated mhDISC1 mice and that resemble aspects of major mental illnesses. Our DISC1 mouse model is a valuable system to study GEI relevant to mental illnesses.

Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders

Strong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-Schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases.

Incidence of atrial flutter/fibrillation in adults with atrial septal defect before and after surgery

BACKGROUND There is controversy about the benefit of surgical repair for atrial septal defect in adults, especially its effect on the incidence of supraventricular dysrhythmias, atrial flutter and fibrillation. We studied their incidence before and after operation. METHODS We examined surface and 24-hour Holter electrocardiograms before, early (between 3 and 7 days), and late (more than 6 months) after operation, performed at age 42.2 years (range, 18.5 to 74.9 years), in 211 adults with atrial septal defect. Patients were arbitrarily divided into three groups: age 18 to 40 years (n = 101), age 40 to 60 years (n = 83), and age more than 60 years (n = 27). All consecutive patients operated on between January 1988 and December 1996 and having a pulmonary to systemic flow ratio of 1.5:1 or greater were included in this study. RESULTS The age of patients without arrhythmias before or after atrial septal defect closure (39+/-13 years) was significantly lower than that of patients with flutter (54+/-12 years) or fibrillation (59+/-8 years). The incidence of atrial flutter was influenced by surgical repair as atrial flutter converted to sinus rhythm late after operation in 10 of 18 patients. However, there was no change in the incidence of atrial fibrillation before (n = 28) and after (n = 21) operation. CONCLUSIONS Our data show that surgical correction of atrial septal defect leads to regression of the incidence of atrial flutter but not fibrillation. Thus, surgical repair of atrial septal defect to abolish supraventricular tachyarrhythmias in adults is warranted, but in patients with fibrillation, it may have to be combined with a Maze operation in the future.

The limbic cortex in schizophrenia: focus on the anterior cingulate.

4. Phencyclidine effects on limbic cortex: animal experiments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 4.1. Study one . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 4.2. Study two . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 4.3. Study three . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Increased cerebellar Purkinje cell numbers in mice overexpressing a human Bcl-2 transgene

The Purkinje cell is a primary organizer in the development of the cerebellum. Purkinje cells may provide positional information cues that regulate afferent innervation, and Purkinje cell target size controls the adult number of afferent olivary neurons and granule cells. While Purkinje cells are necessary for the survival of olivary neurons and granule cells during periods of programmed cell death, little is known about the survival requirements of Purkinje cells in vivo. To determine if Purkinje cells are subject to programmed cell death during development we have analyzed Purkinje cell numbers in two lines of transgenic mice that overexpress a human gene for bcl‐2 (Hu‐bcl‐2). Bcl‐2 is a protooncogene that inhibits apoptosis in many cell types. Overexpression of bcl‐2 in vitro and in vivo rescues neurons from trophic factor deprivation or naturally occurring cell death. In the mice analyzed in this study, transgene expression is driven by the neuron‐specific enolase promoter that is first expressed embryonically in most regions of the brain in one line and postnatally in the second line. We have counted Purkinje cells in three adult control mice, five early overexpressing transgenics, and three late expressing transgenics. The number of Purkinje cells in the Hu‐bcl‐2 transgenic mice is significantly increased above control numbers, with an increase of 43% in the embryonically overexpressing line and an increase of 27% in the postnatally overexpressing line. Because bcl‐2 overexpression has been shown to rescue other neurons from programmed cell death, the increase in Purkinje cell numbers in overexpressing bcl‐2 transgenics suggests that Purkinje cells undergo a period of cell death during normal development.

Engrailed Homeobox Genes Regulate Establishment of the Cerebellar Afferent Circuit Map

The spatial organization of the cerebellar afferent map has remarkable correspondence to two aspects of intrinsic patterning within the cerebellum embodied by a series of lobules and Purkinje cell (PC)-striped gene expression. Using male and female mice, we tested whether the Engrailed (En) homeobox genes are a common genetic substrate regulating all three systems, since they are expressed in spatially restricted domains within the cerebellum and are critical for patterning PC gene expression and foliation. Indeed, we discovered that En1/2 are necessary for the precise targeting of mossy fibers to distinct lobules, as well as their subsequent resolution into discrete parasagittal bands. Moreover, each En gene coordinately regulates afferent targeting and the striped pattern of PC protein expression (e.g., ZebrinII/AldolaseC) independent of regulating foliation. We further found that En1/2, rather than the presence of a full complement of lobules, are critical for generating PC protein stripes and mossy fiber bands, and that PC striped gene expression is determined before afferent banding. Thus, the En transcription factors not only regulate cerebellum circuit topography, but they also link afferent and efferent neurons precisely enough that alterations in PC protein expression can be used as a read out for underlying defects in circuitry. In summary, our data suggest that En1/2 are master regulators of three-dimensional organization of the cerebellum and coordinately regulate morphology, patterned gene expression, and afferent topography.

Elimination of Bax expression in mice increases cerebellar purkinje cell numbers but not the number of granule cells.

Cerebellar Purkinje cells and granule cells have been studied extensively as models for investigating neuron‐target interactions and the regulation of cell numbers in the developing central nervous system. Recent studies of transgenic mice that overexpress a human Bcl‐2 transgene in Purkinje cells suggest both that programmed cell death plays an unexpected role in regulating Purkinje cell number and that Purkinje cells influence the number of granule cells. The role of cell death‐related proteins and Purkinje‐granule cell interactions in cerebellar development was investigated further in this study by counting the number of Purkinje and granule cells in knockout mutants with a deletion in the proapoptotic gene, Bax. The total number of Purkinje cells was estimated using stereological counting principles in six adult wild type mice, four hemizygous Bax +/− controls, and six Bax −/− knockout mutants. The total number of granule cells per cerebellum was estimated in three adult wild type mice, three hemizygous Bax +/− controls, and three Bax −/− knockout mutants. The number of Purkinje cells increased significantly by over 30% in the Bax −/− knockout mutants compared with wild type and hemizygote controls, whereas the number of granule cells was unchanged in the Bax −/− mutants. There was no change in the volume of the cerebellar cortex or in the size of Purkinje cell bodies in the Bax −/− mutants, implying that Purkinje cell density was increased in the Bax −/− mutants. The increase in Purkinje cell numbers in the Bax −/− knockout mice supports previous evidence that Purkinje cells undergo a period of naturally occurring cell death that is mediated at least in part by the cell death proteins Bcl‐2 and Bax. The lack of an effect of Bax gene expression on granule cell numbers indicates that Bax is not an obligate participant in naturally occurring cell death in granule cells. J. Comp. Neurol. 436:82–91, 2001.

Peritoneal dialysis after infant open heart surgery: observations in 27 patients

BACKGROUND The role of peritoneal dialysis (PD) in the management of infants after heart operation is under discussion. The aim of this study was to investigate the effect of PD on fluid balance and outcome. METHODS Twenty-seven (33%) of 81 consecutive infants who underwent heart operation required PD. In 22 patients (81%), PD was started prophylactically at the end of the operation. We recorded hemodynamic data and fluid balance. Patients experiencing acute renal failure (ARF) were compared with the remaining infants. RESULTS Eleven of 81 patients (14%) experienced ARF; 3 of them died (4% of all patients undergoing operation, 27% of those with ARF). Complications of PD, present in 33%, were transitory and of minor significance. Patients with ARF had decreased cardiac function compared with those without ARF but similar fluid balance. CONCLUSIONS Peritoneal dialysis is an effective and safe method for the treatment of ARF in infants after open heart operation. As PD is helpful in modulating postoperative fluid balance, prophylactic use of PD can be recommended for selected patients who are at risk for low cardiac output syndrome.

Regional expression of RGS4 mRNA in human brain

Regulators of G‐protein signalling (RGS) proteins are a recently discovered class of proteins that modulate G‐protein activity. More than 20 RGS proteins have been identified and are expressed throughout the body and brain. In particular, RGS4 appears to regulate dopamine receptor function and has been implicated in several dopamine related diseases, including schizophrenia. This study presents an extensive examination of the regional distribution of RGS4 mRNA in postmortem human brain. Using in situ hybridization, the expression levels of RGS4 mRNA were determined in human hemicoronal (Talairach sections +8 and −20) brain sections. In the rostral slice (Talairach +8) highest levels were found in the inferior frontal cortex, the superior frontal, and the cingulate cortex. Slightly lower levels were found in the insular cortex and inferior temporal cortex. The caudate, putamen and nucleus accumbens had lower levels. In the caudal slice (−20), the cortical layers showed the highest levels, with moderate levels observed in the parahippocampal gyrus, low levels in the CA‐pyramidal region, and almost undetectable levels in the thalamus. In the frontal cortex a dense band was apparent near one of the inner layers of the cortex. In conclusion, RGS4 mRNA distribution in human postmortem tissue from normal persons was very dense in most cortical layers examined, with lower density in the basal ganglia and thalamus.