Initial evidence for sex-specific effects of early emotional abuse on affective processing in bipolar disorder.

PURPOSE: This study investigates the effect of sex and childhood trauma on affective processing in bipolar disorder (BPD) patients. METHODS: In a sample of fifty-six BPD patients, we administered the Childhood Trauma Questionnaire (CTQ), and the Iowa Gambling Task (IGT) and the Affective Go/No-Go (AGNG) to measure affective processing. Analysis of Variance (ANOVA) was used to evaluate the effect of sex and childhood trauma on IGT; Repeated-Measures ANOVAs to measure accuracy and bias measures across conditions on the AGNG. RESULTS: In the context of childhood abuse, females evidenced a more conservative cognitive style than males by selecting fewer cards from the disadvantageous decks [F(1, 49)=14.218; P<0.001] and showed an improvement throughout the task, as noted in a normal learning curve [F(1.49)=4.385; P=0.041)]. For the AGNG, an interaction specific to the negative valence stimuli on response bias measures was found. Abused females scored higher (mean=8.38; SD=6.39) than abused males (mean=0.69; SD=1.19) [F(1.46)=6.348; P=0.015]. CONCLUSION: Severity of childhood trauma was significantly different between sexes. In the context of a history of emotional abuse, male bipolar patients tended toward a more risk-taking behavior compared to female. Further investigations are needed to elucidate potential pathophysiological mechanisms underlying this interaction.

Barth's syndrome-like disorder: a new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation).

An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Barth syndrome-like presentation. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely delayed gross motor milestones, marked muscle weakness, and dilated cardiomyopathy that progressed to congestive heart failure. He also had persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low blood levels of cholesterol. Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogenase, a generalized decrease of COX activity, and abundant ragged-red fibers. Electron microscopic studies revealed multiple mitochondrial abnormalities in lymphocytes and monocytes, in the striated muscle, and in the postmortem samples (muscle, heart, liver, and brain). Biochemical analysis showed a pronounced and constant lactic acidosis, and abnormal urinary organic acid excretion (unchanged in the fasting and postprandial states). In addition, in CSF there was a marked increase of lactate and beta-hydroxybutyrate (beta-HOB) and also a high systemic ratio beta-HOB/acetoacetate. Enzymatic assay of the respiratory chain in biopsied muscle showed 10% of complex I activity and 24% of complex IV activity compared with controls. Molecular studies of the mitochondrial genome revealed an A to G mutation at nucleotide pair 3243 in mitochondrial DNA, a well-known pathogenetic mutation (MELAS mutation) in all the patient's tissues and also in the blood specimens of the probands mother and sibs (4 of 5). The diagnosis of MELAS mutation was reinforced by the absence of an identifiable mutation in the X-linked G4.5 gene of the propositus. The present observation gives additional evidence of the variable clinical expression of mtDNA mutations in humans and demonstrates that all clinical variants deserve adequate investigation to establish a primary defect. It also suggests adding Barth-like syndrome to the list of phenotypes with the MELAS mutation.

Isolated pancreatic amylase deficiency: probable error in maturation.

A boy with failure to thrive and isolated pancreatic amylase deficiency is described. Immunoprecipitation confirmed only salivary isoamylase in duodenal fluid at ages 20 and 33 months. Because normal pancreatic amylase messenger RNA was detected by reverse-transcriptase polymerase chain reaction in the fluid, failure of the normal maturation of pancreatic amylase secretion may explain the deficiency.

Fixing the intestinal mucosa in the bone marrow transplant patient: lessons from other intestinal immunodeficiencies and inflammatory disorders.

Gastrointestinal inflammation is common following bone marrow transplantation. Key pathogenetic events, such as major histocompatibility complex (MHC) expression on intestinal epithelial cells and local production of cytokines in the gastrointestinal mucosa, are common features of many gastrointestinal inflammatory disorders. Drawing from clinical experience of the treatment of other disorders associated with gastrointestinal inflammation, such as ulcerative colitis and Crohn's disease, a number of therapeutic alternatives may be relevant for the bone marrow transplant patient with significant graft-vs.-host disease (GvHD). Options to consider include therapeutics that alter inflammatory cell migration, anti-inflammatory cytokines, direct neutralization of proinflammatory cytokines, and cytokines that promote epithelial restitution in the gastrointestinal mucosa. In addition, a variety of nutritional and other novel treatments are available, which may improve epithelial function or which have anti-inflammatory actions. Prospective studies of combined nutrient and cytokine-modulating treatments for the bone marrow transplant patient are warranted.

Synergistic effects of interferon gamma and tumour necrosis factor alpha on T84 cell function.

BACKGROUND: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation and increased epithelial permeability. Both tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) have been implicated in IBD. AIMS: To understand better the effects of these cytokines on epithelial cell function. METHODS: T84 cells were cultured with IFN-gamma and TNF-alpha and changes in transepithelial resistance (TER), fluorescein isothiocyanate (FITC) dextran flux, short circuit current (I(sc)), cystic fibrosis transmembrane conductance regulator (CFTR) protein levels, cell morphology, TNF receptor gene expression, and apoptosis were assayed. RESULTS: Relative to controls, significant changes (p<0.05) occurred in cells incubated with IFN-gamma for two days: TER was decreased to 20 (6.2)%, FITC-dextran flux was increased by 109 (19)-fold, cAMP and Ca dependent I(sc) were decreased to 51 (6.4)% and 24 (2.2)%, respectively, and CFTR levels were decreased to 47 (11)%. Cell morphology was altered but cell death was not induced. TNF receptor mRNA levels were increased. When added with IFN-gamma, TNF-alpha accelerated IFN-gamma dependent changes. Relative to controls, significant changes occurred after one day of culture with IFN-gamma plus TNF-alpha: TER was decreased to 27 (3.5)%, FITC-dextran flux was increased by 185 (45)-fold, and cAMP and Ca dependent I(sc) were decreased to 66 (12)% and 35 (6.8)%, respectively. TNF-alpha also enhanced IFN-gamma dependent changes in cell morphology but did not induce cell death. CONCLUSION: IFN-gamma alters T84 cell epithelial properties and TNF-alpha can enhance these effects, perhaps due to IFN-gamma dependent increases in TNF receptor gene expression. Overall, these studies suggest that in IBD, TNF-alpha may have synergistic effects on IFN-gamma mediated alterations of epithelial cell function.

Mutation characterization and genotype-phenotype correlation in Barth syndrome.

Barth syndrome is an X-linked cardiomyopathy with neutropenia and 3-methylglutaconic aciduria. Recently, mutations in the G4.5 gene, located in Xq28, have been described in four probands with Barth syndrome. We have now evaluated 14 Barth syndrome pedigrees for mutations in G4.5 and have identified unique mutations in all, including four splice-site mutations, three deletions, one insertion, five missense mutations, and one nonsense mutation. Nine of the 14 mutations are predicted to significantly disrupt the protein products of G4.5. The occurrence of missense mutations in exons 3 and 8 suggests that these exons encode essential portions of the G4. 5 proteins, whose functions remain unknown. We found no correlation between the location or type of mutation and any of the clinical or laboratory abnormalities of Barth syndrome, which suggests that additional factors modify the expression of the Barth phenotype. The characterization of mutations of the G4.5 gene will be useful for carrier detection, genetic counseling, and the identification of patients with Barth syndrome who do not manifest all of the cardinal features of this disorder.

Identification of a testis-expressed creatine transporter gene at 16p11.2 and confirmation of the X-linked locus to Xq28.

Creatine and creatine phosphate act as a buffer system for the regeneration of ATP in tissues with fluctuating energy demands. Following reports of the cloning of a creatine transporter in rat, rabbit, and human, we cloned and sequenced a creatine transporter from a human intestinal cDNA library. PCR amplification of genomic DNAs from somatic cell hybrid panels localized two creatine transporter (CT) genes: CT1 to Xq26-q28 and CT2 to 16p11.2. Refinement of CT1 to Xq28 was confirmed by FISH. Identification of CT2 sequences in YACs and cosmid contigs that had been ordered on human chromosome 16 enabled its assignment to the proximal end of 16p11.2. Sequencing of the CT2 gene identified sequence differences between CT1 and CT2 transcripts that were utilized to determine that CT2 is expressed in testis only. CT2 is the most proximally identified gene on chromosome 16p to date. The existence of an autosomal, testis-specific form of the human creatine transporter gene suggests that creatine transporter activity is critical for normal function of spermatazoa following meiosis.

Acute Hepatitis.

The acute onset of hepatitis may occur in adolescents as a result of hepatic damage from infectious agents, drugs, or toxins, or it may be the initial presentation of a chronic autoimmune or metabolic liver disease. The authors characterize the clinical features of each of these disorders emphasizing recognition and diagnosis.

Soluble interleukin-2 receptor as a predictor of neonatal sepsis.

We prospectively measured soluble interleukin-2 receptor levels in 56 premature infants with suspected sepsis and demonstrated significant differences between those with positive results on blood, urine, or cerebrospinal fluid cultures, and those with negative results. Soluble interleukin-2 receptor levels can be used to facilitate the diagnosis of sepsis in premature infants with negative blood culture results.

Symptomatic Helicobacter pylori infection in young patients with severe neurologic impairment.

Helicobacter pylori infection was identified in five patients with profound neurologic impairment who were undergoing evaluation for gastrointestinal symptoms, and it was subsequently identified in 7 of 61 patients with symptoms whose condition was evaluated prospectively. Institutionalized patients were at greater risk of infection. Treatment of H. pylori infection resulted in symptomatic improvement for the majority of patients.

Evaluation of liquid yeast-derived sucrase enzyme replacement in patients with sucrase-isomaltase deficiency.

BACKGROUND: No enzyme replacement therapy exists for patients with congenital sucrase-isomaltase deficiency (CSID). A by-product of the manufacture of baker's yeast is a liquid preparation containing high sucrase activity. The aim of the present study was to investigate the activity and stability of this preparation and its effect on breath hydrogen excretion and gastrointestinal symptoms after sucrose ingestion in 14 patients with CSID. METHODS: The homogeneity of yeast sucrase was studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its activity was measured. Stability at various temperatures and pH ranges and in the presence of gastric aspirate, pepsin, and bovine serum albumin was assessed. Fourteen patients with CSID underwent double-blind placebo-controlled breath tests with yeast sucrase. They then completed an 8-week dose response study that used different enzyme concentrations while consuming a sucrose-containing diet. RESULTS: Liquid yeast sucrase is highly glycosylated, contains no lactase activity, and is stable at 4 degrees C and over a wide range of pH. Pepsin digestion of the enzyme in vitro can be blunted by bovine serum albumin and by increasing the pH. Yeast sucrase reduces breath hydrogen excretion in patients with CSID who are given a sucrose load (P < 0.001) and allows most patients to consume a sucrose-containing diet. CONCLUSIONS: Liquid yeast sucrase offers effective enzyme replacement therapy for patients with CSID.

Examination of anti-neutrophil cytoplasmic antibodies in childhood inflammatory bowel disease.

The detection of anti-neutrophil cytoplasmic antibodies (ANCA), in a perinuclear fluorescence pattern, in the serum of adults with inflammatory bowel disease has recently been described to be sensitive and specific for a diagnosis of ulcerative colitis in comparison to Crohn's disease and other colitides. We have examined the sera of 41 children and adolescents with ulcerative colitis, 27 with Crohn's disease, and a control group for the presence of ANCA. Anti-neutrophil cytoplasmic antibodies were detected in the serum of 27 of 41 patients with ulcerative colitis (66%), five of 27 with Crohn's disease (19%), and in none of our control subjects or patients with functional abdominal pain. Overall, the presence of ANCA was 66% sensitive and 84% specific for a diagnosis of ulcerative colitis when compared to Crohn's disease. There was no relationship between a positive ANCA value and disease activity or other clinical indicators. We conclude that evaluation for the presence of ANCA may be a useful adjunct for the clinical assessment of patients with inflammatory bowel disease. The presence of ANCA in children and adolescents, however, will not definitively distinguish between patients with ulcerative colitis and Crohn's disease.

Serial measurement of soluble interleukin 2 receptor levels: an early indicator of treatment response for Lyme disease.

Detection of antibodies produced in response to infection with Borrelia burgdorferi provides a valuable aid for diagnosing Lyme disease. However, anti-Borrelial antibody titers are of little value in determining treatment success or providing evidence of persistent infection as levels of specific antibodies can remain elevated even after successful treatment. Pretreatment and posttreatment measurement of soluble interleukin 2 receptor (sIL-2R) levels was evaluated for use in predicting treatment response in Lyme disease. Results indicate that serial measurement of serum sIL-2R levels can provide an early indicator of response to treatment and outcome.

Prevalence and characteristics of Blastocystis hominis infection in children.

Blastocystis hominis, a protozoan whose pathogenicity has been questioned, is sometimes found in the human gastrointestinal tract. We sought to determine the prevalence of Blastocystis in stool and to characterize clinical features of infection with Blastocystis in children. Forty-six (3%) of 1,736 patients undergoing fecal microscopy at Children's Hospital of Pittsburgh between January 1, 1985, and December 31, 1988, harbored Blastocystis. Of these 46 children, 75% had exposure to well water or had been in developing countries. Thirty-nine of the 46 (85%) experienced gastrointestinal symptoms, such as abdominal pain, diarrhea, vomiting, and weight loss. Blastocystis was the only parasite found in 35 of those 39 symptomatic children. Symptoms resolved within one month in 90% of patients receiving antiparasitic pharmacotherapy, but in only 58% (P < .04) of those receiving no therapy. We conclude that children infected with Blastocystis often experience gastrointestinal symptoms and that treatment increases the rate of symptomatic improvement. We speculate that Blastocystis is a human pathogen.

Soluble interleukin-2 receptor levels in infants with bronchopulmonary dysplasia.

Soluble interleukin-2 receptors (sIL2R) in plasma have been identified as a marker of lymphocyte activation. Lymphocyte activation as a manifestation of inflammation may be important in the pathogenesis of bronchopulmonary dysplasia (BPD). To test the hypothesis that infants with BPD have higher sIL2R levels, 12 infants with or at risk of developing BPD (GA +/- SD, 27 +/- 5 weeks; BW +/- SD 1,053 +/- 733 g) had plasma sIL2R levels determined and were compared to 20 infants being ventilated for respiratory distress syndrome (RDS) (GA +/- SD, 28 +/- 3.5 weeks; BW +/- SD, 1,133 +/- 390 g: P = NS for both GA and BW, t test). Tracheal aspirates in both groups were also analyzed for sIL2R levels. To control for the effects of postnatal age (PNA) and study weight (SW) on the sIL2R levels, another group of 16 nonventilated babies (NVB) had plasma analyzed for sIL2R (PNA +/- SD: 39 +/- 40 days NVB vs. 48 +/- 36 days BPD; P = NS); (SW +/- SD: 1391 +/- 250 g NVB vs. 1212 +/- 700 g BPD; P = NS). The following data were obtained for the plasma sIL2R levels (mean +/- SEM U/mL): RDS controls, 1,231 +/- 80; BPD infants, 1,790 +/- 120; NVB controls, 1,319 +/- 76; P = 0.0005 RDS vs. BPD and P = 0.002 BPD vs. NVB. There was no significant difference in the sIL2R levels for the infants at risk of developing BPD vs. the infants with established BPD. Also, when analyzed separately, infants at risk of BPD and the infants with established BPD had higher sIL2R levels than the RDS and NVB controls. No differences were noted in the tracheal sIL2R levels in the BPD vs. RDS groups. These data indicate that infants with BPD had significantly higher sIL2R levels in plasma than either RDS or NVB controls. Therefore, lymphocyte activation may play a role in the pathogenesis of BPD.

Cricopharyngeal dysfunction associated with Chiari malformations.

UNLABELLED: Dysphagia due to upper esophageal sphincter (UES) dysfunction can be a manifestation of Chiari malformation. We evaluated five young children with dysphagia and a Chiari malformation before and after craniocervical decompression. Preoperatively, esophageal manometry with a multilumen perfused catheter revealed failure of complete relaxation of the UES in three patients, pharyngo-UES incoordination in one patient, and both abnormalities in the last patient. Preoperative barium esophagograms were obtained in four of the patients and were normal in two. One patient had nasal regurgitation of barium and delayed passage of barium through the UES. One patient had a posterior pharyngeal impression (bar) at the level of the UES and delayed transit of barium. All patients had clinical and manometric resolution of UES dysfunction following surgical decompression of the Chiari malformation. All swallows were coordinated, and UES relaxations were complete. However, the posterior pharyngeal bar persisted on postoperative esophagogram in the only patient who had had the abnormality preoperatively, although it no longer interfered with passage of barium. Another patient had a narrowed UES with decreased relaxation. Swallowing was radiographically normal in three patients postoperatively. CONCLUSION: Surgical decompression of Chiari malformation may lead to complete clinical and manometric resolution of dysphagia due to upper esophageal sphincter dysfunction. Esophageal manometry is more likely than barium swallow to demonstrate the abnormality, and correlates better with symptomatic improvement postoperatively.

Idiopathic hypereosinophilic syndrome terminating in acute lymphoblastic leukemia.

Idiopathic hypereosinophilic syndrome (IHES) is a heterogeneous group of disorders characterized by multisystem dysfunction and persistent, extreme eosinophilia of unknown cause. We describe a 9-1/2-year-old boy whose course included several unusual clinical features and terminated 2 years after diagnosis in acute lymphoblastic leukemia (ALL). Serial studies suggest that leukemia was not present earlier in his course. We speculate that this child may have had an evolving lymphoproliferative syndrome with a terminal blast crisis to which the eosinophilia was a nonmalignant leukemoid reaction.

Novel primitive swallowing reflex: facial receptor distribution and stimulus characteristics.

We recently described a primitive swallowing reflex: swallowing as a response to a puff of air administered to the face. To identify the facial afferent distribution of this response, the necessary characteristics of the stimulus, and the role of the infant's antecedent behavior, we studied 13 infants who had demonstrated this reflex. We evaluated nine infants by clinically observing for swallowing in response to a total of 135 stimulus applications. All nine had consistently positive responses to the maxillary-ophthalmic area and to the maxillary-mandibular area. Two had consistent responses to stimulation of the mandibular area alone; these were positive. Six had consistent responses to stimulation of the ophthalmic area alone; these were negative. Four infants, evaluated by manometric documentation of swallowing (a total of 137 stimulus applications) demonstrated 47 of 79 (59%) positive responses to stimuli applied to facial areas including any parts of the lips, but only 7 of 28 (25%) positive responses to stimuli applied to facial areas excluding all parts of the lips (chi-square P = 0.002). Light touch to any facial area, including the cornea, failed to produce a swallow in any infant. Crying and sleep were incompatible with the reflex. This newly identified primitive swallow reflex seems to require diffuse stimulation, possibly thermal, to the perioral area of the face in an awake and noncrying infant.