Cell Type-Specific Decomposition of Gingival Tissue Transcriptomes.

Genome-wide transcriptomic analyses in whole tissues reflect the aggregate gene expression in heterogeneous cell populations comprising resident and migratory cells, and they are unable to identify cell type-specific information. We used a computational method (population-specific expression analysis [PSEA]) to decompose gene expression in gingival tissues into cell type-specific signatures for 8 cell types (epithelial cells, fibroblasts, endothelial cells, neutrophils, monocytes/macrophages, plasma cells, T cells, and B cells). We used a gene expression data set generated using microarrays from 120 persons (310 tissue samples; 241 periodontitis affected and 69 healthy). Decomposition of the whole-tissue transcriptomes identified differentially expressed genes in each of the cell types, which mapped to biologically relevant pathways, including dysregulation of Th17 cell differentiation, AGE-RAGE signaling, and epithelial-mesenchymal transition in epithelial cells. We validated selected PSEA-predicted, differentially expressed genes in purified gingival epithelial cells and B cells from an unrelated cohort (n = 15 persons), each of whom contributed with 1 periodontitis-affected and 1 healthy gingival tissue sample. Differential expression of these genes by quantitative reverse transcription polymerase chain reaction corroborated the PSEA predictions and pointed to dysregulation of biologically important pathways in periodontitis. Collectively, our results demonstrate the robustness of the PSEA in the decomposition of gingival tissue transcriptomes and its ability to identify differentially regulated transcripts in particular cellular constituents. These genes may serve as candidates for further investigation with respect to their roles in the pathogenesis of periodontitis.

Catalytic role of 2'-hydroxyl groups within a group II intron active site.

Domain 5 is an essential active-site component of group II intron ribozymes. The role of backbone substituents in D5 function was explored through synthesis of a series of derivatives containing deoxynucleotides at each position along the D5 strand. Kinetic screens revealed that eight 2'-hydroxyl groups were likely to be critical for activity of D5. Through two separate methods, including competitive inhibition and direct kinetic analysis, effects on binding and chemistry were distinguished. Depending on their function, important 2'-hydroxyl groups lie on opposite faces of the molecule, defining distinct loci for molecular recognition and catalysis by D5.

FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of ß-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated ß-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of ß-catenin. At the molecular level, FoxO1 interacts with ß-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated ß-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.

Ruffling membrane, stress fiber, cell spreading and proliferation abnormalities in human Schwannoma cells.

Schwannomas are peripheral nerve tumors that typically have mutations in the NF2 tumor suppressor gene. We compared cultured schwannoma cells with Schwann cells from normal human peripheral nerves (NHSC). Both cell types expressed specific antigenic markers, interacted with neurons, and proliferated in response to glial growth factor, confirming their identity as Schwann cells. Schwannoma cells frequently had elevated basal proliferation compared to NHSC. Schwannoma cells also showed spread areas 5-7-fold greater than NHSC, aberrant membrane ruffling and numerous, frequently disorganized stress fibers. Dominant negative Rac inhibited schwannoma cell ruffling but had no apparent effect on NHSC. Schwannoma cell stress fibers were inhibited by C3 transferase, tyrphostin A25, or dominant negative RhoA. These data suggest that the Rho and Rac pathways are abnormally activated in schwannoma cells. Levels of ezrin and moesin, proteins related to the NF2 gene product, merlin, were unchanged in schwannoma cells compared to NHSC. Our findings demonstrate for the first time that cell proliferation and actin organization are aberrant in schwannoma cells. Because NF2 is mutant in most or all human schwannomas, we postulate that loss of NF2 contributes to the cell growth and cytoskeletal dysfunction reported here.

Transesophageal echocardiographic detection of atrial thrombi in patients with nonfibrillation atrial tachyarrhythmias and congenital heart disease.

OBJECTIVES: We hypothesized an association between atrial thrombi and nonfibrillation atrial tachyarrhythmias in patients with congenital heart disease. BACKGROUND: We observed a fatal thromboembolus after direct current cardioversion in an adolescent with atrial flutter and repaired tetralogy of Fallot. METHODS: Using transesophageal echocardiography, we prospectively studied 19 consecutive patients with congenital heart disease with nonfibrillation atrial tachyarrhythmia (atrial flutter in 18, primary atrial tachycardia in 1) undergoing electrophysiologic procedures (median age 19.6 years, range 7.0 to 53.8; 11 male, 8 female). Transthoracic echocardiograms were available for 17 patients. RESULTS: All transesophageal examinations were performed without incident. No atrial thrombi were detected in 11 patients who subsequently had uncomplicated direct current cardioversion. Eight solitary atrial thrombi were detected (incidence 42%). Six thrombi were located in the right atrium (Fontan repair in four patients, Ebstein's malformation repair in two), and two were noted in the left atrium (congenital hypertrophic cardiomyopathy and atrial septal defect repair in one patient each). Transthoracic echocardiograms were available in seven of eight patients with thrombus detected by transesophageal echocardiography, with only one study conclusive for an atrial thrombus. Cardioversion was deferred in six of eight patients with thrombus, and anticoagulation therapy was initiated. Uncomplicated electrophysiologic procedures were conducted in two patients at the time of detection of right atrial thrombus (atrioventricular node ablation in one patient, direct current cardioversion in the other). CONCLUSIONS: Prothrombin conditions exist in patients with congenital heart disease with nonfibrillation atrial tachyarrhythmias, as indicated by a significant incidence of transesophageally detected atrial thrombi. The need for prophylactic anticoagulation and the safety of pharmacologic or direct current cardioversion are issues that remain unresolved.

Clinical course of idiopathic dilated cardiomyopathy in children.

Previous studies in adults with dilated cardiomyopathy suggest that the presence of arrhythmia, especially ventricular tachycardia, correlates with increased mortality. We performed a retrospective analysis of 63 children with idiopathic dilated cardiomyopathy to determine the prognostic significance of arrhythmias and other findings with respect to mortality. The mean age at diagnosis of the cardiomyopathy was 4.96 +/- 5.3 years. The overall mortality rate was 16% over a 10 year follow-up period. Persistent congestive heart failure and ST-T wave changes correlated with increased mortality (p less than 0.05). No other variables affected outcome. Arrhythmias were found in 46% of the patients; of the arrhythmias, 48% were atrial arrhythmias. Ventricular tachycardia was present in six patients. Death occurred in 4 (14%) of 29 patients with known arrhythmia; 1 of the 5 died suddenly. The remaining 6 deaths in the series occurred in the 34 patients without a documented arrhythmia. It is concluded that 1) arrhythmias are frequently seen in children with dilated cardiomyopathy but are not predictive of outcome; 2) sudden death in children with this disease is rare; and 3) persistent congestive heart failure portends a poor prognosis.

Flecainide and amiodarone: combined therapy for refractory tachyarrhythmias in infancy.

OBJECTIVES: This study assessed the safety and efficacy of combined flecainide and amiodarone therapy in controlling refractory tachyarrhythmias in infants. BACKGROUND: Single-drug as well as standard combination medical therapy for tachyarrhythmias in infants sometimes fails. In those cases, one may consider interventional therapy. However, this option may carry a high risk of morbidity and mortality in infants. The natural history of tachyarrhythmias in infants often favors eventual resolution and reinforces the importance of selecting an effective medical regimen. METHODS: We performed a retrospective analysis of nine infants (median age 2 months) who received combined flecainide and amiodarone therapy for attempted control of refractory tachyarrhythmias. Trough serum drug levels of flecainide were monitored, and 24-h ambulatory electrocardiographic monitoring was used to determine efficacy of therapy. RESULTS: Single-drug treatment with flecainide or amiodarone failed in all of the infants studied. An average of four drugs failed (range one to six) before administration of combined flecainide and amiodarone therapy. During combined therapy, the flecainide dose was 70 to 110 mg/m2 per day, and that for amiodarone was 7.5 to 13.5 mg/kg per day for a mean (+/- SD) of 9 +/- 2 days to load and 5 to 12 mg/kg per day as maintenance. Successful control of tachyarrhythmias was demonstrated in seven (78%) of nine infants (95% confidence interval 46% to 99%) (three of three with congenital junctional ectopic tachycardia, three of three with supraventricular tachycardia and one of three with ventricular tachycardia). During combined therapy, flecainide trough levels ranged from 350 to 731 ng/ml. Corrected QT intervals varied from 0.440 to 0.488 ms. No proarrhythmia occurred. None of the infants required a pacemaker, and all had normal left ventricular dimensions and fractional shortening by echocardiography. Eight of nine infants had a structurally normal heart. One infant had surgical correction of an atrioventricular septal defect. CONCLUSIONS: Combination therapy with flecainide and amiodarone appears to be safe and effective in controlling refractory tachyarrhythmias in infants. The combination of flecainide and amiodarone may obviate the need for early interventional therapy or may allow delay until the child is older.

Computer-guided surgery for tachyarrhythmias in children: current results and expectations.

OBJECTIVES: The purpose of this report is to summarize our entire surgical experience in the treatment of tachyarrhythmias in children. We emphasize our application of a newer computerized mapping system for use in both the electrophysiology laboratory and the operating room to localize points of activation of the tachyarrhythmias. BACKGROUND: A retrospective review was undertaken to examine the results of operative procedures in 290 children undergoing surgical treatment for tachyarrhythmias from 1977 to the present. METHODS: Operative procedures were performed in 290 children and consisted of the following: surgical ablation of accessory pathways of the Kent bundle type (210 children); surgery with cryoablation for atrial ectopic tachycardia (35 children); surgical excision or cryoablation, or both, for ventricular tachycardia (26 children); cryoablation for the permanent form of junctional reciprocating tachycardia (15 children) and atrioventricular (AV) node reentrant tachycardia (4 children). RESULTS: The surgical cure rate for accessory pathway tachycardia in the era before computerized mapping was 80% (41 patients) in the period from 1977 to 1982 and 95% (86 patients) in the period from 1982 to 1988. This rate improved to 100% (83 patients) after the advent of the computerized mapping technique. These improved results are probably due to a combination of factors, including increasing experience in electrophysiologic mapping and surgery, and cannot be attributed to the computerized mapping system alone. Surgical cure or major improvement in symptoms was documented in 33 (94%) of 35 patients with atrial ectopic tachycardia. Surgical cure was accomplished in 25 (96%) of 26 patients with the complex form of ventricular tachycardia. In 19 patients with the permanent form of junctional reciprocating tachycardia and the more typical AV node reentrant tachycardia, the surgical cure rate was 100%. CONCLUSIONS: In all forms of supraventricular reentrant tachycardia that occur in children, preoperative computerized mapping techniques combined with intraoperative computerized mapping and surgical ablation can eliminate tachycardia at a success rate of close to 100%. Computerized mapping techniques are less accurate in patients with atrial ectopic tachycardia because of multiple foci and a broader surface area to be mapped. This experience demonstrates that excellent results can be achieved in the surgical treatment of tachyarrhythmias in children.

Intravenous amiodarone for life-threatening tachyarrhythmias in children and young adults.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of intravenous amiodarone in young patients. BACKGROUND: Oral amiodarone therapy has proved useful for problematic arrhythmias in children, but its pharmacokinetics with the oral route preclude its use in several acute settings. METHODS: Intravenous amiodarone was administered in 1-mg/kg body weight aliquots followed by continuous infusion to patients with potentially life-threatening tachyarrhythmias that had not been abolished by standard therapies. RESULTS: Ten patients (mean age 6.8 years) received intravenous amiodarone: for ventricular tachycardia in seven patients and for atrial tachycardia, junctional tachycardia and multiple arrhythmias in one patient each. Surgery for congenital heart defects had been performed previously in six patients. Two patients had a hamartoma causing ventricular tachycardia. Six of 10 patients had complete resolution of arrhythmia with intravenous amiodarone: 4 of 7 with ventricular tachycardia, 1 of 1 with atrial tachycardia and 1 of 1 with postoperative junctional ectopic tachycardia. Intravenous amiodarone was not successful in the two patients with a hamartoma but slowed ventricular tachycardia in one, allowing successful surgical cure. Average drug load at the time of effect was 4.8 mg/kg body weight. Four patients had transient hypotension during loading, corrected with volume or low dose calcium. Intravenous infusion of amiodarone, 10 mg/kg per day, continued an average of 3 days. Four of 10 patients died, all of nonarrhythmic causes not attributable to intravenous amiodarone. CONCLUSIONS: Intravenous amiodarone was well tolerated in this small series of patients. Postoperative ventricular tachycardia was responsive to intravenous amiodarone in 80% (8 of 10) of the patients (95% confidence interval 40% to 99%). Use of this drug in acute, postoperative tachyarrhythmias may be lifesaving in some patients when standard intravenous therapies fail.

Persistence of ventricular arrhythmia after resolution of occult myocarditis in children and young adults.

OBJECTIVES: We sought to examine whether resolution of occult myocarditis in children with associated ventricular arrhythmia correlated with the presence of arrhythmia at late follow-up. BACKGROUND: Complex ventricular arrhythmias have been documented in children with myocarditis. Therapy is aimed at controlling the arrhythmia and any associated ventricular dysfunction. However, no reported studies have documented whether resolution of myocarditis in children is associated with resolution of the associated arrhythmias. METHODS: We performed a retrospective analysis of 12 patients (mean age 12 years) with myocarditis. Ambulatory electrocardiographic (Holter) monitors were reviewed for ventricular arrhythmias at presentation and follow-up. Patients were assigned to Group I if they received corticosteroids in addition to any antiarrhythmic agents and to Group II if they did not receive steroids. Follow-up endomyocardial biopsy was performed in some patients, and results were analyzed in relation to the presence of arrhythmias at follow-up. RESULTS: Eleven patients had ventricular tachycardia, and one had multiform couplets. Corticosteroids were given to seven patients (Group I). Follow-up biopsy was performed in seven patients (six received steroids), with resolution of inflammation in all; four of the seven still had ventricular arrhythmias but with improved control. Of the five patients without follow-up biopsy, three had persistent arrhythmia. Absence of inflammation at follow-up biopsy did not correlate with loss of ventricular arrhythmias, and there was no difference between Group I and II patients with respect to resolution of arrhythmia (Fisher exact test, p = 0.70, power 11%). CONCLUSIONS: Complex ventricular arrhythmias persist after apparent resolution of occult myocarditis in children. Although these arrhythmias are easier to control after such resolution, the patients may require long-term antiarrhythmic therapy.

Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol.

OBJECTIVE: The purpose of this study was to analyze the efficacy and safety of intravenous amiodarone in young patients with critical, drug-resistant arrhythmias. BACKGROUND: Intravenous amiodarone has been investigated in adults since the early 1980s. Experience with the drug in young patients is limited. A larger pediatric study group was necessary to provide responsible guidelines for the drug's use before its market release. METHODS: Eight centers obtained institutional approval of a standardized protocol. Other centers were approved on a compassionate use basis after contacting the primary investigator (J.C.P). RESULTS: Forty patients were enrolled. Standard management in all failed. Many patients had early postoperative tachyarrhythmias (25 of 40), with early successful treatment in 21 (84%) of 25. Twelve patients had ventricular tachyarrhythmias: seven had successful therapy, and six died, none related to the drug. Eleven patients had atrial tachyarrhythmias: 10 of 11 had immediate success, but 3 later died. Fourteen patients had junctional ectopic tachycardia, which was treated with success (sinus rhythm or slowing, allowing pacing) in 13 of 14, with no deaths. Three other patients had supraventricular tachycardias, with success in two and no deaths. The average loading dose was 6.3 mg/kg body weight, and 50% of patients required a continuous infusion. Four patients had mild hypotension during the amiodarone bolus. One postoperative patient experienced bradycardia requiring temporary pacing. There were no proarrhythmic effects. Deaths (9 [23%] of 40) were not attributed to amiodarone. CONCLUSIONS: Intravenous amiodarone is safe and effective in most young patients with critical tachyarrhythmia. Intravenous amiodarone can be lifesaving, particularly for postoperative junctional ectopic tachycardia, when standard therapy is ineffective.

Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela.

OBJECTIVE: We report 16 infants with complete congenital heart block (CHB) who developed late-onset dilated cardiomyopathy despite early institution of cardiac pacing. BACKGROUND: Isolated CHB has an excellent prognosis following pacemaker implantation. Most early deaths result from delayed initiation of pacing therapy or hemodynamic abnormalities associated with congenital heart defects. METHODS: A multi-institutional study was performed to identify common clinical features and possible risk factors associated with late-onset dilated cardiomyopathy in patients born with congenital CHB. RESULTS: Congenital heart block was diagnosed in utero in 12 patients and at birth in four patients. Ten of 16 patients had serologic findings consistent with neonatal lupus syndrome (NLS). A pericardial effusion was evident on fetal ultrasound in six patients. In utero determination of left ventricular (LV) function was normal in all. Following birth, one infant exhibited a rash consistent with NLS and two had elevated hepatic transaminases and transient thrombocytopenia. In the early postnatal period, LV function was normal in 15 patients (shortening fraction [SF] = 34 +/- 7%) and was decreased in one (SF = 20%). A cardiac pacemaker was implanted during the first two weeks of life in 15 patients and at seven months in one patient. Left ventricular function significantly decreased during follow-up (14 days to 9.3 years, SF = 9% +/- 5%). Twelve of 16 patients developed congestive heart failure before age 24 months. Myocardial biopsy revealed hypertrophy in 11 patients, interstitial fibrosis in 11 patients, and myocyte degeneration in two patients. Clinical status during follow-up was guarded: four patients died from congestive heart failure; seven required cardiac transplantation; one was awaiting cardiac transplantation; and four exhibited recovery of SF (31 +/- 2%). CONCLUSIONS: Despite early institution of cardiac pacing, some infants with CHB develop LV cardiomyopathy. Patients with CHB require close follow-up not only of their cardiac rate and rhythm, but also ventricular function.

Salt effects on ligand-DNA binding. Minor groove binding antibiotics.

Salt dependent electrostatic effects play a central role in intermolecular interactions involving nucleic acids. In this paper, the finite-difference solution to the nonlinear Poisson-Boltzmann (NLPB) equation is used to evaluate the salt dependent contribution to the electrostatic binding free energy of the minor groove binding antibiotics DAPI, Hoechst 33258 and netropsin to DNA using detailed molecular structures of the complexes. For each of these systems, a treatment based on the NLPB equation accurately describes the variation of the experimentally observed binding constant with bulk salt concentration. A solvation formalism is developed in which salt effects are described in terms of three free energy contributions: the electrostatic ion-molecule interaction free energy, delta delta G degrees im; the electrostatic ion-ion interaction free energy, delta delta G degrees ii; and the entropic ion organization free energy, delta delta G degrees org. The electrostatic terms, delta delta G degrees im and delta delta G degrees ii, have both enthalpic and entropic components, while the term delta delta G degrees org is purely a cratic entropy. Each of these terms depends significantly on salt dependent changes in the counterion and coion concentrations around the DNA. In each of the systems studied, univalent ions substantially destabilize charged ligand-DNA complexes at physiological salt concentrations. This effect involves a salt dependent redistribution of counterions near the DNA. The free energy associated with the redistribution of counterions upon binding is dominated by the unfavorable change in the electrostatic ion-molecule interactions, delta delta G degrees im, rather than the change in the cratic entropy of ion organization, delta delta G degrees org. In addition, the observed slope of the salt dependence of the free energy is determined by electrostatic ion-molecule and ion-ion interactions as well as the cratic entropy of ion release. These findings are in contrast to models in which the cratic entropy of counterion release drives binding.

Salt effects on protein-DNA interactions. The lambda cI repressor and EcoRI endonuclease.

In this paper, finite-difference solutions to the nonlinear Poisson-Boltzmann (NLPB) equation are used to calculate the salt dependent contribution to the electrostatic DNA binding free energy for both the lambda cI repressor and the EcoRI endonuclease. For the protein-DNA systems studied, the NLPB method describes nonspecific univalent salt dependent effects on the binding free energy which are in excellent agreement with experimental results. In these systems, the contribution of the ion atmosphere to the binding free energy substantially destabilizes the protein-DNA complexes. The magnitude of this effect involves a macromolecular structure dependent redistribution of both cations and anions around the protein and the DNA which is dominated by long range electrostatic interactions. We find that the free energy associated with global ion redistribution upon binding is more important than changes associated with local protein-DNA interactions (ion-pairs) in determining salt effects. The NLPB model reveals how long range salt effects can play a significant role in the relative stability of protein-DNA complexes with different structures.

Developmental expression of the TGF beta s in the mouse cochlea.

Mice with targeted disruption of the TGF beta 2 gene display defects in epithelial-mesenchymal tissue interactions in several tissues including the developing cochlea. Specifically, the region of the spiral limbus and the overlying interdental cells, structures putatively involved in endolymphatic fluid homeostasis, display morphogenetic abnormalities. These findings prompted us to explore the pre-natal and post-natal expression of all three mammalian TGF beta genes in the developing mouse inner ear. TGF beta 2 mRNA expression was identified throughout the cochlear epithelium at all of the developmental stages examined. TGF beta 3 mRNA expression was identified in the mesenchymal tissues of the cochlea surrounding the otic epithelium. We found no evidence for compensation by the other two TGF beta isoforms in the cochleas of the TGF beta 2 mutants.

Maintenance therapy for chronic depression. A controlled clinical trial of desipramine.

BACKGROUND: Previous studies have shown the efficacy of antidepressants in the treatment of chronic depression. We report the results of a long-term study comparing desipramine hydrochloride and placebo for maintenance therapy of remitted patients with chronic depression. METHODS: Outpatients who met DSM-III-R diagnostic criteria for "pure" dysthymia (n = 51), dysthymia with current major depression ("double depression") (n = 64), or chronic major depression (n = 14) were treated on an open basis with desipramine. Full and partial remitters after 10 weeks entered a continuation phase of open treatment with desipramine for 16 weeks. Remitted patients then were randomized to continue desipramine treatment or tapered to placebo treatment for a maintenance phase of up to 2 years. Relapse rates and time to relapse during maintenance therapy were compared between the two treatment groups. RESULTS: Acute-phase treatment results did not differ significantly according to chronic depression subtype. Remission persisted with a high degree of stability during the continuation phase. Relapse rates during the maintenance phase were 52% for the placebo group and 11% for the active desipramine group (chi 2 = 8.1, P = .004). Most placebo relapses occurred during the first 6 months of maintenance therapy. Active medication was significantly more effective than placebo in that subgroup entering the maintenance phase in full remission and in those patients who fulfilled criteria for a diagnosis of pure dysthymia or double depression on entry to the study. CONCLUSION: Long-term maintenance treatment with desipramine appeared to be effective in the prevention or postponement of relapse of depression in patients who responded to desipramine during the acute and continuation phases.

Identification and mutation analysis of a cochlear-expressed, zinc finger protein gene at the DFNB7/11 and dn hearing-loss loci on human chromosome 9q and mouse chromosome 19.

The DFNB7/11 locus for autosomal recessive non-syndromic hearing loss (ARNSHL) has been mapped to an approx. 1.5 Mb interval on human chromosome 9q13-q21. We have determined the cDNA sequence and genomic structure of a novel cochlear-expressed gene, ZNF216, that maps to the DFNB7/11 interval. The mouse orthologue of this gene maps to the murine dn (deafness) locus on mouse chromosome 19. The ZNF216 gene is highly conserved between human and mouse, and contains two regions that show homology to the putative zinc linger domains of other proteins. To determine it mutations in ZNF216 might be the cause of hearing loss at the DFNB7/11 locus, we screened the coding region of this gene in DFNB7/11 families by direct sequencing. No potential disease-causing mutations were found. In addition, Northern blot analysis showed no difference in ZNF216 transcript size or abundance between dn and control mice. These data Suggest that the ZNF216 gene is unlikely to be responsible for hearing loss at the DFNB7/11 and dn loci.

Retreatment for relapse following desipramine discontinuation in dysthymia.

OBJECTIVE: It is an accepted yet unproven belief that prior favorable response to an antidepressant medication predicts good response to the same antidepressant during a subsequent depressive episode. The authors studied desipramine retreatment for dysthymic patients who had responded to desipramine during acute and continuation treatment and then subsequently relapsed after discontinuation of desipramine. METHOD: The subjects were 12 patients who had pure dysthymia or dysthymia with major depression who relapsed while taking placebo during maintenance treatment. Each patient received open desipramine treatment at a dose equal to or greater than that received during the continuation phase. RESULTS: Eleven (91.7%) of the 12 relapsed patients achieved full remission after an average of 4.7 weeks (range = 2-8 weeks, median = 4 weeks) of desipramine retreatment, a significant response rate. CONCLUSIONS: Positive response to desipramine strongly predicts favorable response to retreatment for depressive relapse following desipramine discontinuation.

Eosinophilic nonallergic rhinitis in children.

Eosinophilic nonallergic rhinitis is a newly described symptom complex reported to occur in a significant percentage of adult patients who have symptoms of perennial rhinitis. They are characterized by nasal eosinophilia, negative allergy skin tests, and a normal serum immunoglobulin E concentration. Twelve children, aged 6 to 17 years, who represent the syndrome of eosinophilic nonallergic rhinitis, have been identified. All have severe perennial rhinitis and nasal eosinophilia. Physical examination revealed pale, boggy membranes with a clear nasal discharge in ten of 12 patients. All 12 patients had a normal serum IgE concentration. All patients initially received an antihistamine-decongestant preparation with subjective improvement in seven of 12 patients. The remaining five patients were placed on a regimen of either topical or systemic steroids and all five had dramatic responses with marked improvement of symptoms. The negative skin tests and normal serum IgE help distinguish this entity from allergic rhinitis, whereas the positive nasal eosinophilia and response to steroids will differentiate eosinophilic nonallergic rhinitis from vasomotor rhinitis. Eosinophilic nonallergic rhinitis is an important cause of perennial rhinitis in children and better knowledge of this entity should lead to more aggressive and efficacious therapy.

Effect of age and surgical technique on symptomatic arrhythmias after the Fontan procedure.

The purpose of this study was to determine the effects of newer Fontan modifications (lateral tunnel with or without fenestration) and patient's age at surgery on the incidence and impact of symptomatic postoperative early and intermediate arrhythmias. Modifications to the Fontan procedure are used to decrease postoperative complications, and the Fontan procedure is now being performed on younger patients to reduce age-related changes in ventricular function. A retrospective review was done of the medical records of 151 consecutive patients, ranging in age from 1 to 49 years, who underwent a Fontan procedure at Texas Children's Hospital between 1987 and 1993. Risk factors were identified for early and intermediate arrhythmias. Age at time of the procedure was an independent predictor of early atrial arrhythmias (p = 0.03), ventricular arrhythmias (p = 0.003), and junctional ectopic tachycardia (JET) (p = 0.05). We found that the older the patient at surgery, the higher the incidence of atrial and ventricular arrhythmias, whereas the younger the patient, the higher the incidence of JET. Using Cox's proportional-hazards model, the risk of intermediate atrial arrhythmias after lateral tunnel modification was 1/3 that after atriopulmonary connection. Younger patients who underwent the Fontan procedure had a lower risk for early atrial and ventricular arrhythmia but an increased risk for JET. The lateral tunnel modification can be performed in order to reduce the risk of intermediate atrial arrhythmias.