De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Adjuvant pretreatment with alum protects neonatal mice in sepsis through myeloid cell activation.

The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants.

Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact.

Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.

Impaired emotion regulation in schizophrenia: evidence from event-related potentials.

BACKGROUND: Although several aspects of emotion seem to be intact in schizophrenia, there is emerging evidence that patients show an impaired ability to adaptively regulate their emotions. This event-related potential (ERP) study examined whether schizophrenia is associated with impaired neural responses to appraisal frames, that is when negative stimuli are presented in a less negative context. METHOD: Thirty-one schizophrenia out-patients and 27 healthy controls completed a validated picture-viewing task with three conditions: (1) neutral pictures preceded by neutral descriptions ('Neutral'), (2) unpleasant pictures preceded by negative descriptions ('Preappraised negative'), and (3) unpleasant pictures preceded by more neutral descriptions ('Preappraised neutral'). Analyses focused on the late positive potential (LPP), an index of facilitated attention to emotional stimuli that is reduced following cognitive emotion regulation strategies, during four time windows from 300 to 2000 ms post-picture onset. RESULTS: Replicating prior studies, controls showed smaller LPP in Preappraised neutral and Neutral versus Preappraised negative conditions throughout the 300-2000-ms time period. By contrast, patients showed (a) larger LPP in Preappraised neutral and Preappraised negative versus Neutral conditions in the initial period (300-600 ms) and (b) an atypical pattern of larger LPP to Preappraised neutral versus Preappraised negative and Neutral conditions in the 600-1500-ms epochs. CONCLUSIONS: Modulation of neural responses by a cognitive emotion regulation strategy seems to be impaired in schizophrenia during the first 2 s after exposure to unpleasant stimuli.

Event-related potential examination of facial affect processing in bipolar disorder and schizophrenia.

BACKGROUND: Patients with bipolar disorder exhibit consistent deficits in facial affect identification at both behavioral and neural levels. However, little is known about which stages of facial affect processing are dysfunctional. METHOD: Event-related potentials (ERPs), including amplitude and latency, were used to evaluate two stages of facial affect processing: N170 to examine structural encoding of facial features and N250 to examine decoding of facial features in 57 bipolar disorder patients, 30 schizophrenia patients and 30 healthy controls. Three conditions were administered: participants were asked to identify the emotion of a face, the gender of a face, or whether a building was one or two stories tall. RESULTS: Schizophrenia patients' emotion identification accuracy was lower than that of bipolar patients and healthy controls. N170 amplitude was significantly smaller in schizophrenia patients compared to bipolar patients and healthy controls, which did not differ from each other. Both patient groups had significantly longer N170 latency compared to healthy controls. For N250, both patient groups showed significantly smaller amplitudes compared with controls, but did not differ from each other. Bipolar patients showed longer N250 latency than healthy controls; patient groups did not differ from each other. CONCLUSIONS: Bipolar disorder patients have relatively intact structural encoding of faces (N170) but are impaired when decoding facial features for complex judgments about faces (N250 latency and amplitude), such as identifying emotion or gender.

Impaired neural response to internal but not external feedback in schizophrenia.

BACKGROUND: Accurate monitoring and integration of both internal and external feedback is crucial for guiding current and future behavior. These aspects of performance monitoring are commonly indexed by two event-related potential (ERP) components: error-related negativity (ERN) and feedback negativity (FN). The ERN indexes internal response monitoring and is sensitive to the commission of erroneous versus correct responses, and the FN indexes external feedback monitoring of positive versus negative outcomes. Although individuals with schizophrenia consistently demonstrate a diminished ERN, the integrity of the FN has received minimal consideration. METHOD: The current research sought to clarify the scope of feedback processing impairments in schizophrenia in two studies: study 1 examined the ERN elicited in a flanker task in 16 out-patients and 14 healthy controls; study 2 examined the FN on a simple monetary gambling task in expanded samples of 35 out-patients and 33 healthy controls. RESULTS: Study 1 replicated prior reports of an impaired ERN in schizophrenia. By contrast, patients and controls demonstrated comparable FN differentiation between reward and non-reward feedback in study 2. CONCLUSIONS: The differential pattern across tasks suggests that basic sensitivity to external feedback indicating reward versus non-reward is intact in schizophrenia, at least under the relatively simple task conditions used in this study. Further efforts to specify intact and impaired reward-processing subcomponents in schizophrenia may help to shed light on the diminished motivation and goal-seeking behavior that are commonly seen in this disorder.

Being small for gestational age is not an independent risk factor for mortality in neonates with congenital diaphragmatic hernia: a multicenter study.

BACKGROUND: Congenital diaphragmatic hernia (CDH) accounts for 8% of all major congenital anomalies. Neonates who are small for gestational age (SGA) generally have a poorer prognosis. We sought to identify risk factors and variables associated with outcomes in neonates with CDH who are SGA in comparison to neonates who are appropriate for gestational age (AGA). METHODS: We used the multicenter Diaphragmatic Hernia Research & Exploration Advancing Molecular Science (DHREAMS) study to include neonates enrolled from 2005 to 2019. Chi-squared or Fisher's exact tests were used to compare categorical variables and t tests or Wilcoxon rank sum for continuous variables. Cox model analyzed time to event outcomes and logistic regression analyzed binary outcomes. RESULTS: 589 neonates were examined. Ninety were SGA (15.3%). SGA patients were more likely to be female (p = 0.003), have a left sided CDH (p = 0.05), have additional congenital anomalies and be diagnosed with a genetic syndrome (p < 0.001). On initial single-variable analysis, SGA correlated with higher frequency of death prior to discharge (p < 0.001) and supplemental oxygen requirement at 28 days (p = 0.005). Twice as many SGA patients died before repair (12.2% vs 6.4%, p = 0.04). Using unadjusted Cox model, the risk of death prior to discharge among SGA patients was 1.57 times the risk for AGA patients (p = 0.029). There was no correlation between SGA and need for ECMO, pulmonary hypertensive medication at discharge or oxygen at discharge. After adjusting for confounding variables, SGA no longer correlated with mortality prior to discharge or incidence of unrepaired defects but remained significant for oxygen requirement at 28 days (p = 0.03). CONCLUSION: Infants with CDH who are SGA have worse survival and poorer lung function than AGA infants. However, the outcome of SGA neonates is impacted by other factors including gestational age, genetic syndromes, and particularly congenital anomalies that contribute heavily to their poorer prognosis.

Transplanting kidneys without points for HLA-B matching: consequences of the policy change.

In 2003, the US kidney allocation system was changed to eliminate priority for HLA-B similarity. We report outcomes from before and after this change using data from the Scientific Registry of Transplant Recipients (SRTR). Analyses were based on 108 701 solitary deceased donor kidney recipients during the 6 years before and after the policy change. Racial/ethnic distributions of recipients in the two periods were compared (chi-square); graft failures were analyzed using Cox models. In the 6 years before and after the policy change, the overall number of deceased donor transplants rose 23%, with a larger increase for minorities (40%) and a smaller increase for non-Hispanic whites (whites) (8%). The increase in the proportion of transplants for non-whites versus whites was highly significant (p < 0.0001). Two-year graft survival improved for all racial/ethnic groups after implementation of this new policy. Findings confirmed prior SRTR predictions. Following elimination of allocation priority for HLA-B similarity, the deficit in transplantation rates among minorities compared with that for whites was reduced but not eliminated; furthermore, there was no adverse effect on graft survival.

Visual masking by object substitution in schizophrenia.

BACKGROUND: Schizophrenia patients demonstrate impairment on visual backward masking, a measure of early visual processing. Most visual masking paradigms involve two distinct processes, an early fast-acting component associated with object formation and a later component that acts through object substitution. So far, masking paradigms used in schizophrenia research have been unable to separate these two processes. METHOD: We administered three visual processing paradigms (location masking with forward and backward masking, four-dot backward masking and a cuing task) to 136 patients with schizophrenia or schizoaffective disorder and 79 healthy controls. A psychophysical procedure was used to match subjects on identification of an unmasked target prior to location masking. Location masking interrupts object formation, four-dot masking task works through masking by object substitution and the cuing task measures iconic decay. RESULTS: Patients showed impairment on location masking after being matched for input threshold, similar to previous reports. After correcting for age, patients showed lower performance on four-dot masking than controls, but the groups did not differ on the cuing task. CONCLUSIONS: Patients with schizophrenia showed lower performance when masking was specific to object substitution. The difference in object substitution masking was not due to a difference in rate of iconic decay, which was comparable in the two groups. These results suggest that, despite normal iconic decay rates, individuals with schizophrenia show impairment in a paradigm of masking by object substitution that did not also involve disruption of object formation.

Determinants of discard of expanded criteria donor kidneys: impact of biopsy and machine perfusion.

We examined factors associated with expanded criteria donor (ECD) kidney discard. Scientific Registry of Transplant Recipients (SRTR)/Organ Procurement and Transplantation Network (OPTN) data were examined for donor factors using logistic regression to determine the adjusted odds ratio (AOR) of discard of kidneys recovered between October 1999 and June 2005. Logistic and Cox regression models were used to determine associations with delayed graft function (DGF) and graft failure. Of the 12,536 recovered ECD kidneys, 5139 (41%) were discarded. Both the performance of a biopsy (AOR = 1.21, p = 0.02) and the degree of glomerulosclerosis (GS) on biopsy were significantly associated with increased odds of discard. GS was not consistently associated with DGF or graft failure. The discard rate of pumped ECD kidneys was 29.7% versus 43.6% for unpumped (AOR = 0.52, p < 0.0001). Among pumped kidneys, those with resistances of 0.26-0.38 and >0.38 mmHg/mL/min were discarded more than those with resistances of 0.18-0.25 mmHg/mL/min (AOR = 2.5 and 7.9, respectively). Among ECD kidneys, pumped kidneys were less likely to have DGF (AOR = 0.59, p < 0.0001) but not graft failure (RR = 0.9, p = 0.27). Biopsy findings and machine perfusion are important correlates of ECD kidney discard; corresponding associations with graft failure require further study.

Oral colostrum priming shortens hospitalization without changing the immunomicrobial milieu.

OBJECTIVE: Oral colostrum priming (OCP) after birth in preterm infants is associated with improved weight gain and modification of the oral immunomicrobial environment. We hypothesized that OCP would modify salivary immune peptides and the oral microbiota in preterm infants. STUDY DESIGN: We conducted a prospective, randomized clinical trial to determine the effects of OCP on salivary immune peptide representation in preterm infants (<32 weeks completed gestation at birth). Saliva samples were collected before and after OCP. Salivary immune peptide representation was determined via mass spectroscopy. Oral microbiota representation was determined via sequencing of the 16S rRNA gene. RESULTS: Neonates who received OCP (n=48) had a 16-day reduction in the median length of hospitalization as compared with infants who did not receive OCP (n=51). No differences in salivary immune peptide sequence representation before OCP between groups were found. Longitudinal changes in peptides were detected (lysozyme C, immunoglobulin A, lactoferrin) but were limited to a single peptide difference (α-defensin 1) between primed and unprimed infants after OCP. We found no difference in microbial diversity between treatment groups at any time point, but diversity decreased significantly over time in both groups. OCP treatment marginally modified oral taxa with a decline in abundance of Streptococci in the OCP group at 30 days of life. CONCLUSIONS: OCP had neither an effect on the salivary peptides we examined nor on overall oral bacterial diversity and composition. Infants who received OCP had a reduced length of hospitalization and warrants further investigation.

Fatty acyl-CoA inhibition of beta-hydroxy-beta-methylglutaryl-CoA reductase activity.

The influence of the fatty acyl-CoA thioesters on rat liver microsomal hydroxymethylglutaryl-CoA reductase activity was tested in vitro to determine if the previously demonstrated inhibition of [14C]acetate incorporation into cholesterol is due to inhibition of this rate limiting step in cholesterol synthesis. The polyunsaturated fatty acyl-CoA thioesters caused the greatest inhibition of enzyme activity, 50 micron arachidonoyl-CoA inhibiting 67% and 5 micron inhibiting 22%. 50 micron linoleoyl-CoA inhibited 56% with the more saturated thioesters causing less inhibition. 50--100 micron free fatty acids, free CoA, cholesterol esters, phospholipids, carnitine derivatives, prostaglandins and non-specific detergents caused little or no inhibition of enzyme activity. Kinetic studies revealed the inhibition to be noncompetitive with respect to hydroxymethylglutaryl-CoA with a Ki for arachidonoyl CoA of 3.10 micron. Fatty acyl-CoA inhibition of in vitro cholesterol synthesis is due to inhibition of hydroxymethylglutaryl-CoA reductase activity. Variation in intracellular concentrations of fatty acyl-CoA thioesters may signficantly alter cholesterol synthesis.

Unsaturated fatty acyl-CoA inhibition of cholesterol synthesis in vitro.

1. The influence of saturated and unsaturated fatty acids and fatty acyl coenzyme A thioesters on cholesterol synthesis in vitro has been studied in a rat liver post-mitochondrial supernatant system. 100 micronM free fatty acids do not influence in vitro cholesterol synthesis. Various fatty acyl-CoA thioesters at 10--100 microntm inhibit [14C]acetate incorporation into digitonin-precipitable sterols, the more unsaturated derivatives causing the greatest inhibition. 10 micronM arachidonoyl-CoA inhibits [14C]acetate incorporation into sterols 17% and 50 micronM inhibits 55%. [14C]Acetyl-CoA incorporation into sterols is similarly inhibited but [14C]mevalonate incorporation is not inhibited. Thus, the inhibition may be on the rate-controlling step of cholesterol synthesis, the conversion of beta-hydroxy-beta-methylglutaryl-CoA to mevalonate. Unsaturated fatty acyl-CoA thioesters may be important in regulating cholesterol synthesis. 2. Studies were undertaken to determine if the previously observed inhibition of cholesterol synthesis by thyroxine in vitro may relate to the thyroxine stimulation of fatty acid desaturation. 50 micronM thyroxine causes a preferential incorporation of [14C]acetate into unsaturated fatty acids while inhibiting acetate incorporation into sterols. However, a sufficient increase in unsaturated fatty acyl-CoA thioesters to account for the thyroxine inhibition of cholesterol synthesis was not demonstrated.

Fatty acid desaturation in experimental diabetes mellitus.

Microsomal fatty acid desaturation is defective in streptozotocin-induced experimental diabetes. This defect is correctable by insulin treatment. The electron transport chain needed for microsomal fatty acid desaturation was studied in liver microsomes of streptozotocin diabetic rats, and the defect was localized to the terminal desaturase enzyme. Cytochrome b5 levels were elevated in the face of decreased fatty acid desaturation and returned to normal after 48 h of insulin treatment; 2 U of regular insulin every 6 h for 24 h repaired the fatty acid desaturation defect, while 0.5 U failed to correct the defect. Both the delta 6 and delta 9 desaturase defects (linoleic acid and stearoyl-CoA desaturation) required similar amounts of insulin and periods of time for correction, although these are different enzymes. This is consistent with the desaturation defect being due to a protein synthetic effect. Diabetic rats treated twice daily with injections of 4 U of NPH insulin showed a "super" repair of their desaturase defect by 48 h: delta 9 desaturase activity increased eight times over control activity, while delta 6 desaturase activity increased two and one-half times over control activity. This, together with the fact that delta 6 desaturase activity in diabetes (64% of control) is altered less than is delta 9 desaturase activity (22% of control), indicates that delta 6 desaturase enzyme activity is less responsive to insulin than is delta 9 desaturase enzyme activity. The physiologic significance of altered fatty acid desaturation in diabetes mellitus is unknown.

QT prolongation and the antiarrhythmic efficacy of amiodarone.

Amiodarone is an antiarrhythmic agent known to cause prolongation of action potential duration which is reflected in the electrocardiogram as a prolongation of the QT interval. Prolongation of the QT interval in patients dying suddenly was compared with that in patients who remained alive to determine whether a difference existed between these two groups. The electrocardiogram and amiodarone levels were evaluated in 33 patients who presented with cardiac arrest and symptomatic ventricular tachycardia in whom no other antiarrhythmic agent was found effective in preventing induction of ventricular tachycardia during electrophysiologic studies. There were 30 men and 3 women (mean age 52 +/- 10 years). Twenty-three are alive after a mean follow-up period of 12 +/- 7 months. Ten died: six suddenly, three of non-cardiac causes and one of congestive heart failure. Using a two-way analysis of variance, the percent change in QT, QTc, JT and JTc intervals before and after amiodarone therapy was analyzed. Marked prolongation in the QT interval was present in patients who remained alive with amiodarone therapy. A significant difference in percent QT prolongation was seen between the latter patients and those who died suddenly (p less than 0.005). No difference was observed in the percent change in QRS interval between the two groups. The levels of amiodarone (2.5 versus 3.2 micrograms/ml) and its metabolite (desethylamiodarone) were not significantly different between the living patients and those who died suddenly. These findings suggest that a prolongation of the QT interval may be a marker for the therapeutic antiarrhythmic effect of amiodarone.

Late results of renal transplantation.

A total of 315 (64%) of 491 primary cadaver and living-related donor transplants performed from 1975 through 1984 were still functioning at 24 months. These selected patients were examined further to assess the impact of several risk factors on late graft and patient survival. Black recipients, patients with underlying diabetes mellitus or hypertension, patients with poor renal function at 24 months, and recipients of cadaver grafts had significantly poorer long-term graft survival. Age greater than or equal to 40, diabetes or hypertension, poor 24-month function, and cadaver donor transplantation were associated with poorer long-term patient survival. Considerable improvement in graft survival at 24 months was seen in 1980-1984 compared with the earlier period, coincident with our adoption of routine pretransplant random donor blood transfusion. In contrast, long-term graft survival in patients with functioning graft at two years did not improve significantly over the same period. Although living-related donor transplants showed greater graft and patient survival than cadaver donor grafts by univariate analysis, no such advantage was demonstrated by multivariate analysis.

Renal transplant patient compliance with free immunosuppressive medications.

BACKGROUND: Noncompliance with immunosuppressive medications after renal transplantation is believed to be a major cause of allograft rejection and graft loss, with the impressive costs of these agents considered a significant reason for noncompliance. Our purpose was to determine the compliance rates of renal transplant patients who received their immunosuppressant therapy free of charge and evaluate their patterns of compliance. METHODS: All patients who received a renal transplant and received their immunosuppressant medications at our institution for their first year posttransplant were included in the study. Compliance rate was calculated and serum immunosuppressant concentrations were obtained to validate compliance assessments. RESULTS: Eighteen patients were included in the study. Approximately 48% of noncompliant patients were found to have subtarget drug concentrations, although only 14% of compliant patients had subtarget levels (chi2=12.9, P<0.001). At 5 months posttransplant, 95% of the patients remained compliant; however, by 12 months posttransplant, only 48% of the patients remained compliant. The mean time to the first noncompliant month was 9.8 months (95% confidence intervals=8.60-11.0). CONCLUSIONS: Patients who received their immunosuppressants free of charge were generally compliant within their first year of transplantation, however, compliance tended to decrease over time. This suggests that drug cost alone does not explain noncompliant behavior. Intensive efforts to increase medication compliance before month 8 posttransplantation should be implemented.

Electrophysiologic evaluation of the antiarrhythmic effects of N-acetylprocainamide for ventricular tachycardia secondary to coronary artery disease.

Antiarrhythmic properties of N-acetylprocainamide (NAPA), an active metabolite of procainamide, were studied in 12 patients with coronary artery disease who presented with cardiac arrest or documented sustained ventricular tachycardia (VT). Programmed electrical stimulation (PES) studies were performed in 10 men and 2 women, aged 52 to 80 years (mean 63), who had a left ventricular ejection fraction of 16 to 69% (mean 33). All patients tested had inducible VT provoked by PES without antiarrhythmic therapy. Patients were then tested with procainamide, 1,000 mg administered intravenously. VT could be provoked after procainamide treatment in 8 of 10 patients. Twenty-four to 36 hours later NAPA was administered, 18 mg/kg body weight intravenously, and PES was performed after 20 minutes. NAPA did not significantly change heart rate, mean arterial blood pressure, electrocardiographic intervals and AH or HV conduction times. The QT interval lengthened, but not significantly. The mean serum NAPA levels were 15.7 +/- 4 micrograms/ml in the group protected by NAPA and 16.2 +/- 4 micrograms/ml in the group not protected by NAPA. Five patients were discharged with NAPA therapy, 1.5 g orally every 8 hours. Two patients have been maintained with chronic NAPA therapy (10 +/- 3 months), and 2 patients had breakthrough VT on follow-up Holter monitoring and alternative therapy was given. One patient died while taking oral therapy. NAPA demonstrates antiarrhythmic efficacy in preventing induction of VT by PES in a high-risk group of patients. During chronic oral therapy in some patients, NAPA appears to be well tolerated, with antiarrhythmic efficacy that may be enhanced with further upward dose titration.

Antiarrhythmic action of bethanidine.

Studies were performed in 20 patients with symptomatic ventricular tachycardia (VT) to determine the efficacy of bethanidine compared with procainamide in preventing VT induced by programmed electrical stimulation. Before administering bethanidine, 5 to 10 mg/kg, the patients received 15 mg of protriptyline orally 24 and 2 hours before electrophysiologic studies to prevent the orthostatic hypotensive effects of bethanidine. Sustained VT (VT not spontaneously stopping) was induced in 8 and nonsustained VT (10 beats or more, terminating spontaneously) was induced in 4 patients. Bethanidine, 5 mg/kg, protected in 7 patients, and 10 mg/kg protected 1 additional patient. Procainamide, 1,000 and 1,500 mg intravenously, protected 8 of 16 patients. Bethanidine prevented VT induction in 50% of the patients not protected by procainamide. Bethanidine facilitated VT induction in 3 patients, while procainamide facilitated VT induction in 1 patient. Four patients with symptomatic VT have received bethanidine therapy for an average of 11 +/- 1.3 months, without clinical recurrence of their VT. Concomitant administration of protriptyline attenuated the acute hemodynamic changes caused by bethanidine and chronic combined therapy of protriptyline and bethanidine abolished the severe orthostatic changes in blood pressure caused by bethanidine. These studies show that bethanidine is effective in preventing VT induction and, thus, its use may not be restricted only to cases of primary ventricular fibrillation.