Deregulation of EIF4E: a novel mechanism for autism.

BACKGROUND: Autism is a common childhood onset neurodevelopmental disorder, characterised by severe and sustained impairment of social interaction and social communication, as well as a notably restricted repertoire of activities and interests. Its aetiology is multifactorial with a strong genetic basis. EIF4E is the rate limiting component of eukaryotic translation initiation, and plays a key role in learning and memory through its control of translation within the synapse. EIF4E mediated translation is the final common process modulated by the mammalian target of rapamycin (mTOR), PTEN and fragile X mental retardation protein (FMRP) pathways, which are implicated in autism. Linkage of autism to the EIF4E region on chromosome 4q has been found in genome wide linkage studies. METHODS AND RESULTS: The authors present evidence that directly implicates EIF4E in autism. In a boy with classic autism, the authors observed a de novo chromosome translocation between 4q and 5q and mapped the breakpoint site to within a proposed alternative transcript of EIF4E. They then screened 120 autism families for mutations and found two unrelated families where in each case both autistic siblings and one of the parents harboured the same single nucleotide insertion at position -25 in the basal element of the EIF4E promoter. Electrophoretic mobility shift assays and reporter gene studies show that this mutation enhances binding of a nuclear factor and EIF4E promoter activity. CONCLUSIONS: These observations implicate EIF4E, and more specifically control of EIF4E activity, directly in autism. The findings raise the exciting possibility that pharmacological manipulation of EIF4E may provide therapeutic benefit for those with autism caused by disturbance of the converging pathways controlling EIF4E activity.

Chromosome 22q11 microdeletion and congenital heart disease--a survey in a paediatric population.

UNLABELLED: Congenital heart disease is a common finding in patients with microdeletion of chromosome 22q11. To determine if the deletion is an epidemiologically important cause of congenital heart disease, we studied a consecutive series of children attending a paediatric cardiac clinic and of neonates diagnosed as having structural congenital heart disease. Venous blood samples were tested by fluorescent in-situ hybridisation analysis for microdeletion of chromosome 22q11 using probe D22S75. Each patient was examined for the other clinical features associated with microdeletion of chromosome 22q11, and any family history of congenital heart disease recorded. Of 151 families approached, 111 participated and a fluorescent in-situ hybridisation result achieved in 87. One patient with microdeletion of chromosome 22q11 was identified; the clinical features were those of DiGeorge syndrome. Two patients with CHARGE association, two with nasal speech, ten with high arched palate, and 15 with minor facial dysmorphic features had no deletion. CONCLUSION: Microdeletion of chromosome 22q11 detected by probe D22S75 is rare in this consecutive series of patients with structural congenital heart disease.

Motor vehicle occupant deaths among Hispanic and black children and teenagers.

OBJECTIVE: To determine the risk of motor vehicle occupant deaths per unit of travel for Hispanic, non-Hispanic black, and non-Hispanic white children (aged 5-12 years) and teenagers (aged 13-19 years). DESIGN: Comparison of 1989 to 1993 motor vehicle occupant death rates of children and teenagers by race, ethnicity, and sex by using data on mortality from the National Center for Health Statistics, travel data from the 1990 Nationwide Personal Transportation Survey, and 1990 US census data. RESULTS: Among children 5 to 12 years old, race/ ethnicity differences per 100000 persons were unremarkable, but per billion vehicle-miles of travel, the rates were 14 for non-Hispanic blacks, 8 for Hispanics, and 5 for non-Hispanic whites. Among teenagers aged 13 to 19, the rates per 100000 persons were highest for non-Hispanic whites; however, the rates per billion vehicle-miles were 45 for Hispanics, 34 for non-Hispanic blacks, and 30 for non-Hispanic whites. Black and Hispanic male teenagers had substantially higher death rates per billion vehicle-miles of travel than either white male teenagers or female teenagers in any racial/ethnic group. CONCLUSIONS: Black and Hispanic children and teenagers are at higher risk of dying in motor vehicle crashes when they travel. Greater public health attention is needed to address these increased risks.

Mosaicism for a tandem duplication dup(1)(q12q22) in an 18 year old female.

The clinical features and cytogenetic results of an 18 year old mentally handicapped female found to be a mosaic for a tandem duplication of chromosome 1 (46,XX,dup(1)(q12q22)/46,XX) are reported. The case is compared with the three previously described cases and possible mechanisms for the origin of the duplication are discussed. This patient was not found to have features of Proteus syndrome which was previously reported in a subject mosaic for a tandem duplication involving chromosome (1)(q11q25).

Biliary, pancreatic, and sphincter of Oddi electrical and mechanical signals recorded during ERCP.

Measurements of biliary tract motility have focused on radiologic and pressure measurements to quantify biliary motility rather than measurements of electrical activity of the biliary tract. We previously reported the recording of biliary electrical signals during ERCP and now report on the continued development and validation of a system to measure biliary tract electrical activity as well as biliary mechanical activity. In 26 patients presenting with a variety of clinical indications, we recorded measurements of electrical activity from the common bile duct sphincter (16 patients), pancreatic duct sphincter (eight patients), and/or sphincter of Oddi (eight patients). Electrical recordings were performed with a specially modified ERCP catheter, using two circular electrodes as well as a custom catheter that measured both electrical and mechanical activity. Electrical activity of the biliary tract was successfully recorded in 25 of 26 patients (96%), including the common bile duct sphincter (16 patients, 62%), pancreatic duct sphincter (eight patients, 31%) and sphincter of Oddi (eight patients, 31%). Along with the electrical recordings, common bile duct sphincter mechanical activity was recorded in 12 patients (67%), pancreatic duct sphincter mechanical activity in six patients (33%), and sphincter of Oddi mechanical activity in six patients (33%). Frequency analysis of electrical signals revealed a mean frequency (cycles/min) of 4.7 +/- 0.5 in the common bile duct sphincter, 4.1 +/- 0.6 in the pancreatic duct sphincter, and 4.9 +/- 0.7 in the sphincter of Oddi. Phasic mechanical frequency in cycles per minute was recorded at a frequency of 4.8 +/- 0.5 in common bile duct sphincter, 4.0 +/- 0.6 in pancreatic duct sphincter, and 5.3 +/- 0.9 in sphincter of Oddi. Tonic pressure (averaged 12.1 +/- 1.5 mm Hg) in common bile duct sphincter, 12.4 +/- 1.4 mm Hg in pancreatic duct sphincter, and 15.0 +/- 5.1 mm Hg in sphincter of Oddi. Analysis of wave form propagations (noted as percentage antegrade, retrograde, or indeterminant) revealed 50% antegrade, 23% retrograde, and 27% indeterminant). One patient was recorded on two occasions via ERCP; the same patient had an intraoperative recording. All three recordings showed similarities. We conclude that measurements of biliary, pancreatic, and sphincter of Oddi electrical and mechanical activity are feasible and can be done as part of ERCP. There was good correlation between biliary tract electrical and mechanical events and different wave form characteristics were noted for different parts of the biliary tree. Further studies are warranted to evaluate the potential usefulness of measurement of biliary tract electrical activity, and to confirm its correlation with mechanical events in the pancreato-biliary tree.

Crash involvement rates by driver gender and the role of average annual mileage.

The effects of four predictor variables-driver age, driver gender, time of day, and average annual mileage-on crash involvement rates were estimated through the use of multivariate modelling techniques. Separate models were developed for fatal, injury, and property damage only crashes. All four predictor variables proved to be highly significant in explaining variations in observed rates. Rates predicted by the models after substituting the mean average annual mileage value for all driver age/gender groups were also calculated. These 'adjusted rates' show men to have a consistently higher risk of crash involvement per mile driven than women for all six combinations of crash severity and light condition examined. This contrasts with women's higher involvement rates in non-fatal crashes compared with men in the observed data. The results of the modelling are consistent with the idea that women's typically low average annual mileage is a factor in their observed higher non-fatal crash involvement rates.

The effects of instructional match and content overlap on generalized reading performance.

This study examined the effects of instructional match and content overlap on students' ability to generalize from passage reading instruction. Four students with mild disabilities served as participants. Using a multielement design, students were instructed with passages at two levels of text difficulty (instructionally matched vs. instructionally mismatched), and generalization was assessed with passages at two levels of similarity to those instructed (low vs. high content overlap). Results indicated that students' oral reading accuracy and fluency showed the greatest degree of generalization when instructional materials were matched to the students' skill level and assessment materials were similar to those used during instruction. Moreover, these results were maintained at 1-month follow-up. The implications of these findings for classroom reading instruction and the assessment of students' reading skills are discussed.

The dose-dependent effect of misoprostol on indomethacin-induced renal dysfunction in well compensated cirrhosis.

Misoprostol (200 micrograms) has been shown to acutely counteract the indomethacin-induced renal dysfunction in well compensated cirrhotic patients. The aim of this study was to determine if the prophylactic value of misoprostol was dose-dependent. Parameters of renal hemodynamics and tubular sodium and water handling were assessed by clearance techniques in 26 well compensated cirrhotic patients before and after an oral combination of 50 mg of indomethacin and various doses of misoprostol. The 200-micrograms dose was able to totally abolish the deleterious renal effects of indomethacin, whereas the 800-micrograms dose resulted in significant worsening of renal hemodynamics and sodium retention. These changes were maximal in the hour immediately after medications and slowly returned toward base-line levels thereafter. These results suggest that the renal protective effects of misoprostol is dose-dependent. However, until this apparent ability of 200 micrograms of misoprostol to prevent the adverse effects of indomethacin on renal function is confirmed with chronic frequent dosing, it would be prudent to avoid nonsteroidal anti-inflammatory therapy in patients with cirrhosis.

The effect of misoprostol on indomethacin-induced renal dysfunction in well-compensated cirrhosis.

BACKGROUND/AIMS: Indomethacin has been shown to have adverse effects on renal function in patients with well-compensated alcoholic cirrhosis. The aim of this study was to determine whether an oral prostaglandin E1 analogue, misoprostol, could prevent this indomethacin-induced renal dysfunction. METHODS: Six patients with well-compensated alcoholic cirrhosis were studied. Renal hemodynamics and tubular function were assessed by clearance techniques before and after an oral dose of (i) 50 mg of indomethacin alone (I50), and (ii) a combination of I50 and 200 micrograms of misoprostol. RESULTS: I50 produced a significant reduction in glomerular filtration rate, a fall in effective renal plasma flow and an increase in renal vascular resistance. Two hundred micrograms of misoprostol was able to abolish the deleterious renal effects of indomethacin totally, yielding an increase in glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance as well as an increase in urinary volume and urinary sodium excretion. These beneficial effects were maximal in the hour immediately following medication, but were only transient, and this may be a limiting factor in its clinical use. CONCLUSIONS: If the beneficial renal effects of misoprostol could be confirmed after chronic administration, then the vasodilatory, natriuretic and diuretic potential of 200 micrograms of misoprostol could be of potential therapeutic value in patients with well-compensated alcoholic cirrhosis who require non-steroidal anti-inflammatory drug therapy.

Traffic accident involvement rates by driver age and gender.

Passenger-vehicle travel data from the 1990 Nationwide Personal Transportation Survey were combined with crash data from the 1990 Fatal Accident Reporting System and the 1990 General Estimates System to produce crash involvement rates per vehicle-mile of travel. Elevated rates were observed for drivers aged 16-19 and 75 and over. The oldest drivers had the highest fatal involvement rate, while the youngest drivers had the highest rate of involvement in all police-reported crashes. Men had a higher risk than women of experiencing a fatal crash, while women had higher rates of involvement in injury crashes and all police-reported crashes.

Use and fabrication of temporary orthotics.

Orthotics are effective for altering compensatory motions which result from abnormalities in the foot and lower extremity. In specific cases, temporary use of an orthosis is beneficial for reducing abnormal stresses while allowing involved structures to heal. Additionally, a temporary orthotic may provide a trial period to determine if the athlete would benefit from a permanent orthosis. A step-by-step procedure is presented for the fabrication of a temporary semirigid orthotic. Used as an adjunct to the treatment and rehabilitation program, temporary orthotics are effective in encouraging early weight-bearing tolerance, while placing the foot near the subtalar joint neutral position.

Renal response to a saline load in well-compensated alcoholic cirrhosis.

A total of 29 patients with well-compensated alcoholic cirrhosis and 9 healthy control subjects of similar age and sex were studied to assess their response to a challenge of 2 L of normal saline infused over a 1 hr period. Patients with cirrhosis had an adequate effective arterial blood volume in the basal state as assessed by neurohumoral markers of vascular filling. They also had a lower renal vascular resistance (p = 0.048) and a higher glomerular filtration rate (p = 0.014) than the controls, indicating the presence of renal vasodilation. Both groups were in sodium balance, but the patients with cirrhosis had a higher filtered load of sodium, an increased proximal tubular reabsorption of sodium (p = 0.015) and a decreased fractional excretion of sodium (p < 0.001). The administration of a saline load was not accompanied by any significant changes in the renal circulation in the patients with cirrhosis. They were unable to suppress their proximal tubular reabsorption of sodium to the same extent as the controls (p = 0.012), so by the fourth hour a significant difference in the rate of urinary excretion of sodium was evident. In the patients with cirrhosis, glomerular filtration rate before and after the saline load correlated significantly with indocyanine green extraction (r = 0.65; p = 0.002), whereas the tubular handling of sodium was dependent on antipyrine clearance (r = 0.80; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Nifedipine: its effects on renal hemodynamics and sodium homeostasis in well-compensated alcoholic cirrhosis.

Following the administration of 10 mg of nifedipine to 11 patients with well-compensated alcoholic cirrhosis, there was a significant fall in mean arterial blood pressure, accompanied by an increase in heart rate, presumably due to a significant decrease in systemic vascular resistance. Despite the fall in renal perfusion pressure, there was an increase in the effective renal plasma flow and a significant decrease in renal vascular resistance. The glomerular filtration rate was preserved, suggesting that the decrease in renal vascular resistance was due to a preferential decrease in afferent arteriolar tone. There were no significant changes in the filtered sodium load or the tubular reabsorption of sodium and urinary sodium, and urinary volume did not alter significantly. Although the current study indicates that nifedipine can improve the renal circulation in patients with cirrhosis, the significant effects on the systemic circulation suggest that its potential to reverse the intense renal vasoconstriction that can complicate the clinical course of advanced liver disease is unlikely to be of value in the treatment of the hepatorenal syndrome.

Dose-dependent effects of oral misoprostol on renal function in alcoholic cirrhosis.

BACKGROUND/AIMS: Prostaglandins are important modulators of renal physiology, particularly when the effective circulatory volume is decreased. The aim of this study was to determine the dose-dependent effects of an oral prostaglandin E1 analogue, misoprostol, on renal function in patients with well-compensated alcoholic cirrhosis. METHODS: Renal hemodynamics and tubular function were assessed by clearance techniques, before and after 100-microgram, 200-microgram, 400-microgram, or 800-microgram oral doses of misoprostol. RESULTS: Overall, the results indicate that low-dose misoprostol is vasodilatory, natriuretic, and diuretic whereas high-dose misoprostol increases renal vascular tone and inhibits sodium and water excretion. The 200-microgram dose produced a transient but significant increase in the glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance. Urinary volume and urinary sodium excretion increased and urinary osmolality decreased. CONCLUSIONS: The results suggest that, in patients with well-compensated cirrhosis, the renal effects of misoprostol are determined by a bell-shaped dose-response curve. The renal vasodilatory, natriuretic, and diuretic potential of 200-micrograms of misoprostol suggests that it may be of therapeutic value in patients with cirrhosis.

Development of a collision typology for evaluation of collision avoidance strategies.

This paper summarizes the results of an effort to identify and rank vehicle collision scenarios in order to create a "collision typology" that could aid in the assessment of the potential benefit of accident avoidance technologies. Data from four computerized accident files were used to construct an 18-level collision configuration variable. This variable includes the number of vehicles involved, their relative orientation, intent to turn, relation to intersection, and traffic control at the intersection. Distributions of the collision configuration variable were generated for several factors of interest using 1989 Michigan data. Five of the most prevalent collision types were selected for more detailed review based on the original police accident reports. The case studies lent additional insight into the circumstances of different accident types. Among other findings, the review suggested that in collisions at nonsignalized intersections, older drivers often stopped and then pulled out into oncoming traffic, while younger drivers more often failed to stop at all.

Indomethacin-induced renal dysfunction in patients with well-compensated cirrhosis.

BACKGROUND: Patients with cirrhosis and ascites are especially sensitive to the adverse renal effects of indomethacin-induced inhibition of prostaglandin synthesis. The aim of this study was to determine whether indomethacin affects renal function in patients with well-compensated cirrhosis. METHODS: Clearance techniques were used to assess renal hemodynamics and sodium and water homeostasis. RESULTS: The oral administration of 50 mg of indomethacin to well-compensated patients with alcoholic cirrhosis was followed by a significant decrease in glomerular filtration rate (GFR) and effective renal plasma flow because of a preferential increase in afferent arteriolar tone. Indomethacin was both antidiuretic and antinatriuretic due principally to decreased free water clearance and increased proximal tubular reabsorption of sodium. The acute changes in renal function were not sustained. Patients with a high basal GFR were particularly sensitive to the adverse renal effects of indomethacin. CONCLUSIONS: This study indicates that in patients with well-compensated cirrhosis renal prostaglandins are functionally active and may contribute to the pathogenesis of glomerular hyperfiltration. Nonsteroidal anti-inflammatory drugs should be used with caution in all patients with cirrhosis.

Glomerular hyperfiltration in patients with well-compensated alcoholic cirrhosis.

BACKGROUND: Peripheral and splanchnic arteriolar tone is often decreased in patients with cirrhosis. The responsible circulating vasodilator(s) would be expected to also lower renal vascular resistance. To examine this possibility we have undertaken a hemodynamic study of the renal circulation in patients with stable, well characterized, compensated cirrhosis and in healthy controls of similar age and sex. METHODS: Clearance techniques were used to assess splanchnic and renal hemodynamics and hepatocellular function. RESULTS: Renal vascular resistance was significantly reduced in the cirrhotic patients (P = 0.048) and was accompanied by a significant (P = 0.014) and proportional (r = -0.45; P = 0.016) increase in glomerular filtration rate. The hepatic extraction of indocyanine green, a measure of functional intrahepatic portasystemic shunts, was the only independent predictor of glomerular filtration rate (r = -0.65; P = 0.002). CONCLUSIONS: The results support the hypothesis that, in patients with cirrhosis, the presence of portasystemic shunts results in an increased delivery of endogenous vasodilator(s) into the systemic circulation where their principal action on the renal circulation is to preferentially decrease afferent arteriolar tone. The resultant glomerular hyperfiltration may contribute to the pathogenesis of cirrhotic glomerulosclerosis.

Incidence of Hyperpronation in the ACL Injured Knee: A Clinical Perspective.

Assessing abnormal biomechanics when treating various lower extremity pathologies provides the athlete with comprehensive management and promotes injury prevention. However, there have been few previous investigations of abnormal biomechanical forces on ligamentous pathologies of the knee. During this clinical study we investigated the incidence of hyperpronation in subjects who have had an anterior cruciate ligament (ACL) injury. Fifty subjects with a past medical history of ACL rupture and 50 subjects without a history of lower extremity pathology participated in our study. Hyperpronation of the foot and ankle complex was measured with the navicular drop test. The ACL injured subjects had greater navicular drop test scores than noninjured subjects. This suggests that hyperpronation of the foot and ankle complex may increase the risk of injury to the ACL. There is a need for further investigation into possible pre-loading stresses on knee ligaments.

Renal sodium retention in cirrhosis: tubular site and relation to hepatic dysfunction.

Renal sodium handling, assessed by the response to acute saline loading, was investigated in 14 well-compensated, nonascitic alcoholic cirrhotics and six normal controls. Urinary sodium excretion in cirrhotic patients (199 +/- 141 mumoles per min) was significantly lower than in controls (387 +/- 104 mumoles per min; p less than 0.01) at 3 hr postinfusion. In contrast to controls, renal plasma flow and glomerular filtration rate did not increase in the cirrhotics in response to acute saline loading. Proximal fractional reabsorption of sodium was estimated by clearance techniques in the presence of a hypotonic diuresis. Cirrhotic subjects with impaired functional liver cell mass as assessed by antipyrine clearance were unable to decrease proximal fractional reabsorption of sodium significantly in response to saline loading. Assessment in the cirrhotics included measurement of hepatic vein pressure gradient, indocyanine green extraction ratio, indocyanine green clearance, and antipyrine clearance as indices of portal pressure, intrahepatic shunting, hepatic blood flow and functional hepatocellular mass, respectively. Urinary sodium excretion in the cirrhotics correlated strongly with antipyrine clearance (r = 0.839, p less than 0.0001) and weakly with portal pressure (r = 0.562, p = 0.037). No correlation was seen with the other indices of hepatic blood flow and shunting. The findings of this study suggest that alcoholic cirrhosis is associated with a decline in hepatocellular function which results in either a decreased clearance of a salt-retaining hormone or decreased synthesis of a natriuretic hormone.(ABSTRACT TRUNCATED AT 250 WORDS)