Autism severity is associated with child and maternal MAOA genotypes.

Autism severity is associated with child and maternal MAOA genotypes. We replicated and extended a previously reported association between autism severity and a functional polymorphism in the monoamine oxidase A (MAOA) promoter region, MAOA-uVNTR, in a sample of 119 males, aged 2-13 years, with autism spectrum disorder from simplex families. We demonstrated that (i) boys with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, and aggression, and worse social communication skills than males with the high activity allele; and (ii) problems with aggression, as well as with fears and rituals, were modified by the mothers' genotype. Boys with the 4-repeat high activity allele who had homozygous 4-repeat mothers showed increased severity of these behaviors relative to those born to heterozygous mothers. These findings indicate the importance of considering maternal genotype in examining associations of MAOA and other genes with behavior in male offspring.

Association of aggressive behaviours with psychiatric disorders, age, sex and degree of intellectual disability: a large-scale survey.

BACKGROUND: The link between aggression and mental disorders has been the focus of diverse studies in persons with and without intellectual disabilities (ID). Because of discrepancies in the finding of studies in persons with ID to date, and because of differences in research design, instruments used and the population studied, more research is needed. The purpose of this study was to delineate any significant association between certain psychiatric disorders and specific domains of aggressive behaviours in a large sample of persons with ID controlling for sex, age, autism and degree of ID. METHOD: Data from the present study were obtained from 47% of all persons with ID receiving services from New York State agencies, using the Institute for Basic Research - Modified Overt Aggression Scale (IBR-MOAS between 2006 and 2007). The IBR-MOAS was completed by the chief psychologists of 14 agencies based on information from the participants' files. Demographic information obtained included the psychiatric diagnosis made by the treating psychiatrist as well as information on age, sex and degree of ID. Data from 4069 participants were analysed. RESULTS: Impulse control disorder and bipolar disorder were strongly associated with all five domains of aggressive behaviour in the IBR-MOAS. Psychotic disorder was highly associated with four domains except for physical aggression against self (PASLF), which was of borderline significance. Anxiety was most associated with PASLF and verbal aggression against self (VASLF); depression with VASLF; obsessive compulsive disorder with physical aggression against objects (PAOBJ); personality disorders with verbal aggression against others (VAOTH), VASLF and PASLF; and autism with physical aggression against others (PAOTH), PAOBJ and PASLF. Mild to moderate ID was associated with VAOTH and VASLF and severe to profound ID with PAOBJ and PASLF. Female sex was most associated with VASLF. CONCLUSIONS: Impulse control, mood dysregulation and perceived threat appear to underlie most of the aggressive behaviours reported. Psychosis and depression appeared to have been over-diagnosed in persons with mild to moderate ID and under-diagnosed in persons with severe and profound ID. These findings replicate and extend findings from previous studies. The pattern of associations reported can be used as helpful indicators by professionals involved in the treatment of aggressive behaviours in persons with ID.

An artificial neural network analogue of learning in autism.

An artificial neural network is simulated that shares formal qualitative similarities with the selective attention and generalization deficits seen in people with autism. The model is based on neuropathological studies which suggest that affected individuals have either too few or too many neuronal connections in various regions of the brain. In simulations where the model was taught to discriminate children with autism from children with mental retardation, having too few simulated neuronal connections led to relatively inferior discrimination of the two groups in a training set and, consequently, relatively inferior generalization of the discrimination to a novel test set. Too many connections produced excellent discrimination but inferior generalization because of overemphasis on details unique to the training set. It is concluded that, within the context of the current model, the neuropathological observations that have been described in the literature are sufficient to explain some of the unique pattern recognition and discrimination learning abilities seen in some people with autism as well as their problems with generalization and concept acquisition. The model generates testable hypotheses that have implications for understanding the pathogenesis, treatment, and phenomenology of autism.

Autism and the fragile X syndrome.

The fragile X chromosome is an important factor in inherited mental retardation in males. It has also been reported that infantile autism is associated with fragile X. Recently, an article reported an examination of a small sample of autistic children in whom the fragile X chromosome was not found. Its authors concluded that if an association between fragile X and autism exists, it is infrequent. In the present study of 144 autistic male subjects, 18 were found to have the fragile X chromosome, supporting other (epidemiological) findings that the association between fragile X and autism occurs relatively frequently.

Syntactic delay and pragmatic deviance in the language of fragile X males.

The expressive language of 19 fragile X [fra(X)] males with chronological ages between 5 and 36 years and Vineland Adaptive Behavior Scores between 21 and 79 was examined for syntactic as well as pragmatic proficiency. The production of deviant repetitive language was observed with this group, corroborating the results of an earlier study with a smaller sample of fra(X) males. In contrast, when 2 syntax scores, mean length of utterance (MLU), and Index of Productive Syntax (IPSyn) were derived from naturalistic language observations, the relation of complexity to length was observed to be very similar to the known relationship of these 2 facets of syntactic ability in normal preschoolers. These results, and the absence of correlations between syntactic scores and proportions of deviant repetitive language are consistent with the notion that the syntactic development of fra(X) males is typically delayed rather than deviant. For effective assessment and remediation of communicative problems associated with the syndrome to be developed, it is argued, language must be considered as a combination of competencies rather than as a unitary skill.

Screening developmentally disabled male populations for fragile X: the effect of sample size.

The fra(X) or Martin-Bell syndrome is the most common cause of inherited mental retardation (MR) in males. It is also associated with a variety of unusual behavioral and developmental disorders. Recent studies found great variability in the estimated strength of association between "autism" and the fra(X) syndrome, but not between MR and fra(X). We examined 31 studies which investigated the association of fra(X) syndrome with either MR or "autism" and found that the conclusion of those researchers could be significantly affected by sample size. Different behavioral and cytogenetic protocols will also influence the strength of association between fra(X) and autism.

Effects of age and communication level on eye contact in fragile X males and non-fragile X autistic males.

Dyadic social gaze and eye contact were examined in fragile X [fra(X)] males and in non-fra(X) autistic males as a function of age and level of communicative ability. Lag sequential analysis showed that responsive eye contact was highly correlated with age and communicative ability in non-fra(X) autistic males but not in fra(X) males. Older, more communicative non-fra(X) autistic males exhibited more responsive eye contact than their fra(X) cohorts. Implications of these observations for theory and intervention are discussed.

Folic acid treatment of fragile X males: a further study.

Investigations of the effect of high dose folic acid treatment of fragile X syndrome in males has produced mixed results. However, no study had examined the possible drug effects of folic acid on non-fragile X control males. Therefore, we examined the effect of folic acid on fragile X males using non-fragile X control males. Subjects were assigned randomly to an ABA or BAB design. Duration of either folic acid or placebo condition was 4 months. Folic acid or placebo was given in a double-blind fashion. At the end of each condition, the subjects' behavior was assessed. At the end of the study, parents were asked to complete a questionnaire. Using parents' responses, we examined 22 items on the Autistic Descriptors Checklist and two subscales from the Vineland Adaptive Behavior Scale which corresponded to areas of behavior parents' noted to have shown improvement. We did not find significant differences between fragile X males and control males, within subjects, nor across folic acid and placebo conditions. Thus, our follow-up study confirms and extends our original findings, as well as those of other researchers: namely, that no dramatic changes in behavior result from high dose folic acid. Moreover, subtle improvements observed in earlier investigations were not confirmed.

Folic acid therapy in the fragile X syndrome.

Two brothers with fra(X) positive X-linked mental retardation (XLMR) were treated with folic acid. Initially a double blind cross-over design was employed followed by a long-term high dose trial. A decrease in the frequency of fra(X) positive cells was observed when low folic acid culture medium was used but not when an FUdR induction system was employed. Selected behavioral characteristics improved in both while receiving folic acid. Decreased hyperactivity, greater attention span, increased motor coordination, increased quantity and quality of speech were noted. Improvement in Leiter mental age and regression after cessation of treatment was seen in one subject but not in the other. Further controlled trials with larger numbers of subjects using high doses of folic acid over longer periods of time are needed to assess the possible benefits of this experimental form of treatment.

Brief screening questionnaire for determining affected state in fragile X syndrome: a consensus recommendation.

New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene(s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.

High dose folic acid treatment of fragile (X) males.

We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome.

Mosaicism for the FMR1 gene influences adaptive skills development in fragile X-affected males.

Fragile X syndrome is one of the most common forms of inherited mental retardation, and the first of a new class of genetic disorders associated with expanded trinucleotide repeats. Previously, we found that about 41% of affected males are mosaic for this mutation in that some of their blood cells have an active fragile X gene and others do not. It has been hypothesized that these mosaic cases should show higher levels of functioning than those who have only the inactive full mutation gene, but previous studies have provided negative or equivocal results. In the present study, the cross-sectional development of communication, self-care, socialization, and motor skills was studied in 46 males with fragile X syndrome under age 20 years as a function of two variables: age and the presence or absence of mosaicism. The rate of adaptive skills development was 2-4 times as great in mosaic cases as in full mutation cases. There was also a trend for cases with autism to be more prevalent in the full-mutation group. These results have implications for prognosis, for the utility of gene or protein replacement therapies for this disorder, and for understanding the association between mental retardation, developmental disorders, and fragile X syndrome.

Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome.

The effect of mode of inheritance on expression of fragile X syndrome [fra(X)] was investigated in nonretarded female carriers. Examination included cognitive and molecular measures. A priori predictions about cognitive impairment and size of an unstable region of DNA containing a CGG repeat on the X chromosome were tested in age and education matched heterozygotes grouped according to parental inheritance. Nine carriers with a maternal fra(X) chromosome, 11 carriers with a paternal fra(X) chromosome and 15 control mothers of children with non X-linked developmental disabilities were tested. Inheritance was established through DNA linkage analysis. Cognitive skills were assessed using the Wechsler Adult Intelligence Scale-Revised and the Benton Visual Retention Test. Molecular status was assessed by Southern blot analysis of genomic DNA digested with Eco RI and Eag I, and probed with StB 12.3. Results supported the inheritance models' predictions. Heterozygotes who inherited the fra(X) from their fathers appeared to be a homogeneous group. They were indistinguishable from controls on cognitive measures and all had genomic insertions of less than 500 base pairs. In contrast, heterozygotes who inherited the fra(X) chromosome from their mothers appeared to be made up of 2 sub-populations. They were as a group deficient in measures of attention and visual memory, but not other measures, with scores of some women consistently below the other subjects. Further, they had some members with greater than 500 base pair inserts.(ABSTRACT TRUNCATED AT 250 WORDS)

Fragile X and autism: a multicenter survey.

We screened 183 autistic males for the fra(X) and found 24 (13.1%) to be positive. Adding the subjects of this study to those of 11 other surveys, of which 6 were positive and 5 were negative, a total of 614 autistic males have been screened. Overall 47 (7.7%) were positive. Based on this estimate and the prevalence of autism and fra(X), we estimate that 12.3% of fra(X) males are autistic. We have found that 17.3% of our fra(X) males were autistic and overall a 21.2% frequency has been reported, these higher figures are most likely due to biases in age and ascertainment. With an overall 7.7% frequency of fra(X) among autistic males and an estimated 12.3% of autism among fra(X) males, we conclude there is likely to be a significant association of fra(X) with autism. Because fra(X) appears to be the single most common cause of the condition, chromosomal testing is recommended for any autistic person with undiagnosed etiology.

Investigating the impact of age on outcome of mechanical ventilation using a population of 41,848 patients from a statewide database.

STUDY OBJECTIVE: To examine the impact of age on outcome from mechanical ventilation. DESIGN: Retrospective analysis of a statewide database. SETTING: All acute-care hospitals in New York State. PATIENTS: All patients, aged 18 years and over, requiring mechanical ventilation during 1990 who could be identified with a mechanical ventilation procedure code (93.92) were studied. Data were obtained in aggregate form (six or more cases) from the New York State Department of Health. This process required a detailed request letter to the Statewide Planning and Cooperative System (SPARCS). Transmission of confidential information was not desired or permitted. MEASUREMENTS AND RESULTS: Age and mortality rate (MR) fit a cuboidal regression model best (MR = -25.55 + 3.98Age - 0.072Age2 + 0.00043Age3, R2 = 0.85). Mortality rates vary significantly across various broad diagnostic groups (p < 0.01, analysis of variance [ANOVA]) and increase as a function of ICU duration (p < 0.01, ANOVA). CONCLUSIONS: Age has an important effect on outcome from mechanical ventilation. Other factors, such as ICU duration and diagnosis, also influence outcome, and age should not be used as a sole criterion in evaluating the potential benefit of mechanical ventilation to an individual patient. Large, existing databases, such as SPARCS, may be useful in studying the application of mechanical ventilation.

"Pseudo auto-PEEP"? A new cause for discrepancy between the end-expiratory occlusion plateau pressure and airway opening pressure.

The purpose of this study is to describe an unexpected degree of differences between expiratory occlusion plateau pressure (EPO) and airway opening pressure (Pawo) measured level of intrinsic positive end-expiratory pressure above externally applied (auto-PEEP) that was found in six critically ill patients. In six patients (ten studies), the presence and degree of auto-PEEP found during the EPO maneuvers was not confirmed by Pawo measurements. In five studies, flow tracings showed prolonged near zero flow toward end expiration and a slow rise to plateau during the EPO maneuver. Because of the static nature of the EPO determination, a rise in pressure could conceivably be caused by the presence of subcutaneous or mediastinal emphysema and retrograde flow across the airway defect during exhalation. We suggest another cause for auto-PEEP-dynamic hyperinflation from extrapulmonary flow limitation.

The effects of ventilator working pressure during pressure support ventilation.

The purpose of this study was to examine the consequences of altering ventilator working pressure on airway pressure and flow characteristics during pressure support ventilation (PSV). A ventilator (Siemens Servo 900C) and single lung simulator were used, and graphic read outs, in triplicate, were taken at a variety of combinations of PSV, working pressure, lung compliance, and airway resistance. The graphic read outs were then analyzed for a number of "dependent variables," and multiple regression analyses were performed using working pressure, PSV level, compliance, and resistance as "independent variables." The results show that the relative impact of working pressure on airway pressure and flow will vary with other lung and airway characteristics; also, excessive working pressure results in significantly greater flow rates at 40 ms after onset of inspiratory flow and at maximum flow, greater ringing or overshoot in the circuit, reduced tidal volume and inspiratory time, and reduced area under the airway pressure curve. In conclusion, adjusting ventilator working pressure will significantly affect lung-ventilator interaction in a quantifiable fashion. Further, these findings support clinical evidence that working pressure and/or initial flow rate need to be individualized to ensure optimal airway flow and pressure characteristics.

Recurrent Pseudomonas aeruginosa pneumonia in an intensive care unit.

We reviewed the records of all patients in the intensive care unit (ICU) who had Pseudomonas aeruginosa pneumonia over a 2.5-year period. Of patients with P aeruginosa pneumonia, 20 of 34 survived the initial episode of pneumonia. Ten of these 20 developed recurrence. In the nonrecurrent group, nine of ten survived hospitalization, compared to only four of ten in the recurrent group. Comparing the recurrent to the nonrecurrent group, factors associated with recurrence were the APACHE 2 score (12.3 +/- 2.7 vs 8.6 +/- 4.2 [p less than 0.03]), APS score (7.0 +/- 3.5 vs 2.7 +/- 2.1 [p less than 0.01]), and chronic pulmonary disease (8/10 vs 2/10 [p less than 0.05]). The recurrent P aeruginosa group was younger (63 +/- 10 vs 74 +/- 11 years old [p less than 0.03]) and spent more time receiving mechanical ventilation (95 +/- 64 vs 26 +/- 36 days [p less than 0.01]), in the ICU (101 +/- 61 vs 33 +/- 35 days [p less than 0.01]), and in the hospital (144 +/- 77 vs 84 +/- 32 days [p less than 0.03]). Although not statistically significant, in the recurrent group, eight of ten patients had tracheostomy and seven of ten had COPD, vs three of ten and two of ten, respectively, in the nonrecurrent group. Recurrent P aeruginosa pneumonia in the ICU is associated with increased morbidity and mortality and does not appear to be related to the adequacy of antibiotic treatment. Chronic lung disease appears to predispose patients to recurrent P aeruginosa pneumonia.

Clinical and economic outcome of mechanically ventilated patients in New York State during 1993: analysis of 10,473 cases under DRG 475.

STUDY OBJECTIVES: To examine and describe the relationship between age and disposition in patients undergoing mechanical ventilation. DESIGN: Retrospective analysis of a statewide database. SETTING: All acute-care hospitals in New York State. PATIENTS: All patients (n=10,473) aged > or = 18 years discharged from hospital during 1993 with a final diagnosis related group (DRG) coding of 475. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The final disposition, according to six codes (other acute-care facility, residential health-care facility, other health-care facility, home, home health-care services, and death) were examined for the whole population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relationship between survival rate and age was observed and this resulted in an age-related increased cost per survivor. Also, survivors in older age groups have an increasing rate of hospital discharge to residential health-care facilities. CONCLUSION: Patients who undergo mechanical ventilation are expensive to care for. The older they are, the less satisfactory is the outcome both from clinical and economic perspectives.

Fick-derived hemodynamics. Oxygen consumption measured directly vs oxygen consumption calculated from CO2 production under steady state and dynamic conditions.

Indirect calorimetry is being used increasingly as a tool for hemodynamic monitoring via the Fick equation. This investigation was undertaken to examine the use of carbon dioxide elimination (VCO2A) and related respiratory quotient (RQA) to calculate oxygen uptake (VO2A) and estimate oxygen consumption (VO2) during steady-state and dynamic hemodynamic conditions. Nine patients undergoing abdominal aortic surgery were studied intraoperatively and Fick-derived hemodynamic measurements were made using a monitoring system employing indirect calorimetry, pulse oximetry, and pulmonary artery oximetry. Comparisons were made between measured VO2A and calculated VO2A derived from the VCO2A and the initial RQA (RQi), which is assumed not to change. Prior to aortic crossclamping (steady state), there were no significant differences between the measured and calculated methods with respect to oxygen consumption (184 +/- 24 ml/min vs 185 +/- 17 ml/min), oxygen delivery (753 +/- 141 ml/min vs 769 +/- 178 ml/min), and cardiac output (4.7 +/- 0.6 L/min vs 4.7 +/- 0.7 L/min). However, immediately following aortic unclamping (dynamic state), the RQA changed precipitously from the baseline RQi. Consequently, significant differences between the measured and calculated methods were noted in oxygen uptake (213 +/- 41 ml/min vs 193 +/- 25 ml/min, p < 0.001), oxygen delivery (780 +/- 297 ml/min vs 716 +/- 296 ml/min, p < 0.001), and cardiac output (5.8 +/- 2.2 L/min vs 5.3 +/- 1.8 L/min, p < 0.001). Additionally, following unclamping, the peak VO2A was 242 +/- 49 compared with a cVO2A of only 198 +/- 22 (p < 0.01). We conclude that the use of VCO2A to calculate VO2A may lead to erroneous measurements under dynamic conditions, such as unclamping of the abdominal aorta.