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Biomedical subjects

D R McLeod

Publications and source records attributed to D R McLeod.

At least 19 recordsLinked to original sources
PubMed2006

Normal physiological emotions but differences in expression of conscious feelings in children with high-functioning autism.

To provide insight into what aspects of the emotional circuit might be affected in high-functioning autism, we measured indices of physiological emotions and of the expression of conscious feelings in 10 children with high-functioning autism or Asperger syndrome and 10 comparison participants. Pleasant, unpleasant, and neutral pictures were presented while skin conductance responses were measured. Self-report ratings of pleasantness and interestingness were taken between pictures. Skin conductance responses did not differ between the groups. Self report ratings were different, with the children with autism giving more similar answers to the two questions than the comparison children. Impairments in socio-emotional expression in autism may be related to deficits in perception and/or expression of conscious feelings; physiological emotions may be relatively preserved.

Adolescent↗
PubMed2005

Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition.

BACKGROUND: A novel autosomal recessive condition, dilated cardiomyopathy with ataxia (DCMA) syndrome, has been identified in the Canadian Dariusleut Hutterite population, characterised by early onset dilated cardiomyopathy with conduction defects, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria. OBJECTIVE: To map DCMA syndrome and identify the mutation underlying this condition. METHODS: A genome wide scan was undertaken on consanguineous Hutterite families using a homozygosity mapping approach in order to identify the DCMA associated chromosomal region. Mutation analysis was carried out on positional candidate genes in this region by sequencing. Reverse transcriptase polymerase chain reaction and bioinformatics analyses were then used to characterise the mutation and determine its effect on the protein product. RESULTS: The association of DCMA syndrome with a 2.2 Mb region of chromosome 3q26.33 was found. A disease associated mutation was identified: IVS3-1 G-->C in the DNAJC19 gene, encoding a DNAJ domain containing protein of previously unknown function (Entrez Gene ID 131118). CONCLUSIONS: The DNAJC19 protein was previously localised to the mitochondria in cardiac myocytes, and shares sequence and organisational similarity with proteins from several species including two yeast mitochondrial inner membrane proteins, Mdj2p and Tim14. Tim14 is a component of the yeast inner mitochondrial membrane presequence translocase, suggesting that the unique phenotype of DCMA may be the result of defective mitochondrial protein import. It is only the second human disorder caused by defects in this pathway that has been identified.

Abnormalities, Multiple↗
PubMed2003

Bowen-Conradi syndrome: a clinical and genetic study.

The purpose of the study was to delineate the anomalies and the natural life history of persons with the Bowen-Conradi syndrome [Bowen and Conradi 1976: Birth Defects: Orig Artic Ser XII(6):101-108]. We ascertained 39 cases and personally examined almost all. For those who were not seen, their clinical record were scrutinized. Pedigree analysis of all 39 was done and kinship coefficients computed. The birth prevalence was estimated to be 1/355 live births.

Craniofacial Abnormalities↗
PubMed2002

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.

BACKGROUND: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC, and SDHD, cause hereditary paraganglioma (PGL). METHODS: We assessed the frequency of SDHB, SDHC, and SDHD gene mutations by PCR amplification and sequencing in a set of head and neck paraganglioma patients who were previously managed in two otolaryngology clinics in the USA. RESULTS: Fifty-five subjects were grouped into 10 families and 37 non-familial cases. Five of the non-familial cases had multiple tumours. Germline SDHD mutations were identified in five of 10 (50%) familial and two of 37 ( approximately 5%) non-familial cases. R38X, P81L, H102L, Q109X, and L128fsX134 mutations were identified in the familial cases and P81L was identified in the non-familial cases. Both non-familial cases had multiple tumours. P81L and R38X mutations have previously been reported in other PGL families and P81L was suggested as a founder mutation. Allelic analyses of different chromosomes carrying these mutations did not show common disease haplotypes, strongly suggesting that R38X and P81L are potentially recurrent mutations. Germline SDHB mutations were identified in two of 10 (20%) familial and one of 33 ( approximately 3%) non-familial cases. P131R and M71fsX80 were identified in the familial cases and Q59X was identified in the one non-familial case. The non-familial case had a solitary tumour. No mutations could be identified in the SDHC gene in the remaining four families and 20 sporadic cases. CONCLUSIONS: Mutations in SDHD are the leading cause of head and neck paragangliomas in this clinic patient series. SDHD and SDHB mutations account for 70% of familial cases and approximately 8% of non-familial cases. These results also suggest that the commonness of the SDHD P81L mutation in North America is the result of both a founder effect and recurrent mutations.

Alleles↗
PubMed2001

Cerebral blood flow in obsessive-compulsive patients with major depression: effect of treatment with sertraline or desipramine on treatment responders and non-responders.

We examined the effects of sertraline and of desipramine on patients with OCD and comorbid major depressive episodes at study entry. Sixteen patients, 9 receiving sertraline and 7 desipramine, received HMPAO SPECT scans while free of medication and after 12 weeks of treatment. Patients on sertraline showed significantly reduced regional cerebral blood flow (rCBF) in the right prefrontal and temporal regions. Patients on desipramine showed more diffuse rCBF reductions in frontal and temporal regions, more so in the left side. In a second analysis, patients who had a symptom reduction on the Yale-Brown Obsessive Compulsive Scale (YBOCS), irrespective of the type of medication, were retrospectively classified as 'responders' to treatment. Eleven patients were 'responders' and 5 'non-responders'. Before being medicated, responders differed from non-responders through higher rCBF in prefrontal regions, mostly on the left, and higher rCBF in the cingulate and basal ganglia bilaterally. After 12 weeks of treatment, responders showed a diffuse reduction of rCBF in prefrontal regions while non-responders showed only a few scattered low-frequency responses. Thus, higher prefrontal and subcortical activity was associated with better response to drug treatment. In addition, clinical change, but not the administration of medication as such, was associated with a decrease of prefrontal rCBF.

Adult↗
PubMed2001

Combination of renal agenesis with respiratory and alimentary tract atresia results in normal lung development.

The VACTERL complex comprises renal agenesis and atresias of the alimentary and respiratory tracts. We report on a case with this combination causing severe oligohydramnios but with normal lung development. The likely protective mechanism for pulmonary development was an increase in alveolar pressure and reduced alveolar fluid loss due to the esophageal-tracheal malformation. This suggests the possible treatment of oligohydramnios by tracheal occlusion.

Abnormalities, Multiple↗
PubMed2000

Anxiety and arousal: physiological changes and their perception.

Contrary to self-reports, most patients with chronic anxiety disorders exhibit increased muscle tension but not autonomic hyperarousal when at rest. Under everyday stress they tend to react with less physiological flexibility than normal controls. However, they overreact subjectively and physiologically to stimuli that are anxiety-provoking. Diminished physiological flexibility may be either a constitutional trait in anxious individuals, a partial but inadequate adaptation to prolonged stress or the result of a disregard for stressors that are not related to psychopathology. The effects of diminished physiological flexibility on general health are not known. There is only a weak relationship, and in some instances a desynchrony, between physiological changes and perception of change under stress. The inconsistencies between self-reports of physiological states and physiological recordings can be explained by alterations of body sensations through psychological factors, predominantly expectations and attention to bodily states, that lead to perceptual distortions.

Adaptation, Psychological↗
PubMed2000

Relative timing of inspiration and expiration affects respiratory sinus arrhythmia.

1. The effect of a variation in inspiration and expiration times on heart rate variability was studied in 12 healthy subjects (mean age 30+/-6 years; five females). 2. Two 2 min trials of controlled breathing, with either short inspiration followed by long expiration or long inspiration followed by short expiration, were compared. Average expiration/inspiration time ratios were 1.0 and 3.4, respectively. The respiration rate in both trials was approximately 10 cycles/min. 3. In trials with short inspiration followed by long expiration, respiratory sinus arrhythmia (RSA; as measured by mean absolute differences and by the high frequency band) was significantly larger than in trials with long inspiration followed by short expiration. This effect could not be accounted for by differences in respiration rate or respiratory amplitude. The higher RSA during fast/slow respiration is primarily due to a more pronounced phasic heart rate increase during inspiration, indicating that inspiratory vagal blockade is sensitive to the steepness of inspiration. 4. Respiration rate and tidal volume are respiratory variables known to modulate RSA. The results of the present study indicate that RSA can also be modulated by a third respiratory variable, the expiratory/inspiratory time ratio.

Adult↗
PubMed2000

Therapeutic effects of imipramine are counteracted by its metabolite, desipramine, in patients with generalized anxiety disorder.

Imipramine has been shown to reduce anxiety in patients with generalized anxiety disorder (GAD). However, some properties of imipramine may diminish or counteract its anxiolytic effects. The authors previously found that the greater the reduction in cardiac vagal control after 6 weeks of imipramine treatment, the smaller the improvement in anxiety-related symptoms. The purpose of this study was to determine whether the authors' previous findings were replicable and to gather information on the plasma levels of imipramine, desipramine (the major metabolite of imipramine), and anticholinergic levels. Fourteen patients with GAD were administered imipramine for 6 weeks. Their scores from self-administered and investigator-administered rating scales were obtained before and after the treatment, and the changes in these scores were contrasted with the changes in cardiac vagal tone, along with the absolute plasma levels of imipramine, desipramine, and anticholinergic activity at the end of week 6. The authors observed a greater improvement in symptoms of anxiety in those who showed the smallest decreases in cardiac vagal tone and in those who showed the smallest increases in desipramine and anticholinergic plasma levels. Moreover, strong relationships were observed between desipramine and anticholinergic levels. These results demonstrate that imipramine not only has therapeutic effects, but it may also have properties that result in physiologic states that counteract its therapeutic effects. Future research should investigate the direct anticholinergic effects of desipramine and determine whether there is a parallel between the anticholinergic effects and the clinical outcome of other pharmacologic treatments, including antidepressants with predominantly norepinephrine or serotonin reuptake inhibitory properties.

Adrenergic Uptake Inhibitors↗
PubMed1999

Polytopic anomalies with agenesis of the lower vertebral column.

We describe clinical, pathological and radiological findings in 15 cases of sporadic and familial lower spine agenesis with additional anomalies of the axial skeleton and internal organs and speculate about the cause and pathogenesis of this malformation complex. We show that all of these findings are defects of blastogenesis, originate in the primary developmental field and/or the progenitor fields, thus representing polytopic field defects. This concept appears applicable in our cases and makes such terms such as "caudal regression syndrome" or "axial mesodermal dysplasia spectrum" redundant.

Abnormalities, Multiple↗
PubMed1999

VACTERL manifestations in two generations of a family.

Most cases of the VACTERL "association" [Martinez-Frias et al., Am. J. Med. Genet. 76: 291-296, 1998] are sporadic, with an empiric recurrence risk of 1% or less. Rare families with recurrence of VACTERL-H association are described with patterns consistent with single gene inheritance. Also described are occasional single anomalies of the VACTERL association in sibs or parents of affected individuals. We describe a mother and son with typical VACTERL anomalies. The patient was born by cesarean section to a 27-year-old G1 mother following an uncomplicated pregnancy. He was found to have an asymmetric crying face, preaxial polydactyly on the right, a small midmuscular ventricular septal defect with an incomplete right bundle branch block on echocardiogram, a small cleft in T3, and incomplete development of the left half of the sacrum. The kidneys were normal ultrasonographically. The patient's mother was born with an H-type tracheo-esophageal fistula, imperforate anus, rectovaginal fistula, a triphalangeal thumb, hypoplastic left kidney, and vertebral anomalies. There were no other individuals with VACTERL anomalies in the family. No families with VACTERL association in the offspring of an affected individual have been reported previously.

Abnormalities, Multiple↗
PubMed1998

Increased heart rate in depressed subjects in spite of unchanged autonomic balance?

A clinical study was conducted to examine the effects of depression on cardiac autonomic control. Cardiac autonomic control was measured in 26 nonmedicated patients (19 females) suffering from Major Depression, melancholic type, and in 26 age- and sex-matched normal controls. We measured heart rate and high frequency heart rate variability (respiratory sinus arrhythmia), pulsewave velocity and blood pressure, during 10 min of supine rest under controlled conditions. Using a log transformed time domain measure of respiratory sinus arrhythmia (logRSA), we found an inverse linear dependence between cardiac vagal tone and age in the healthy subjects as well as the depressed patients. logRSA was 0.22+/-0.25 in the patients and 0.25+/-0.16 in the control group. While this difference was not significant (P > 0.1), the deviations from the regression line were significantly (P < 0.0005) greater in the patients (0.21+/-0.12) than in the control group (0.09+/-0.07), indicating a more heterogeneous vagal tone in the depressed patients. Heart rate was also significantly (P < 0.03) greater in the depressed patients (76.6+/-12.4) than in the control group (69.5+/-6.9). No between-group differences were found in pulsewave velocity or systolic blood pressure, but diastolic blood pressure was lower in depressed patients (73.5+/-8.7 vs. 80.8+/-9.1). We discuss the possibility that the increased heart rate seen in the absence of vagal tone changes may not be due to altered vagal or sympathetic tone, as measured in this study. Other factors, including altered autonomous heart rate, may be responsible for the higher heart rate in the depressed group.

Adolescent↗
PubMed1997

Does muscle tension reflect arousal? Relationship between electromyographic and electroencephalographic recordings.

Increased muscle tension and heightened arousal are the most consistent finding in patients with anxiety disorders. This study examined the relationship between frontalis and gastrocnemius electromyographic (EMG) and electroencephalographic activity on 14 female generalized anxiety disorder patients and 14 female control subjects. In GAD patients, gastrocnemius but not frontalis EMG was correlated with right but not left hemisphere activity. For the non-anxious subjects, there was a pattern for both beta 1 and beta 2 waves to be positively associated with both frontalis and gastrocnemius muscle tension levels. The results, while preliminary, suggest that EMG activity may reflect central nervous system arousal.

Adult↗
PubMed1996

Familial cardiomyopathy with cataracts and lactic acidosis: a defect in complex I (NADH-dehydrogenase) of the mitochondria respiratory chain.

Four patients in one generation of a multiply consanguineous pedigree died with cardiomyopathy, cataracts, and lactic acidemia. Postmortem heart and skeletal muscle tissues from one patient were analyzed. A low (12% control) activity of NADH-CoQ reductase (complex I) in heart and normal activity in skeletal muscle mitochondria was found. Cultured skin fibroblasts obtained from two individuals in the pedigree showed elevated lactate to pyruvate ratios in the range of 2 to 3.5 times normal and decreased complex I + III activity (42 and 54% of control activities) in isolated mitochondria. Western blot analysis and enzymatic assay showed normal levels of CuZn-superoxide dismutase, but grossly elevated levels of the mitochondrial Mn-superoxide dismutase. Southern blot analysis in heart muscle cells from the patient tested revealed multiple mitochondrial DNA deletions which indicate free oxygen radical damage. We hypothesize that a nuclear-encoded defect in the respiratory chain is responsible for excessive free oxygen radical production in these infants which contributes to the prenatal onset of cardiomyopathy and cataracts.

Acidosis, Lactic↗
PubMed1995

Is hyperarousal essential to obsessive-compulsive disorder? Diminished physiologic flexibility, but not hyperarousal, characterizes patients with obsessive-compulsive disorder.

OBJECTIVE: To examine the hypothesis that the pathologic features of obsessive-compulsive disorder (OCD) are facilitated by abnormal levels of arousal, we compared patients with OCD with controls on self-reports and psychophysiologic measures. METHODS: Twenty-three patients with OCD were compared with 21 controls on rating scales and on psychophysiologic measures (ie, heart interbeat interval, skin conductance, respiration, blood pressure, and electromyographic activity) during rest and during two psychologically stressful tasks. RESULTS: Patients rated themselves higher on psychic and somatic anxiety scales. Mean physiologic activities were not elevated at rest. During tasks, changes in electrodermal, cardiovascular (except blood pressure), and muscle activities were smaller in patients with OCD, indicating decreased physiologic flexibility. CONCLUSIONS: Hyperarousal, measured peripherally, is not an essential pathologic feature of OCD. Decreased physiologic flexibility indicates an anxiety-related, but not OCD-specific, impairment of psychophysiologic reactivity to one's environment.

Adult↗