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PubMed2002

Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons.

Voltage-gated potassium channels, Kv1.1, Kv1.2 and Kv1.6, were identified as PCR products from mRNA prepared from nodose ganglia. Immunocytochemical studies demonstrated expression of the proteins in all neurons from ganglia of neonatal animals (postnatal days 0-3) and in 85-90 % of the neurons from older animals (postnatal days 21-60). In voltage clamp studies, alpha-dendrotoxin (alpha-DTX), a toxin with high specificity for these members of the Kv1 family, was used to examine their contribution to K(+) currents of the sensory neurons. alpha-DTX blocked current in both A- and C-type neurons. The current had characteristics of a delayed rectifier with activation positive to -50 mV and little inactivation during 250 ms pulses. In current-clamp experiments alpha-DTX, used to eliminate the current, had no effect on resting membrane potential and only small effects on the amplitude and duration of the action potential of A- and C-type neurons. However, there were prominent effects on excitability. alpha-DTX lowered the threshold for initiation of discharge in response to depolarizing current steps, reduced spike after-hyperpolarization and increased the frequency/pattern of discharge of A- and C-type neurons at membrane potentials above threshold. Model simulations were consistent with these experimental results and demonstrated how the other major K(+) currents function in response to the loss of the alpha-DTX-sensitive current to effect these changes in action potential wave shape and discharge.

Algorithms↗
PubMed2003

The impact of increased Al filtration on x-ray tube loading and image quality in diagnostic radiology.

Previous work has shown that for nine common radiographic projections (AP abdomen, AP cervical spine, LAT cervical spine, PA chest, LAT chest, AP hip, AP lumbar spine, LAT lumber spine, and AP pelvis) increasing the total x-ray tube filtration from 2.5 mm Al equivalent (the regulatory minimum for general diagnostic radiology) to 4.0 mm Al equivalent, reduces the average effective dose and average skin entrance dose by 9% and 16%, respectively, using a 400 speed screen-film system. In this study, the effects of this filtration increase on x-ray tube loading and image quality were assessed. For the above projections and filtration increase, mean absolute and percentage increases in tube loading were 2.9 mAs and 15%, respectively, for a constant film density and fixed kVp. Tube current (mA) increases of 25% (a worst case) resulted in no statistically significant loss in focal spot resolution due to blooming for both large (1.2 mm) and small (0.6 mm) focal spot sizes, except at high mA low kVp techniques. The latter losses were below 10%, and when the image receptor blur was incorporated, the total system spatial resolution losses were on the order of one-quarter to one-half these values for typical clinical geometries. Radiographs of a contrast phantom taken with 2.5 and 4.0 mm total Al equivalent x-ray tube filtration were compared at 60, 70, 81, 90, 102, and 121 kVp. No statistically significant changes were observed with regard to (1) test object conspicuity as reported by three observers, (2) image contrast, as measured using a densitometer with a 3 mm aperture (+/-0.0017 OD, 95% confidence level), and (3) pixel value image noise, image contrast-to-noise ratios, and image signal-to-noise ratios, as measured using a scanning densitometer with a 12-bit acquisition depth and 85 micron pixel size (+/-2.5%, +/-3.1%, and +/-2.5%, 95% confidence levels, respectively). These results, combined with the linear no-threshold model for radiation risk and the ALARA principle, suggest that general radiography should be carried out using a minimum of 4.0 mm total Al equivalent filtration.

Dose-Response Relationship, Radiation↗
PubMed2001

Aging and the osteogenic response to mechanical loading.

The osteogenic response to mechanical stress is blunted with aging. It has been postulated that this decline in responsiveness is related to (a) a limited ability to engender the strain necessary to reach the bone modeling threshold, due to decreased muscle mass and strength, and/or (b) a decline in certain hormones or growth factors that may interact with mechanical signals to change the sensitivity of bone cells to strain. There is reason to believe that both of these factors contribute to the reduced ability to increase bone mass through exercise with advancing age. Weight-bearing endurance exercise and resistance exercise have both been found to increase bone mass in older women and men. However, exercise training studies involving older individuals have generally resulted in increased bone mineral density only when the exercise is quite vigorous. There is also evidence that the osteogenic response to mechanical loading is enhanced by estrogens. Whether age-related changes in other factors (e.g., other hormones, growth factors, cytokines) also contribute to the reduced responsiveness of the aged skeleton to mechanical loading remains to be investigated.

Aging↗
PubMed2003

Genetic influences in gastro-oesophageal reflux disease: a twin study.

BACKGROUND: A number of families have been described which include multiple members with symptomatic, endoscopic, or complicated gastro-oesophageal reflux disease (GORD). First degree relatives of patients with GORD are more likely to suffer with GORD symptoms. These observations raise the possibility of a genetic contribution to the aetiology of GORD. AIMS: To determine the relative contribution of genetic factors to GORD by evaluating GORD symptoms in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 4480 unselected twin pairs, identified from a national volunteer twin register, were asked to complete a validated symptom questionnaire. GORD was defined as symptoms of heartburn or acid regurgitation at least weekly during the past year. RESULTS: Replies were obtained from 5032 subjects (56% response rate). A total of 1960 twin pairs were evaluable: 928 MZ pairs (86 male pairs, mean (SD) age 52 (13) (range 19-81) years) and 1032 DZ pairs (71 male pairs, mean age 52 (13) (20-82) years). The prevalence of GORD among both groups of twins was 18%. Casewise concordance rates were significantly higher for MZ than DZ twins (42% v 26%; p<0.001). Multifactorial liability threshold modelling suggests that additive genetic effects combined with unique environmental factors provide the best model for GORD. Heritability estimates suggest that 43% (95% confidence interval 32-55%) of the variance in liability to GORD is due to additive genetic factors. CONCLUSIONS: There is a substantial genetic contribution to the aetiology of GORD.

Adult↗
PubMed1982

A three generation family study of cleft lip with or without cleft palate.

A family study of cleft lip, with or without cleft palate, was based on those treated by operation at The Hospital for Sick Children, London, between 1920 and 1939 in order to give information on the proportion affected of children and grandchildren. The probands were those who had survived, were successfully traced, and found to have had at least one child. Care was taken to exclude patients who were traced through a child, whether normal or affected, and not through the usual tracing procedure. Patients with recognised syndromes were also excluded. Because the series was based on patients who had survived and reproduced it was biased in favour of those with milder degrees of the malformation, and against those with any severe associated malformation. The proportion affected of children of probands was 3.15% (+/- 0.56), of sibs 2.79% (+/- 0.52), and of parents 1.18% (+/- 0.37), respectively. The lower proportion of parents affected is attributed to reduced reproductive fitness of patients born two generations ago. The proportion affected of nephews and nieces, aunts and uncles, and grandchildren was 0.47% (+/- 0.18), 0.59% (+/- 0.13), and 0.8% (+/- 0.6) respectively. The proportion affected of first cousins was 0.27% (+/- 0.08). The birth frequency of cleft lip (+/- cleft palate) is estimated to be about 0.1% in England. There were two first cousin and one second cousin marriages among the marriages of the parents. There was no increase of cleft palate among the relatives of the probands. The proportion of sibs affected increased with increasing severity of the malformation in the proband, where the proband was female, and where the proband had an affected parent or already had one affected sib. It was not, however, increased where a more remote relative was affected. The proportion of children affected was not increased when the proband had an affected parent or sib, but few families provided information. The most economical hypothesis to explain the findings is the multifactorial threshold model. The birth frequency of the malformation and the family patterns found make it improbable that one single mutant gene makes a major contribution to the liability to develop the condition.

Adult↗
PubMed1982

A family study of isolated cleft palate.

A family study was based on 245 boy and 329 girl patients treated surgically for non-syndromic cleft palate between 1920 and 1929; 86 and 81 respectively were traced and had had children. These 167 were the probands for the family study and were interviewed in their homes. None was born to a consanguineous marriage. Altogether they had had 384 children of whom 11 had cleft palate (2.9 +/- 0.9%). They had 398 sibs of whom five had cleft palate, 117 grandchildren of whom one was affected, and 517 nephews and nieces of whom one was affected. This is the largest series yet available on which to base an estimate of the risks to children of patients with non-syndromic cleft palate. The risk is probably increased where a parent or sib of the proband is affected and increased to a lesser degree where a second or third degree relative is affected. The family patterns in these and other studies suggest that the aetiology of cleft palate is heterogeneous, with some families showing modified dominant inheritance. This is in contrast to cleft lip (+/- cleft palate) where the data are consistent with a multifactorial threshold model.

Adult↗
PubMed1993

Linkage analysis of infantile pyloric stenosis and markers from chromosome 9q11-q33: no evidence for a major gene in this candidate region.

A genetic component in the aetiology of infantile pyloric stenosis (PS) is well established. Segregation analysis is compatible with a multifactorial sex modified threshold model of inheritance but a major gene of low penetrance has not been excluded. PS has been reported to occur in 57% (four of seven) of cases with duplication of chromosome 9q11-q33. Twenty families with PS were studied using genetic markers at loci D9S55, D9S111, D9S15, D9S12, D9S56, D9S59, and ASS from this region of chromosome 9. Pairwise lod scores of -2 were obtained with all these markers at recombination fractions greater or equal to 0.04 under both autosomal dominant and autosomal recessive models of inheritance. This provides evidence against the existence of a major locus predisposing to PS within chromosome 9q11-q33.

Chromosomes, Human, Pair 9↗
PubMed1994

Neuropsychological effects of exposure to naphtha among automotive workers.

The association between exposure to naphtha and neurobehavioural measures was examined prospectively over one year among workers employed at an automotive plant that used naphtha to calibrate fuel injectors. The neurobehavioural tests included those that assess mood, basic intelligence, and functioning of the cerebral frontal lobes and limbic system and were designed so that acute, reversible, and chronic effects of solvent exposure could be assessed. Participants were 248 workers in June 1988, and the testing was repeated on 185 of these workers in 1989. Concentrations of naphtha at the plant ranged from six to 709 mg/m3, although exposure was greater in 1988 than in 1989. Duration of exposure for individual subjects ranged from 0.8 to 7.3 years. Cross sectional data analyses showed significant associations between level of exposure to naphtha and slower timed scores on trails A, and greater reports of negative affective symptoms on profile of mood states scales in 1988 but not 1989. Threshold model analyses of the 1989 data showed an association between score on visual reproductions immediate recall and daily exposure to naphtha at or above 1050 h x mg/m3. Models of chronic exposure showed no associations between chronic exposure and negative neurobehavioural outcome. Results suggest that naphtha produces mild acute reversible effects on function of the central nervous system at or above daily exposures of 540 h x mg/m3 (approximately 90 ppm/h).

Adult↗
PubMed1981

Genetics society of Canada award of excellence lecture. The genetics of common familial disorders--major genes or multifactorial?

The common familial disorders were, until recently, neglected by geneticists because their familial distributions did not neatly fit the Mendelian mold, and no specific genes could be identified. The multifactorial-threshold model made the familial characteristics of these disorders more intelligible. Although it originally postulated a polygenic genetic component the model can also accommodate one or more major genes with low penetrance. The resulting upsurge of interest has led to (1) the development of increasingly sophisticated mathematical models from which to calculate recurrence risks for specific family situations and (2) the identification of specific predisposing genes in a number of such disorders. One of the corollaries of the model is that any pharmacological agent at therapeutic doses is likely to be teratogenic to at least some embryos, so that regulation should be in terms of "acceptably low" levels of teratogenicity rather than "safety".

Abnormalities, Drug-Induced↗
PubMed1985

Effect of sinusoidal forcing of ventilatory volume on avian breathing frequency.

Awake chickens were unidirectionally ventilated at 3.6 l . min-1 with 3.2-4.8% CO2 in air. The air sacs on each side were made confluent and implanted with exit tubes connected to the following three devices: 1) a system of constant-flow generators which remove air at exactly the same rate that it entered the trachea, allowing no port for spontaneous volume changes; 2) a sinusoidal pump to force volume changes in the chicken; and 3) a pressure transducer to record air sac pressure, which reflected the sum of two pressure components, the passive pressure changes created by the pump and the active pressure changes due to breathing efforts. Over a range of pump frequencies, the amplitude of measured air sac pressure changes varied inversely with frequency. Above and below this range, pressure showed a beat pattern, indicating a difference in the frequencies of the two pressure components. Within the range lacking a beat pattern, breathing movements and the pump stroke had the same frequency. This range was greater at increased stroke volume. Breathing efforts worked with the pump at the high end of the range and against the pump at the low end. These findings show further evidence of the presence of a response to volume forcing and fit a previously described volume threshold model.

Animals↗
PubMed1996

Light enhances hydrodynamic signaling in the multimodal caudal photoreceptor interneurons of the crayfish.

1. The caudal photoreceptor (CPR) interneurons in the sixth abdominal ganglion of the crayfish are complex, multi-modal interneurons. These cells respond directly to light with tonic spike discharges, and they integrate synaptic input from an array of fili-form mechanoreceptors on the tailfan. They also provide input to rostral command centers, inducing backward walking at high firing frequencies, and thus directly influence behavior. 2. We recorded CPR activity in response to weak hydrodynamic stimulation of the tailfan mechanoreceptors while under varying intensities of light shined on the sixth ganglion. Spike trains were characterized according to the mean discharge rate (MDR) and the power spectrum from which the signal-to-noise ratio (SNR) was calculated. 3. Illumination of the CPR enhances the efficiency of transmitting mechanosensory signals. It does so by increasing the SNR of mechanosensory input received from tailfan receptors. A sevenfold, nonlinear increase in the SNRs was observed with increasing light intensity, an effect especially pronounced for weak hydrodynamic stimuli. In comparison with the dark, illumination of the ganglion lowered the hydrodynamic threshold and heightened the response to suprathreshold stimulation. Unlike the SNR, the MDR is little affected by mechanosensory input. 4. These results are compared with simulated electronic activity from an analogue threshold model and are discussed with respect to the mechanism of stochastic resonance.

Animals↗
PubMed1976

Estimation of polygenic recurrence risk for cleft lip and palate.

Data on cleft lip with or without cleft palate are utilized to evaluate a new method for estimating recurrence risk under the polygenic threshold model. The influence of critical factors on the accuracy of the estimated risks are evaluated. The model is relatively sensitive to the estimate of heritability employed and relatively robust to the population prevalence estimate and to family size. The calculated risks for cleft lip with or without cleft palate are contrasted with the empiric figures from studies on Caucasians and Japanese populations.

Cleft Lip↗
PubMed1979

Aetiological studies of hypospadias in Hungary.

A complex aetiological (epidemiological, teratological and genetic) study was made in 294 index patients with simple isolated hypospadias. The epidemiological study conducted by the help of personal interviews of the mothers revealed a higher frequency of index patients among children born between August and December, among twins, mainly monozygotic, and finally in the lower birth weight groups and among first-borns. The teratological study showed a higher frequency in mothers of index patients who had had sex hormone treatment, mainly progestogen, before the 16th gestational week. This seems to indicate the aetiological role of fetal androgen deficit caused by the regulation disturbances of human choriogonadotropin. The genetic family study completed by personal examination of first-degree male relatives showed a familial clustering (4.0% versus a point prevalence of 0.44% in live-births). Both the pattern of affected relatives (h2 values 0.62 +/- 0.21 and 0.72 +/- 0.33 in fathers and brothers, respectively, not differing significantly from each other) and further characteristics (other malformations were not frequent in relatives) correspond to the multifactorial-threshold model.

Abnormalities, Drug-Induced↗
PubMed1994

Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype.

The genetic basis of familial combined hyperlipidemia (FCHL) has eluded investigators for 20 years, despite the apparent segregation of FCHL as an autosomal dominant disorder affecting 1% to 2% of individuals. Etiologic heterogeneity and additive effects of traits controlled by other genetic loci have been suggested. Two traits have been implicated in FCHL. The first is the predominance of a small, dense low-density lipoprotein (LDL), LDL subclass phenotype B, which segregates as a mendelian trait. The second is a mendelian locus with large effects on apolipoprotein (apo) B levels that is defined by complex segregation analysis (predicted apoB level genotype). This study shows that these factors appear to be separate genetic effects, both of which aid in the prediction of FCHL in four large pedigrees. The results suggest that FCHL may be best predicted by a threshold model in which apoB level genotype and LDL subclass phenotype each act to increase the risk of FCHL. Heterogeneity in the transmission of apoB levels among families is suggested, supporting the etiologic heterogeneity of FCHL. These results emphasize the advantages inherent in the study of large pedigrees when disease heterogeneity is suspected.

Adult↗
PubMed2002

Genetic basis of variation in carotid artery plaque in the San Antonio Family Heart Study.

BACKGROUND AND PURPOSE: In contrast to the commonly used quantitative marker of subclinical atherosclerosis, namely intima-media thickness, we investigated the extent to which the presence or absence of carotid artery plaque (CAP) was under genetic control. METHODS: The study population consisted of 750 individuals distributed across 29 randomly ascertained extended Mexican American pedigrees who participated in the second examination cycle of the San Antonio Family Heart Study. Extracranial focal CAP was identified by B-mode ultrasound bilaterally in the internal carotid artery or the carotid bulb. Using a variance decomposition approach implemented in the SOLAR computer program, we performed genetic analysis on the discrete trait CAP (ie, liability to disease) using a threshold model. Covariates considered in the analysis included age, sex, diabetes, current smoking status, lipid levels, and markers of hypertension and obesity. RESULTS: Fifty-one of 461 women and fifty-seven of 289 men with a mean age of 42.1 years had evidence of a plaque in the right and/or left carotid artery. The age- and sex-adjusted heritability (h(2)+/-SE) for CAP was significant (h(2)=0.28+/-0.15, P=0.01). Furthermore, after adjustment for additional covariates that contributed significantly to the model (P<0.05; diabetes, hypertension, body mass index, waist circumference, and smoking status), heritability remained significant (h(2)=0.23+/-0.15, P=0.03). CONCLUSIONS: Our data indicate that after established cardiovascular risk factors are controlled for, the variation of the discrete trait CAP is under appreciable additive genetic influences.

Adolescent↗
PubMed1985

Evidence for autosomal recessive inheritance in 46 families with multiple incidences of autism.

The authors ascertained 46 families with multiple incidences of autism (41 with two and five with three autistic probands). Classical segregation analyses revealed a maximum likelihood estimate of the segregation ratio of p = 0.19 +/- 0.07. This is not significantly less than 0.25, the expected value for autosomal recessive inheritance. However, it is significantly less than 0.50, the expected value for autosomal dominant inheritance. The polygenic threshold model was tested and rejected over a full range of values of heritability and ascertainment probability for these families. These results are most consistent with the hypothesis of autosomal recessive inheritance in this subset of 46 families with multiple incidences of autism.

Adolescent↗
PubMed1999

Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins.

OBJECTIVE: Most twin and adoption studies of alcoholism have ascertained cases through treatment settings or archival data; these subjects may differ from affected subjects identified epidemiologically. The authors studied the importance of genetic influences on risk of alcohol-related disorders in a new population-based twin sample. METHOD: Structured personal interviews were used to assess DSM-III-R-defined and DSM-IV-defined alcohol abuse and dependence among 3,516 twins from male-male pairs born in Virginia between 1940 and 1974. RESULTS: The magnitude of resemblance among twin pairs was similar across several definitions of alcoholism and was substantially higher among 861 identical pairs than among 653 fraternal pairs. On the basis of a liability threshold model, 48%-58% of the variation in liability was attributed to additive genetic factors, with the remainder attributed to environmental influences not shared by family members. When a treatment-based proband concordance model was used, evidence for shared environmental as well as genetic influences emerged. CONCLUSIONS: In this first population-based study of male twins from the United States, it was found that genetic factors played a major role in the development of alcoholism among males, with similar influence for alcohol abuse and alcohol dependence. Prior findings implicating the influence of common environment may be attributable to sampling strategy; in this population-based sample, environmental factors shared by family members appear to have had little influence on the development of alcoholism in males.

Adolescent↗