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Biomedical subjects

B Fowler

Publications and source records attributed to B Fowler.

At least 73 records · Page 4Linked to original sources
PubMed1996

Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis.

BACKGROUND: Venous and arterial thromboembolism occurs in only about one third of patients homozygous for homocystinuria, which suggests that other, contributory factors are necessary for the development of thrombosis in these patients. Factor V Leiden, an R506Q mutation in the gene coding for factor V, is the most common cause of familial thrombosis and could be a potentiating factor. METHODS: We determined activated partial-thromboplastin times in the presence and absence of activated protein C and tested for the factor V Leiden mutation in 45 members of seven unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. RESULT: Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (age, 0.2 to 8 years). All six also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden has received warfarin therapy since birth and has not had thrombosis (age, 18 months). Of four patients with homocystinuria who did not have factor V Leiden, none had thrombosis (ages at this writing, 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. CONCLUSIONS: Patients with concurrent homocystinuria and factor V Leiden can have an increased risk of thrombosis. Screening for factor V Leiden may be indicated in patient with homocystinuria and their family members.

Adolescent↗
PubMed1996

Effect of methionine loading on 5-methyltetrahydrofolate, S-adenosylmethionine and S-adenosylhomocysteine in plasma of healthy humans.

1. Elevated plasma homocysteine concentration, either in the fasting state or after methionine loading, is an independent risk factor for vascular disease in man. Methionine loading has been used to investigate impaired methionine metabolism, especially of the trans-sulphuration pathway, but most studies have focused on changes in homocysteine. 2. We investigated the effect of methionine excess on total plasma homocysteine, 5-methyltetrahydrofolate (which is the active form of folate in the remethylation of homocysteine to methionine), S-adenosyl-methionine (the first metabolite of methionine) and S-adenosylmethionine) (the demethylated product of S-adenosylmethionine) over 24h in 12 healthy subjects. 3. As well as the expected increase in homocysteine (from 8.0 +/- 1.3 to 32.6 +/- 10.3 mumol/l, mean +/- SD, P < 0.001), S-adenosylmethionine showed a significant transient increase (from 37.9 +/- 25.0 to 240.3 +/- 109.2 nmol/l, P < 0.001), which correlated well with homocysteine (r2 = 0.92, P < 0.001). 5-Methyltetrahydrofolate values decreased significantly (from 23.2 +/- 7.2 to 13.1 +/- 2.9 nmol/l, P < 0.01), and gradually returned to baseline levels after 24h. No significant change over the time of measurement was found for S-adenosylhomocysteine. 4. The sequence of metabolic changes observed in this study strongly suggests that a change in either homocysteine or S-adenosylmethionine may cause a reduction in 5-methyltetrahydrofolate. This must be considered in evaluating the relationship between folate and homocysteine in vascular disease. The metabolic relationships illustrated in this study should be evaluated in the search for pathogenetic mechanisms of mild hyperhomocysteinaemia and vascular disease.

Adult↗
PubMed1996

An AFM investigation of the effects of acute hypoxia on mental rotation.

To determine if the stimulus identification stage of information processing is slowed by hypoxia, eight highly trained subjects performed a mental rotation task involving same or different responses to pairs of two-dimensional figures rotated in the picture plane. They breathed low oxygen mixtures adjusted to maintain arterial blood oxygen saturation at 64%. The results showed that hypoxia increased the intercept rather than the slope of the linear function relating reaction time to angle of rotation. According to Additive Factors Method logic, this result indicates that hypoxia does not slow stimulus identification. This is further evidence against the long-held view that hypoxia impairs information processing mechanisms throughout the system--the multiple loci hypothesis. The authors propose instead the early slowing hypothesis. According to this view, the slowing produced by hypoxia is highly specific to one or two early stages of visual processing, and this early slowing acts as a bottleneck to later processing.

Adult↗
PubMed1996

Defects in human methionine synthase in cblG patients.

Inborn errors resulting in isolated functional methionine synthase deficiency fall into two complementation groups, cblG and cblE. Using biochemical approaches we demonstrate that one cblG patient has greatly reduced levels of methionine synthase while in another, the enzyme is specifically impaired in the reductive activation cycle. The biochemical data suggested that low levels of methionine synthase activity in the first patient may result from mutations in the catalytic domains of the enzyme, reduced transcription, or generation of unstable message or protein. Using Northern analysis, we demonstrate that the molecular basis for the biochemical phenotype in this patient is associated with greatly diminished steady-state levels of methionine synthase mRNA. The biochemical data on the second patient cell line implicated mutations specific to reductive activation, a function that is housed in the C-terminal AdoMet-binding domain and the intermediate B12-binding domain, in the highly homologous bacterial enzyme. We have detected two mutations in a compound heterozygous state, one that results in conversion of a conserved proline (1173) to a leucine residue and the other a deletion of an isoleucine residue (881). The crystal structure of the C-terminal domain of the Escherichia coli MS predicts that the Pro to Leu mutation could disrupt activation since it is embedded in a sequence that makes direct contacts with the bound AdoMet. Deletion of isoleucine in the B12-binding domain would result in shortening of a beta-sheet. Our data provide the first evidence for mutations in the methionine synthase gene being culpable for the cblG phenotype. In addition, they suggest directly that mutations in methionine synthase can lead to elevated homocysteine, implicated both in neural tube defects and in cardiovascular diseases.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Low whole-blood S-adenosylmethionine and correlation between 5-methyltetrahydrofolate and homocysteine in coronary artery disease.

Mild elevation of plasma homocysteine is an independent risk factor for vascular disease. We studied the role of 5-methyltetrahydrofolate (5-MTHF), the folate form directly involved in homocysteine metabolism, in contrast to previous studies, which used total folate measurements, in 70 coronary artery disease (CAD) patients and control subjects. We also measured S-adenosylmethionine (SAM), which controls the activity of critical enzymes of homocysteine metabolism. Fasting plasma total homocysteine was elevated (> 12.4 mumol/L for women, > 13.3 mumol/L for men) in 17% of patients, in accordance with earlier studies. These patients showed lower 5-MTHF (12.4 +/- 1.0 mumol/L, mean +/- SD) than control subjects (24.2 +/- 15.0, P < .001), and there was a clear correlation (multiple linear regression analysis: P = .002) of this relevant form of folate with homocysteine. However, 37% of the normohomocysteinemic patients also revealed similarly low 5-MTHF levels, suggesting that a decrease of 5-MTHF does not necessarily cause hyperhomocysteinemia. SAM was significantly decreased in patients (1.4 +/- 0.4 mumol/L) compared with control subjects (1.8 +/- 0.3, P < .001) but was not correlated to homocysteine or 5-MTHF. The correlation between homocysteine and 5-MTHF that was found in CAD patients but not in control subjects confirms the direct relationship between these compounds in vivo. The new finding of low SAM in patients demands further studies, since it might indicate that low levels pose risk and that SAM might be a protective factor against the development of CAD.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1995

Thrombomodulin and ristocetincofactor in homocystinuria: a study in two siblings.

Homocystinuria due to cystathionine-beta-synthase deficiency (CBS-def-HOCY) initially often presents with vascular disorders, e.g. thromboembolic events. The measurement of vascular endothelial markers in plasma could help to assess endothelial damage. We determined von Willebrand factor (measured as Ristocetincofactor, RiCoF) and thrombomodulin (TM), two endothelial cell markers to our knowledge not measured systematically before in homocystinuria patients in a longitudinal study of two homocystinuric patients: Patient1 with thromboembolic disease and his asymptomatic sister, patient2. Before start of therapy in patient 1, TM and RiCoF levels both were increased. In patient 2 a moderately elevated RiCoF and a normal level of TM were found. Vitamin therapy with 15 mg folate and 600 mg pyridoxine per day led to almost complete normalization of amino acids in urine and plasma, and complete normalization of RiCoF and TM levels in both patients. Thus, TM and RiCoF elevations demonstrate that CBS-def-HOCY leads to endothelial cell damage, which resolved under vitamin therapy in the patients studied.

Adult↗
PubMed1995

Biotinidase Km-variants: detection and detailed biochemical investigations.

We describe a simple method for the detection of biotinidase Km-variants and detailed biochemical investigations in 5 such patient. They were detected among 103 patients with plasma biotinidase activity which ranged from undetectable to 30% of the mean normal value. Two different types of biotinidase Km-variants were found. (1) In 3 infants biotinidase had a single 105-430-fold elevated Km for biocytin. Biotinidase showed very low activities (0.2-4% of the mean normal value) in the routine colorimetric assay and was not functional in vivo. Accordingly, these patients presented with classical clinical illness. (2) In two patients biotinidase showed biphasic kinetics indicating the presence of one component with a normal Km and reduced Vmax (1.7% and 12%), and another with 330- and 59-fold elevated Km, respectively. In these two patients, biotinidase proved to be at least partially functional in vivo. However, the first patient developed severe symptoms and biotin deficiency late, at the age of 10-15 years, and the second had marginal biotin deficiency at the age of 2 years but no clinical symptoms. Comparative studies revealed that both patients had more severe biotin deficiency than age-matched patients with similar levels of residual biotinidase activity and a single normal Km. Therefore, all patients with residual biotinidase activity should be evaluated for the presence of a Km-mutation, since such patients should be treated with biotin. These can easily be detected by including a second substrate concentration (1.5 mmol/L) in the routine colorimetric biotinidase assay which is performed with 0.15 mmol/L biotin. Increased activity with the higher substrate concentration indicates the presence of a Km-mutation. Detailed kinetic studies are needed to evaluate the distinct forms of Km-variants.

Amidohydrolases↗
PubMed1995

Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level.

Hyperhomocysteinemia occurs in approximately 30% of the patients with premature occlusive arterial disease (POAD). Some of these exhibit significantly reduced fibroblast cystathionine beta-synthase (CBS) activities, suggesting that they may be heterozygous for CBS deficiency. To test this possibility, we studied cDNA derived from four well characterized patients with POAD, exhibiting hyperhomocysteinemia and reduced CBS activities, from four normal controls, and from four obligatory heterozygotes for CBS deficiency. Lysates of individual colonies of E.coli, containing full-length PCR-amplification products in the expression vector, pKK388.1, were tested for CBS activity. cDNA from at least seven of the eight possible independent POAD alleles encoded catalytically active, stable CBS which exhibited normal response to both PLP and AdoMet. The sequences of all 3'-untranslated regions of all seven isolated POAD alleles were identical to the normal, 'wild-type' CBS sequences. The results of the expression studies were confirmed for one POAD patient by determining the full-length cDNA sequences for both alleles; these were entirely normal over the complete length of the cDNA. In contrast, the screening method correctly distinguished mutant from normal alleles in all four obligatory heterozygotes studied. We conclude that CBS mRNAs from POAD individuals are free from inactivating mutations, including all 33 previously identified in heterozygous carriers and homocystinuric patients.

Alleles↗
PubMed1995

Cardiomyopathy in respiratory chain disorders.

Disorders of mitochondrial oxidative phosphorylation may disturb cardiac energy metabolism and cause cardiomyopathy. Twenty one cases from the literature and one further patient with cardiomyopathy due to biochemically defined respiratory chain defects were reviewed for clinical course, morphology, and pathophysiological mechanisms of the cardiomyopathy. All cases showed concentric hypertrophy of the myocardium without an outflow tract obstruction. In most patients the cardiomyopathy was diagnosed early in infancy and showed rapid deterioration with death before the age of 2 years. Hypertrophy of the myocardium appears to result from swelling of the cardiomyocytes caused by accumulation of mitochondria and by morphologically abnormal megamitochondria.

Cardiomyopathy, Hypertrophic↗
PubMed1995

A comparison of visual and auditory reaction time and P300 latency thresholds to acute hypoxia.

To investigate the influence of stimulus modality on the slowing produced by hypoxia, thresholds were estimated using reaction time (RT) and the event-related brain potential P300. Six trained subjects responded to oddball light flashes or tone pips while breathing low-oxygen mixtures that were manipulated to produce arterial blood oxygen saturations (SaO2) ranging from 77-86%. Both RT and P300 were slowed in a dose-dependent manner. The threshold for slowing was independent of stimulus modality for both measures, and estimated to be in the range 81-82% SaO2. P300 amplitude dissociated from the response time measures by exhibiting an inverted-U dose-response function. We draw three conclusions from these results: a) the failure to observe a higher visual threshold for the response time measures is inconsistent with the traditional belief that audition is relatively insensitive to hypoxia; b) the equal sensitivity of P300 latency and RT to hypoxia implicates stimulus evaluation processes in slowing; and c) P300 amplitude may reflect the activity of physiological compensatory mechanisms to hypoxia.

Adult↗
PubMed1995

Dissociation of the behavioral and subjective components of nitrogen narcosis and diver adaptation.

We investigated adaptation to nitrogen narcosis by compressing 11 highly experienced divers in a hyperbaric chamber to the equivalent of 54.6 meters of seawater once a day for 5 consecutive days. The behavioral component of narcosis was assessed with a serial choice-reaction time (RT) task, and the subjective component with a global magnitude estimate. Supplementary magnitude estimates were obtained with adjectives describing work effectiveness and body sensations. The results showed that there was no adaptation on the RT task, although learning was evident. In contrast, the global estimate dissociated from RT and showed clear adaptation by Day 3. The work effectiveness adjectives followed RT and did not show adaptation. Some body sensation adjectives showed clear adaptation, but others did not. These results lead to the conclusion that the anecdotal reports of adaptation by divers can probably be attributed to the subjective rather than the behavioral component of narcosis. Dissociation of these components suggests mediation by different brain mechanisms, and it is speculated that the gamma-aminobutyric acidA/benzodiazepine receptor complex, which has been implicated in both the anesthetic and anxiolytic properties of agents such as nitrous oxide, may be involved.

Adaptation, Physiological↗
PubMed1994

Discriminating the effects of triazolam on stimulus and response processing by means of reaction time and P300 latency.

The benzodiazepines slow information processing and the sites of this slowing were mapped using the Additive Factors Method in combination with the P300 component of the event-related brain potential. It was assumed that P300 largely reflects the time to evaluate a stimulus while reaction time (RT) reflects this time plus the time to select and execute a response. Twelve subjects were administered 0.25 mg triazolam in a repeated measures single-blind design. A visual 80-20% oddball task was used in which stimulus intensity and signal quality were manipulated with accuracy of responding held constant at a high level. RT and EEG data were collected simultaneously and the P300 elicited by the low probability stimuli was measured on a single trial basis. Triazolam slowed RT (172 ms, P < 0.0003) more than P300 (88 ms, P < 0.0007), but both measures exhibited a drug x stimulus intensity interaction. RT also exhibited a drug x signal quality interaction but P300 did not. These results suggest that triazolam has selective effects on perceptual processing by slowing an early pre-processing stage but not a later feature extraction stage. In addition, the drug appears to slow some aspect of response processing. This evidence is taken as support for a multiple process rather than a general sedation view of benzodiazepine effects on stages of processing.

Adult↗
PubMed1994

Coagulation factors and markers of activation of coagulation in homocystinuria (HOCY): a study in two siblings.

Homocystinuria due to cystathionine-beta-synthase deficiency (CBS-def-HOCY) initially often present with thromboembolic events. In most cases in which coagulation factors have been analysed, a deficiency of AT-IIIc and factor VIIc has been reported, the cause of which has not been elucidated. Activation of coagulation with consumption of coagulation factors has been postulated as the mechanism. This paper reports a longitudinal study of two patients: patient 1 with thromboembolic disease and his asymptomatic sister, patient 2. Before start of therapy in patient 1, a reduction of FVIIc, other coagulation factors, and AT-IIIc was found. Markers of activation of coagulation (F1 + 2, TAT, FM, D-dimers) were elevated only in patient 1, and only at the time of thrombotic complications. In patient 2 reduced levels of FVIIc and other coagulation proteins, and a low borderline AT-IIIc level was found. Thus, in the two patients, sustained activation of coagulation can be reasonably excluded to be the cause of low levels of coagulation proteins. Vitamin therapy with 15 mg folate and 600 mg pyridoxine per day led to almost complete normalization of amino acids in urine and plasma. Thrombosis has not recurred to date. FVIIc and the other coagulation proteins and AT-IIIc increased in parallel with the biochemical remission. Direct inhibition of the activity of AT-III and coagulation factor VIII and other factors by homocysteine was attempted in vitro but could not be shown at HC concentrations known to occur in the plasma of HOCY patients. Therefore, in these patients, deficient synthesis of coagulation factors and AT-III due to a disturbance of amino acid metabolism is still the most probable explanation for the observed low levels.

Adult↗
PubMed1994

P300 as a measure of workload during a simulated aircraft landing task.

The P300 component of the event-related brain potential was assessed as a measure of mental workload using 12 subjects who flew simulated visual flight rules final approaches and landings under workloads varied by manipulating turbulence and hypoxia. P300 was elicited with auditory and visual "oddball" subsidiary tasks requiring the detection of infrequent tones or flashes of an artificial horizon. The results showed that root mean square error flying performance was systematically degraded by both workload manipulations. P300 amplitude exhibited a complex pattern that was not strongly related to performance. By contrast P300 latency covaried closely with performance, increasing as a function of workload in both modalities. These results suggest that P300 latency indexes the slowing of perceptual/cognitive processing caused by workload and that this measure is sensitive to an important aspect of flying.

Adult↗