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Biomedical subjects

A D Smith

Publications and source records attributed to A D Smith.

At least 37 records · Page 2Linked to original sources
PubMed2004

Patients with bladder and lung cancer: a long-term outcome analysis.

OBJECTIVES: To report on patient characteristics, stage of disease and long-term outcome and prognosis of patients with dual bladder and lung cancers, as there is an established increased risk of smoking-related second primary cancers, especially lung cancer, developing in patients with bladder cancer. PATIENTS AND METHODS: We reviewed our hospital tumour registry database from 1990 to 2002, and identified 27 patients who had both bladder and lung cancers among 1038 with bladder cancer and 2427 with lung cancer. Seventeen patients had bladder cancer detected before lung cancer (group 1), and the remaining 10 had lung cancer diagnosed first (group 2). RESULTS: Group 1 and 2 were comparable in terms of patients' characteristics, mean interval between cancer detection and their use of tobacco. Group 1 patients had a tendency towards more invasive lung cancer at diagnosis than had group 2 patients (11/17 vs 2/10 stage >/= IIB, respectively; P = 0.082). The mean follow-up was 49.8 and 64.5 months for groups 1 and 2, respectively (not significant). The mean (sd) interval to death from the date of diagnosis of lung cancer was 18 (17) months for group 1 and 65 (42) months for group 2 (P < 0.05). CONCLUSIONS: Patients with bladder and lung cancer who have lung cancer detected first have a lower lung cancer stage and higher overall survival rate than patients diagnosed with bladder cancer first.

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PubMed2004

Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease.

BACKGROUND: There is evidence that iron may play a role in the pathology of Alzheimer's disease (AD). There may be genetic factors that contribute to iron deposition resulting in tissue damage thus exacerbating AD. METHODS: We have genotyped 269 healthy elderly controls, 191 cases with definite or probable AD, and 69 with mild cognitive impairment (MCI) from the OPTIMA cohort. RESULTS: We have examined the interaction between the C2 variant of the transferrin (TF) gene and the C282Y allele of the haemochromatosis (HFE) gene as risk factors for developing AD. Our results showed that each of the two variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. The interaction was significant by logistic regression (p = 0.014) and by synergy factor analysis (p = 0.015, synergy factor = 5.1). Further, carriers of these two alleles plus apolipoprotein E epsilon4 (APOE4) were at still higher risk of AD: of the 14 tri-carriers of the three variants, identified in this study, 12 had AD and two MCI. CONCLUSION: We suggest that the combination of TF C2 and HFE C282Y may lead to an excess of redox-active iron and the induction of oxidative stress in neurones, which is exacerbated in carriers of APOE4. Since 4% of Northern Europeans carry the two iron-related variants and since iron overload is a treatable condition, these results merit replication.

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PubMed2003

The automatic pilot of honeybees.

Using scanning harmonic radar, we make visible for the first time the complete trajectories of "goal-vector" flights in honeybees. We demonstrate that bees captured at an established feeding station, and released elsewhere, nevertheless embark on the previously learned vector flight that would have taken them directly home from the station, had they not been artificially displaced. Almost all of the bees maintained accurate compensation for lateral wind drift, and many completed the full length of the vector flight before starting to search for their hive. Our results showed that bees tend to disregard landscape cues during these vector flights, at least initially, and rely on the "optic flow" of the ground beneath them, and their sun compass, to judge both direction and distance.

Animals↗
PubMed2003

Association of the androgen receptor CAG repeat polymorphism with Alzheimer's disease in men.

We examined the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) in an Oxford cohort of 150 cases (101 men) of definite or probable Alzheimer's disease (AD) and 190 elderly controls (140 men). We found that short alleles (< or = 20 CAG repeats) were associated with AD (adjusted odds ratio = 2.5, 95% confidence intervals: 1.2-5.0) in men, but not in women. This association appeared stronger in early-onset AD (< 65 years). We conclude that this AR polymorphism is of potential relevance to the risk of AD in men.

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PubMed2003

Prevalence of dementia in a semi-urban population in Sri Lanka: report from a regional survey.

BACKGROUND: The prevalence of dementia in Sri Lanka, which has a rapidly ageing population, is unknown. OBJECTIVE: This study aimed to determine the prevalence of Alzheimer's disease (AD) and other dementias in a semi-urban elderly Sinhala-speaking population in Ragama, Sri Lanka. METHODS: The study was conducted in two phases. Phase I: After informed consent 703 subjects aged > or =65 years from the study area (population 15 828) were screened for cognitive impairment using the Sinhalese Mini Mental State Examination. Subjects scoring < or =17 were regarded as suspected dementia cases. Phase II: All subjects who screened positive in phase I were included in phase II for detailed evaluation for dementia according DSM IV and NINCDS-ADRDA criteria which included structured neuropsychiatric assessment, laboratory investigations, an axial CT scan of the brain and an informant interview. RESULTS: In the study sample, 61% were female and 86% were between 65-75 years. 42 subjects screened positive in phase I. Of these, 28 subjects were diagnosed as having dementia, giving an overall prevalence rate of 3.98% (95% Confidence Intervals (CI) =2.6-5.7%). Of these, 20 (71.4%) had probable AD, four had vascular dementia (14.3%), two had mixed (vascular and AD) dementia (7.1%), one had Lewy body dementia, and one had dementia due to syphilis. Greater age, illiteracy and female gender were associated with higher prevalence of dementia. CONCLUSION: Comparison with other community studies performed in North India suggests that dementia prevalence is higher in Sri Lanka. This may be due to regional differences in disease incidence.

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PubMed2003

Low vitamin B-12 status in confirmed Alzheimer's disease as revealed by serum holotranscobalamin.

OBJECTIVE: To examine the possible association of holotranscobalamin, the active fraction of serum cobalamin, with Alzheimer's disease. METHODS: 51 patients with pathologically confirmed Alzheimer's disease and 65 cognitively screened elderly controls were studied. Serum holotranscobalamin was measured by a new solid phase radioimmunoassay. RESULTS: Geometric mean levels showed no significant case-control differences for serum total cobalamin, but lower levels of holotranscobalamin in Alzheimer's disease (41.1 pmol/l) than in controls (57.1 pmol/l) (p < 0.001). The odds ratio of Alzheimer's disease was significant for low holotranscobalamin but not for low total cobalamin. CONCLUSIONS: Disturbed cobalamin status is common in Alzheimer's disease and accordingly measurement of holotranscobalamin should be considered in the assessment of cognitively impaired patients.

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PubMed2003

The validity and reliability of 6 sets of clinical criteria to classify Alzheimer's disease and vascular dementia in cases confirmed post-mortem: added value of a decision tree approach.

Data from 204 participants from the Oxford Project to Investigate Memory and Ageing, who were diagnosed post-mortem using the histopathological criteria of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), were used to assess the validity of the clinical criteria for Alzheimer's disease (AD) of the 'National Institute of Neurological and Communicative Disorders and Stroke/the Alzheimer's Disease and Related Disorders Association' (NINCDS/ADRDA). Cases who had been diagnosed as NINCDS/ADRDA 'probable AD' in life were usually confirmed at autopsy, but half of the NINCDS/ADRDA 'negative' cases were not (low specificity). It was hypothesized that the overall clinical impression may have taken precedence over the use of the actual criteria. We therefore investigated the validity and reliability of the clinical criteria using a computerized 'dementia diagnosis system' for each of 6 sets of criteria [Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), NINCDS/ADRDA and three sets of criteria specifically for vascular dementia (VaD): NINCDS-AIREN, State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC), and Vascular Cognitive Impairment (VCI)] to classify a subset (n = 96) of the cases confirmed post-mortem. The use of the computerized system significantly (p = 0.01) increased the specificity (81%, similar to sensitivity) of the NINCDS/ADRDA diagnoses, which were shown to have 'moderate' inter-rater reliability. The DSM-IV criteria had good validity for AD when compared with post-mortem confirmation and showed 'substantial' inter-rater reliability. The ADDTC and VCI criteria for VaD had good specificity (88%) and sensitivity (75%), but only for one rater. The DSM-IV and NINCDS-AIREN criteria for VaD showed poor validity and inter-rater reliability. We conclude that the forced use of decision trees through a computerized system enhances the accuracy of the clinical diagnoses of dementia.

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PubMed2002

Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men.

OBJECTIVES: To assess the association between testosterone levels and APOEepsilon4 in cases with AD and controls. METHOD: We included 61 men with definite or probable Alzheimer's disease (AD) and 55 elderly male controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA). Testosterone was measured using a competitive enzyme immunoassay (Bayer). RESULTS: We found that both low serum testosterone and the interaction between testosterone and APOEepsilon4 were associated with AD. Furthermore, testosterone levels were lower in APOEepsilon4-positive controls (mean: 11.3 nmol/L) than in controls without the allele (19.1 nmol/L). CONCLUSIONS: Low testosterone is potentially a modifiable risk factor, which may prove relevant to APOEepsilon4 carriers who are at risk of AD.

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PubMed2002

Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time.

Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. However, the effect of smaller lesions on a reaction time task has not been systematically assessed. We, therefore, used this test to examine behavioral deficits as a function of striatal dopamine loss. When injected at doses that produced striatal DA depletion <50%, 6-hydroxydopamine infused in the medial forebrain bundle produced no reliable impairment in the reaction time task. Higher doses producing > or = 60% DA depletion in the striatum produced a decrease in the percent correct responding throughout the 5 week testing period and akinetic deficits expressed by an increase in delayed responding. In addition, larger DA depletions (> or = 95%) profoundly altered motor control with decreases in percent correct responses, increases in delayed responses and increases in reaction time. These results suggest that reaction time may be a relatively sensitive measure of preclinical or subtle deficits, although it might be even more useful in quantitating the severity of depletion once overt deficits or symptoms appear and has the advantage of measuring such deficits over time to follow recovery of function. Furthermore since reaction time deficits required extensive loss of dopamine, these results are consistent with a predominant role of extrasynaptic dopamine in the mediation of relatively skilled motor tasks.

Adrenergic Agents↗
PubMed2002

Neutrophil CD11b, L-selectin and Fc IgA receptors in patients with dermatitis herpetiformis.

BACKGROUND: The skin lesions found in patients with dermatitis herpetiformis (DH) are characterized by the presence of neutrophils at the dermal papillary tips in areas where the diagnostic cutaneous IgA deposits are found. Although the presence of the skin lesions of DH is known to be associated with gluten-sensitive enteropathy, the mechanisms that control the development of skin lesions are not known. OBJECTIVES: To determine if circulating neutrophils from patients with DH have evidence of priming as shown by increased expression of CD11b, decreased expression of L-selectin and increased function of neutrophil Fc IgA receptor. METHODS: Neutrophils from 12 normal subjects and 10 DH patients with active, ongoing disease and 14 DH patients with quiescent disease activity were examined by fluorescence-activated cell sorter for expression of cell surface CD11b, L-selectin expression, Fc IgA expression (CD89) and for the function of the Fc IgA receptor by determining the binding capacity of neutrophils for monoclonal human IgA. RESULTS: Neutrophils from patients with active, ongoing DH had increased expression of CD11b when compared with patients with inactive DH or normal subjects [mean net geometric mean channel fluorescence (GMCF): active DH, 403.3; inactive DH, 237.8; normal subjects, 290.5; P < 0.05]. L-selectin expression in both groups of DH patients was significantly lower than that seen in normal subjects (mean net GMCF: active DH, 363.2; inactive DH, 375.2; normal subjects, 432.7; P < 0.05). No difference in CD89 expression was seen in any of the groups; however, the function of Fc IgA receptor was increased in patients with active DH when compared with patients with inactive DH and normal subjects. CONCLUSIONS: Neutrophils from patients with active, ongoing DH show an increased expression of CD11b, decreased expression of L-selectin and increased ability to bind IgA, consistent with a pattern of priming of the neutrophils. This priming may occur in the gut as a result of the ongoing mucosal immune response that is present in patients with DH on a gluten-containing diet and may predispose neutrophils to localize in the skin of patients with DH.

Adult↗
PubMed2002

Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease.

Reductions in regional cerebral perfusion, particularly in the posterior temporo-parietal lobes, are well recognized in Alzheimer's disease. We set out to correlate perfusion changes, using (99m)Tc-HMPAO single photon emission tomography (SPET), with the pathological stage of Alzheimer's disease. The 'Braak stage' of the distribution of neurofibrillary pathology in post-mortem brains was used to classify SPET scans taken in life from a mixed (dementia and control) elderly population into the entorhinal stage (n = 23 subjects), limbic stage (n = 30 subjects) and neocortical stage (n = 36 subjects) Alzheimer's disease pathology. The SPET scans were then registered to a common, standard Talaraich space, and single template scans produced for each pathological stage. Comparison of these templates revealed an evolution in the pattern of reduction in regional perfusion. Additional comparisons were performed using earlier SPET scans obtained 5 years before death. For comparisons between templates, a threshold of 10% perfusion change was chosen so as to be clinically relevant as well as statistically significant. Reduced perfusion appears between the entorhinal and limbic stages in the anterior medial temporal lobe, subcallosal area, posterior cingulate cortex, precuneus and possibly the supero-anterior aspects of the cerebellar hemispheres. Large posterior temporo-parietal perfusion defects then appear between the limbic and neocortical stages, before finally large frontal lobe perfusion defects. The time course of these perfusion defects appears relatively long, suggesting that perfusion changes may have scope to be a diagnostic aid in staging Alzheimer's disease in life. The reduction in anterior medial temporal lobe perfusion may have future relevance on modern high resolution SPET and PET systems and also perfusion-type MRI sequences.

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PubMed2002

Serial brain MRI at 3-6 month intervals as a surrogate marker for Alzheimer's disease.

A surrogate marker is needed for Alzheimer's disease (AD) both to aid diagnosis and to assess interventions. Despite widespread use, brain imaging markers have largely been confounded by overlap with "normal" ageing. 39 elderly subjects completed up to four serial volumetric brain MRI scans with intervals from 2.5 months to 7 months. By National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria, five subjects had probable AD, two possible AD and 32 were negative for AD, although this group included memory-impaired subjects. Total brain and ventricular volumes were measured for each scan, and rates of change for each interval calculated. The rate of change in ventricle-to-brain ratio was 15.6% per year (standard deviation (SD) 2.8%) for probable AD compared with 4.3% per year (SD 1.1%) for negative AD (p<0.001). There was no significant difference between these groups' mean ventricle-to-brain ratios measured at a single time point (p=0.25). Rates of change in brain or ventricular volume over time also differed between the two groups (p<0.001). Power calculations reveal that to detect a 20% reduction in the excess rate of atrophy of a probable AD cohort in just 6 months, with 90% power, 135 subjects would be required in each arm of a randomized placebo controlled trial. For a 30% reduction in the excess rate of atrophy, 61 subjects would be required. Rate of change analysis makes serial brain MRI a valuable surrogate marker for Alzheimer's disease. Since only 6 months or less is required between scans, this procedure has both clinical relevance and potential for monitoring interventions.

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PubMed2001

IscA, an alternate scaffold for Fe-S cluster biosynthesis.

An IscA homologue within the nif regulon of Azotobacter vinelandii, designated (Nif)IscA, was expressed in Escherichia coli and purified to homogeneity. Purified (Nif)IscA was found to be a homodimer of 11-kDa subunits that contained no metal centers or other prosthetic groups in its as-isolated form. Possible roles for (Nif)IscA in Fe-S cluster biosynthesis were assessed by investigating the ability to bind iron and to assemble Fe-S clusters in a NifS-directed process, as monitored by the combination of UV-vis absorption, Mössbauer, resonance Raman, variable-temperature magnetic circular dichroism, and EPR spectroscopies. Although (Nif)IscA was found to bind ferrous ion in a tetrahedral, predominantly cysteinyl-ligated coordination environment, the low-binding affinity argues against a specific role as a metallochaperone for the delivery of ferrous ion to other Fe-S cluster assembly proteins. Rather, a role for (Nif)IscA as an alternate scaffold protein for Fe-S cluster biosynthesis is proposed, based on the NifS-directed assembly of approximately one labile [4Fe-4S](2+) cluster per (Nif)IscA homodimer, via a transient [2Fe-2S](2+) cluster intermediate. The cluster assembly process was monitored temporally using UV-vis absorption and Mössbauer spectroscopy, and the intermediate [2Fe-2S](2+)-containing species was additionally characterized by resonance Raman spectroscopy. The Mössbauer and resonance Raman properties of the [2Fe-2S](2+) center are consistent with complete cysteinyl ligation. The presence of three conserved cysteine residues in all IscA proteins and the observed cluster stoichiometry of approximately one [2Fe-2S](2+) or one [4Fe-4S](2+) per homodimer suggest that both cluster types are subunit bridging. In addition, (Nif)IscA was shown to couple delivery of iron and sulfur by using ferrous ion to reduce sulfane sulfur. The ability of Fe-S scaffold proteins to couple the delivery of these two toxic and reactive Fe-S cluster precursors is likely to be important for minimizing the cellular concentrations of free ferrous and sulfide ions. On the basis of the spectroscopic and analytical results, mechanistic schemes for NifS-directed cluster assembly on (Nif)IscA are proposed. It is proposed that the IscA family of proteins provide alternative scaffolds to the NifU and IscU proteins for mediating nif-specific and general Fe-S cluster assembly.

Amino Acid Sequence↗
PubMed2001

Mortality in mice infected with an amyocarditic coxsackievirus and given a subacute dose of mercuric chloride.

An amyocarditic strain of coxsackievirus B3 (CVB3/0) induces heart damage when inoculated into selenium (Se)-deficient mice. Mercury (Hg), an Se antagonist, is known to aggravate viral infections. The experiments reported here assessed the effect of prior Hg treatment in mice subsequently inoculated with an amyocarditic strain of coxsackievirus. A pilot study showed that under our conditions the maximum tolerated dose of HgCl2 in uninfected mice was 6 mg HgCl2/kg body weight. In the main study, doses of 0, 3 or 6 mg HgCl2/kg body weight were administered intraperitoneally (ip) to 7-wk-old male mice fed a standard chow diet. Two hours later, half the mice were inoculated ip with CVB3/0. Ten days postinoculation, no mortality was observed in mice given only virus. In mice not given virus, 10% injected with 6 mg HgCl2/kg body weight died. On the other hand, 64% of the mice given both virus and 6 mg HgCl2/kg body weight died. Fifteen percent of the hearts from virus-infected mice given 3 mg HgCl2/kg body weight and 33% of the hearts from virus-infected mice given 6 mg HgCl2/kg body weight exhibited a higher incidence of lesions than hearts from mice-given virus alone. Moreover, viral heart titers were elevated in infected mice injected with 6 mg HgCl2/kg body weight compared to infected mice receiving no Hg. Thus, an amyocarditic coxsackievirus given to mice after a nonlethal subacute dose of Hg results in mortality, increased incidence of heart lesions, and elevated viral heart titers. These results demonstrate the important role of toxic elements in determining the severity of viral infections.

Analysis of Variance↗
PubMed2001

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study.

OBJECTIVE: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. METHODS: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. RESULTS: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of "probable" AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was "possible" AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. CONCLUSIONS: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.

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