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Biomedical subjects

K Jones

Publications and source records attributed to K Jones.

At least 37 records · Page 2Linked to original sources
PubMed2002

Oral and dermal exposure to propetamphos: a human volunteer study.

Propetamphos ((E)-O-2-isopropylcarbonyl-1-methylvinyl-O-methylethyl phosphoramidothioate) is an organophosphate pesticide (OP) and has been used as an active ingredient in sheep dip where there is the potential for significant dermal exposure during dipping. Biological monitoring of exposure to propetamphos has until recently relied on the measurement of cholinesterase activity in plasma. Following the development of a novel method for the determination of propetamphos metabolites in urine, it is now possible to biologically monitor exposure using urine samples. This paper describes a human volunteer study involving oral and dermal exposure to propetamphos.

Administration, Cutaneous↗
PubMed2002

MRI measures of entorhinal cortex vs hippocampus in preclinical AD.

BACKGROUND: MRI measures of the entorhinal cortex and the hippocampus have been used to predict which nondemented individuals with memory problems will progress to meet criteria for AD on follow-up, but their relative accuracy remains controversial. OBJECTIVES: To compare MRI measures of the entorhinal cortex and the hippocampus for predicting who will develop AD. METHODS: MRI volumes of the entorhinal cortex and the hippocampus were obtained in 137 individuals comprising four groups: 1) individuals with normal cognition both at baseline and after 3 years of follow-up (n = 28), 2) subjects with memory difficulty but not dementia both at baseline and after 3 years of follow-up (n = 73), 3) subjects with memory difficulty at baseline who were diagnosed with probable AD within 3 years of follow-up (n = 21), and 4) patients with mild AD at baseline (n = 16). RESULTS: Measures of both the entorhinal cortex and the hippocampus were different for each of the pairwise comparisons between the groups (p < 0.001) and were correlated with tests of memory (p < 0.01). However, the volume of the entorhinal cortex differentiated the subjects from those destined to develop dementia with considerable accuracy (84%), whereas the measure of the hippocampus did not. CONCLUSION: These findings are consistent with neuropathologic data showing substantial involvement of the entorhinal cortex in the preclinical phase of AD and suggest that, as the disease spreads, atrophic change develops within the hippocampus, which is measurable on MRI.

Aged↗
PubMed2002

The unilateral opaque maxillary sinus on computed tomography.

Computed tomography (CT) is the imaging method of choice for conditions that affect the paranasal sinuses. We reviewed all paranasal CT scans in the ear nose and throat (ENT) and maxillofacial surgery departments in 1 year. Of these 372 scans, unilateral opacity of the maxillary sinus was seen in 20 cases. Neoplastic disease was diagnosed in six of these, four of which were malignant. We describe the cases of neoplastic disease, particularly features of the history, examination, and scans that should alert the clinician to the possibility of sinister pathology. We emphasise the importance of nasendoscopic examination in the accurate assessment of sinonasal disease.

Adult↗
PubMed2002

Measurement of systemic oxygen uptake during low-flow anaesthesia with a standard technique vs. a novel method.

We assessed agreement between measurement of systemic oxygen uptake using the Fick-derived method, and a novel method described by Biro, based on the difference in oxygen concentrations of the delivered fresh gas and the gas circulating in the circle system. Twenty-nine patients undergoing elective cardiac surgery were studied during stable haemodynamic and ventilatory conditions. Systemic oxygen uptake was measured using the two methods in each patient before and after cardiopulmonary bypass. Limits of agreement were found to be wide (-162 to 311 ml.min-1 before bypass, and -257 to 401 ml.min-1 after bypass), indicating poor agreement between the methods. No significant difference was found between the pre- and post cardiopulmonary bypass values for each method. We conclude that the Biro method, although attractive in terms of its simplicity, is an unreliable measure of systemic oxygen uptake under these conditions.

Adult↗
PubMed2002

The influence of 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene promoter on the incidence, growth and operative risk of abdominal aortic aneurysm.

BACKGROUND: a single base pair deletion/insertion (4G/5G) polymorphism in the plasminogen activator inhibitor (PAI-1) promoter appears to influence PAI-1 synthesis (increased PAI-1 and inhibition of fibrinolysis with the 4G allele) and survival after severe trauma. OBJECTIVE: to identify whether the 4G/5G polymorphism influences the natural history of abdominal aortic aneurysm (AAA). METHODS: Four hundred and sixty patients with small AAA were genotyped for the 4G/5G polymorphism. AAA growth was assessed from serial ultrasonographic measurements, subject to linear regression analysis. Mortality following eventual elective surgery was recorded. RESULTS: the frequency of the 3 genotypes (4G4G, 4G5G and 5G5G) was in Hardy-Weinberg equilibrium and similar to that in a healthy population. The mean aneurysm growth rate was 0.37, 0.35 and 0.44 cm/year respectively for patients of 4G4G, 4G5G and 5G5G genotype respectively, p = 0.07. The 30d mortality following open elective aneurysm repair was 8% (7/87), 8% (11/145) and 0% (0/56) for patients of 4G4G, 4G5G and 5G5G genotype respectively, giving a higher mortality for those carrying a 4G allele p = 0.03. CONCLUSIONS: polymorphism of the PAI-1 gene promoter does not influence the development of AAA, although AAA growth is faster for patients of 5G5G genotype. However, this genotype (5G5G), which is associated with enhanced fibrinolysis, appears protective following open aneurysm repair. This effect of PAI-1 genotype on survival following surgery is likely to have widespread significance in vascular and general surgery.

Aged↗
PubMed2002

Biguanide-atovaquone synergy against Plasmodium falciparum in vitro.

The synergistic potential of a range of biguanides, their triazine metabolites, tetracyclines, and pyrimethamine in combination with atovaquone has been assessed. All five biguanides tested interacted synergistically with atovaquone against Plasmodium falciparum in vitro. All of the other compounds tested were either additive or antagonistic.

Animals↗
PubMed2002

Outreach health adviser in a community clinic screening programme improves management of genital chlamydia infection.

OBJECTIVE: To assess the effectiveness of an outreach health adviser on treatment, partner notification and outcome for clients diagnosed with genital chlamydia (CT) infection at a community young people's clinic. METHODS: From August 1999 to March 2000, a genitourinary medicine (GUM) based health adviser helped to develop testing and undertook outreach management of clients aged under 26 years diagnosed with CT infection. In addition to facilitating referral to GUM, she gave antibiotic treatment based on a GUM derived patient group direction to those not wishing to travel to the GUM clinic. She also advised them on contact tracing and the need for a compliance check (CC). RESULTS: Chlamydia positive tests with ligase chain reaction (LCR), on first void urine, were obtained for 62 (12.9%) of 481 female clients, one (5%) of 20 male clients, and nine (53%) of 17 male contacts of female positive cases. All 72 testing positive received their result and were treated. Two urine samples positive for CT showed positive LCR tests for gonorrhoea. Proportions of named contacts seen (67%) and reattendances for compliance checks (60%) were similar to those for women seen in GUM services. CONCLUSIONS: Health adviser input with the ability to treat can be effective in reducing the growth of identified but untreated genital chlamydia infection consequent upon community based screening. Such a strategy appears comparable with, and can add to, GUM based treatment of infection. It helps to address the need for alternative management strategies in the light of the national sexual health strategy.

Adolescent↗
PubMed2001

Characterization of surface antigen from Lyme disease spirochete Borrelia burgdorferi.

Borrelia burgdorferi, the Lyme disease spirochete, possesses a surface protein, VlsE (variable major protein-like sequence, expressed), that undergoes antigenic variation. Unlike conserved regions of other proteins involved in antigenic variation, the most conserved invariable region of VlsE is immunodominant in Lyme-disease patients. Physicochemical analyses of pure recombinant VlsE yielded the following results: The protein appeared oligomeric in solution, with a secondary structure dominated by alpha-helices. Thermal denaturation (pH 7) probed by calorimetry involved two transitions: oligomer-to-monomer conversion (around 40 degrees C) followed by protein unfolding (55 +/- 1 degrees C). Chemical denaturation monitored by far-UV circular dichroism (20 degrees C, pH 7) sensed only polypeptide unfolding and took place in a single transition (Delta G(U)(H(2)O) = 23 +/- 2 kJ/mol). VlsE did not adopt a native structure at pH 3; at pH 10 the stability was significantly reduced. Knowledge of biophysical properties of VlsE may aid in understanding the mechanism of VlsE antigenic variation in B. burgdorferi.

Amino Acid Sequence↗
PubMed2001

P-Glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance?

BACKGROUND: The multidrug transporters P-glycoprotein (P-gp) and MRP1 are functionally expressed in several subclasses of lymphocytes. HIV-1 protease inhibitors interact with both; consequently the transporters could reduce the local concentration of HIV-1 protease inhibitors and, thus, influence the selection of viral mutants. OBJECTIVES: To study the effect of the expression of P-gp and MRP1 on the transport and accumulation of HIV-1 protease inhibitors in human lymphocytes and to study the effects of specific P-gp and MRP1 inhibitors. METHODS: The initial rate and the steady-state intracellular accumulation of radiolabelled ritonavir, indinavir, saquinavir and nelfinavir was measured in three human lymphocyte cell lines: control CEM cells, CEM-MDR cells, which express 30-fold more P-gp than CEM cells, and CEM-MRP cells, which express fivefold more MRP1 protein than CEM cells. The effect of specific inhibitors of P-gp (GF 120918) and MRP1 (MK 571) was also examined. RESULTS: Compared with CEM cells, the initial rates of uptake and the steady-state intracellular concentrations of all protease inhibitors are significantly reduced in CEM-MDR cells. The intracellular concentrations of the protease inhibitors are increased upon co-administration with GF 120918, in some cases to levels approaching those in CEM cells. The intracellular concentrations of the protease inhibitors are also significantly reduced in CEM-MRP cells. Co-administration with MK -571 can partially overcome these effects. CONCLUSIONS: The overexpression of multidrug transporters significantly reduces the accumulation of protease inhibitors at this major site of virus replication, which, potentially, could accelerate the acquisition of viral resistance. Targeted inhibition of P-gp may represent an important strategy by which this problem can be overcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

C-cell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET.

Gain-of-function mutations in the gene encoding the receptor tyrosine kinase RET have been identified as the aetiological factor for multiple endocrine neoplasia type 2A (MEN2A). MEN2A is a dominantly-inherited cancer predisposition syndrome characterized by medullary thyroid carcinoma, a tumour of the calcitonin-producing thyroid C-cells. There are three isoforms of RET: RET9, RET43 and RET51, and although in vitro evidence suggests they vary in cellular transformation activities, little is known about their function in tumorigenesis in vivo. To address this, we used RET51 cDNA to construct mice in which the most frequent MEN2A mutation, Cys-634-Arg, was expressed under the control of the human calcitonin promoter (CT-2A mice). These mice developed C-cell tumours resembling human MTC and follicular tumours resembling human papillary thyroid carcinoma (PTC) depending on the founder line examined. One founder line developed compound MTC/PTC at low frequency (8%) and pancreatic cystadenocarcinoma. CT-2A mice also displayed a developmental defect in thyroid follicular structure, in which much of the thyroid was occupied by large irregular cystic follicles thought to be derived from the ultimobranchial body, a developmental precursor of the thyroid gland. The CT-2A mice will provide a suitable model to further study the effects of the MEN 2A RET mutation in vivo.

Amino Acid Substitution↗
PubMed2001

Presenilin-1-associated abnormalities in regional cerebral perfusion.

OBJECTIVE: To investigate the influence of the presenilin-1 gene (PS-1) mutation on regional cerebral perfusion, SPECT was evaluated in 57 individuals. The subjects were members of a large pedigree from Colombia, South America, many of whom carry a PS-1 mutation for early-onset AD. METHODS: Members of this large kindred who were cognitively normal and did not carry the PS-1 mutation (n = 23) were compared with subjects who were carriers of the mutation but were asymptomatic (n = 18) and with individuals with the mutation and a clinical diagnosis of AD (n = 16). Cerebral perfusion was measured in each subject using hexamethylpropyleneamine oxime SPECT. The data were analyzed in two ways: 1) Mean cerebral perfusion in each of 4320 voxels in the brain was compared among the groups using t-tests (t-maps); and 2) each individual received a weighted score on 20 vectors (factors), based on a large normative sample (n = 200), using a method known as singular value decomposition (SVD). RESULTS: Based on t-maps, subjects with the PS-1 mutation who were asymptomatic demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. Discriminant function analysis of the vector scores derived from SVD (adjusted for age and gender) accurately discriminated 86% of the subjects in the three groups (p < 0.0005). CONCLUSION: Regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of AD in carriers of the PS-1 mutation.

Adult↗
PubMed2001

Equilibrium unfolding of dimeric desulfoferrodoxin involves a monomeric intermediate: iron cofactors dissociate after polypeptide unfolding.

Here we report the conformational stability of homodimeric desulfoferrodoxin (dfx) from Desulfovibrio desulfuricans (ATCC 27774). The dimer is formed by two dfx monomers linked through beta-strand interactions in two domains; in addition, each monomer contains two different iron centers: one Fe-(S-Cys)(4) center and one Fe-[S-Cys+(N-His)(4)] center. The dissociation constant for dfx was determined to be 1 microM (DeltaG = 34 kJ/mol of dimer) from the concentration dependence of aromatic residue emission. Upon addition of the chemical denaturant guanidine hydrochloride (GuHCl) to dfx, a reversible fluorescence change occurred at 2-3 M GuHCl. This transition was dependent upon protein concentration, in accord with a dimer to monomer reaction [DeltaG(H(2)O) = 46 kJ/mol of dimer]. The secondary structure did not disappear, according to far-UV circular dichroism (CD), until 6 M GuHCl was added; this transition was reversible (for incubation times of < 1 h) and independent of dfx concentration [DeltaG(H(2)O) = 50 kJ/mol of monomer]. Thus, dfx equilibrium unfolding is at least three-state, involving a monomeric intermediate with native-like secondary structure. Only after complete polypeptide unfolding (and incubation times of > 1 h) did the iron centers dissociate, as monitored by disappearance of ligand-to-metal charge transfer absorption, fluorescence of an iron indicator, and reactivity of cysteines to Ellman's reagent. Iron dissociation took place over several hours and resulted in an irreversibly denatured dfx. It appears as if the presence of the iron centers, the amino acid composition, and, to a lesser extent, the dimeric structure are factors that aid in facilitating dfx's unusually high thermodynamic stability for a mesophilic protein.

Circular Dichroism↗
PubMed2001

Lipid-lowering interventions in managed care settings.

Effective screening, treatment, and follow-up of patients with elevated serum lipid levels is important because of the very strong association between this condition and coronary heart disease (CHD). Screening of patients with and without CHD for hyperlipidemia is not generally carried out properly by managed care organizations (MCOs) or in other settings. Primary and secondary prevention are inadequate in most patients with this condition; even in patients who are treated, lipid-lowering therapy is often not used to its full potential. These trends have been confirmed by findings in the first of a three-phase hyperlipidemia outcomes management program carried out at 27 US MCOs. The efficacy of lipid-lowering therapy can be enhanced by physician education and comprehensive, integrated quality improvement programs. The cost-effectiveness of such treatment can be improved by individualizing both drug and dose to achieve National Cholesterol Education Program goals at the lowest drug acquisition cost. The quality improvement program described and others like it have the potential to reduce the morbidity and mortality associated with CHD while decreasing the huge economic burden associated with this disease. Several such programs have been undertaken at MCOs, some with more success than others. Interventions and assessments of the type planned in phases 2 and 3 of this program can help to reduce the cost of lipid-lowering therapy without compromising cholesterol goal achievement.

Anticholesteremic Agents↗
PubMed2001

Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport.

OBJECTIVES: To investigate the intracellular accumulation of HIV protease inhibitors (PI) and to assess the effect of active transport on this accumulation. METHODS: CEM cells were incubated with a PI for 18 h and the intracellular concentration determined using cell number and radioactivity. The effect of active transport was investigated using cells expressing P-glycoprotein (CEM(VBL)) and cells expressing multidrug resistance-associated protein 1 (MRP1; CEM(E1000)). Incubations were also carried out at 4 degrees C and in the presence of 2-deoxyglucose plus rotenone to examine the effect of inhibiting active transport. RESULTS: Nelfinavir (NFV) accumulated to the greatest extent (> 80-fold) followed by saquinavir (SQV; approximately 30-fold), ritonavir (RTV; 3-7-fold) and finally indinavir (IDV; extracellular equivalent to intracellular). In CEM(VBL) cells there was a significant reduction in the intracellular accumulation of NFV, SQV and RTV and in CEM(E1000) cells there was reduced accumulation of SQV and RTV. Inhibition of active transport processes caused a reduction in SQV and RTV accumulation but had no effect on IDV accumulation in all cell types. NFV accumulation was increased in CEM(VBL) cells as a result of inhibition of active transport. CONCLUSIONS: Marked differences can be detected in the intracellular accumulation of HIV PI drugs in vitro. Both P-glycoprotein and MRP1 may play a role in limiting the intracellular concentration of the PI and active influx mechanisms may contribute to drug accumulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Enteric parasitosis in northern Thailand dairy heifers and heifer calves.

A cross-sectional study was designed to: (1) determine the prevalences of enteric parasitic infections in dairy heifers and heifer calves (Bos taurus) in northern Thailand, and (2) determine the risk factors associated with the observed prevalences of infection. A stratified random sample of 87 farms was selected for study, and fecal and blood samples were collected from 439 out of 450 heifers and heifer calves from these farms. Fecal samples were processed by floatation and modified Benedek sedimentation methods, and then examined microscopically for the presence of enteric parasitic ova. Complete blood counts typically were within the reference range (done using standard methods). The overall prevalence for enteric parasites in heifers and heifer calves was 54%; most were of trematodes (41%) and nematodes (26%). Risk-factors analysis at the farm level yielded no significant results. Increased age significantly increased the odds of enteric parasite infection (OR=1.02, 95% CI 1.01-1.04).

Animals↗
PubMed2001

Transgenic mice with cardiac-specific expression of activating transcription factor 3, a stress-inducible gene, have conduction abnormalities and contractile dysfunction.

Activating transcription factor 3 (ATF3) is a member of the CREB/ATF family of transcription factors. Previously, we demonstrated that the expression of the ATF3 gene is induced by many stress signals. In this report, we demonstrate that expression of ATF3 is induced by cardiac ischemia coupled with reperfusion (ischemia-reperfusion) in both cultured cells and an animal model. Transgenic mice expressing ATF3 under the control of the alpha-myosin heavy chain promoter have atrial enlargement, and atrial and ventricular hypertrophy. Microscopic examination showed myocyte degeneration and fibrosis. Functionally, the transgenic heart has reduced contractility and aberrant conduction. Interestingly, expression of sorcin, a gene whose product inhibits the release of calcium from sarcoplasmic reticulum, is increased in these transgenic hearts. Taken together, our results indicate that expression of ATF3, a stress-inducible gene, in the heart leads to altered gene expression and impaired cardiac function.

Activating Transcription Factor 3↗
PubMed2001

Correlates of clinic referral for early conduct problems: variable- and person-oriented approaches.

The current study utilized both variable- and person-oriented analyses to examine correlates of early disruptive behavior problems. Participants included 80 preschool boys referred to a child psychiatry clinic and diagnosed with oppositional defiant disorder (with or without attention-deficit hyperactivity disorder) and 80 case-matched normal comparison boys. The study examined four domains of correlates: vulnerable child characteristics, poor parenting practices, insecure attachment, and adverse family ecology. Results indicated that the combination of these factors provided relatively high sensitivity (81%) and specificity (85%), clearly differentiating referred from comparison boys. A dramatic increase in clinic status occurred when three or more factors were present, and specific combinations of factors were differentially predictive of conduct problems. However, no correlates were found to be either necessary or sufficient for clinic status. By maintaining the integrity of individual cases, person-oriented analyses were able to answer different questions than more traditional variable-oriented analyses. Discussion focuses on the value of person-oriented analyses for understanding heterogeneous clinical groups.

Ambulatory Care↗