Biomedical subjects

J M Harris

Publications and source records attributed to J M Harris.

At least 37 records · Page 2Linked to original sources

PubMed2001

Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function.

OBJECTIVE: To characterize immune phenotype and thymic function in HIV-1-infected adults with excellent virologic and poor immunologic responses to highly active antiretroviral therapy (HAART). METHODS: Cross-sectional study of patients with CD4 T cell rises of > or = 200 x 10(6) cells/l (CD4 responders; n = 10) or < 100 x 10(6) cells/l (poor responders; n = 12) in the first year of therapy. RESULTS: Poor responders were older than CD4 responders (46 versus 38 years; P < 0.01) and, before HAART, had higher CD4 cell counts (170 versus 35 x 106 cells/l; P = 0.11) and CD8 cell counts (780 versus 536 x 10(6) cells/l; P = 0.02). After a median of 160 weeks of therapy, CD4 responders had more circulating naive phenotype (CD45+CD62L+) CD4 cells (227 versus 44 x 10(6) cells/l; P = 0.001) and naive phenotype CD8 cells (487 versus 174 x 10(6) cells/l; P = 0.004) than did poor responders (after 130 weeks). Computed tomographic scans showed minimal thymic tissue in 11/12 poor responders and abundant tissue in 7/10 responders (P = 0.006). Poor responders had fewer CD4 cells containing T cell receptor excision circles (TREC) compared with CD4 responders (2.12 versus 27.5 x 10(6) cells/l; P = 0.004) and had shorter telomeres in CD4 cells (3.8 versus 5.3 kb; P = 0.05). Metabolic labeling studies with deuterated glucose indicated that the lower frequency of TREC-containing lymphocytes in poor responders was not caused by accelerated proliferation kinetics. CONCLUSION: Poor CD4 T cell increases observed in some patients with good virologic response to HAART may be caused by failure of thymic T cell production.

Adult↗

PubMed2001

Characterization of silane-modified immobilized gold colloids as a substrate for surface-enhanced Raman spectroscopy.

Immobilized gold colloid particles coated with a C-18 alkylsilane layer have been characterized as a substrate for surface-enhanced Raman scattering (SERS) studies of adsorption onto hydrophobic surfaces. Atomic force microscopy images, optical extinction spectra, and SERS measurements are reported as a function of accumulation of gold colloid on glass. As the metal particles become increasingly aggregated on the surface, the SERS enhancement increases until the plasmon resonance shifts to wavelengths longer than the excitation laser. The gold colloid substrates are stable and exhibit reproducible SERS enhancement. When octadecyltrimethoxysilane is self-assembled over the gold, the metal surface is protected from exposure to solution-phase species, as evidenced by the inhibition of chemisorption of a disulfide reagent to the overcoated gold surface. The results show that interactions with gold can be blocked by a silane layer so as not to significantly influence physisorption of molecules at the C-18/solution interface. The SERS enhancement from these C-18-overcoated gold substrates is reproducible for different films prepared from the same colloidal suspension; the substrates are also stable with time and upon exposure to laser irradiation.

Journal Article↗

PubMed2001

Are the estrogen receptors involved in Alzheimer's disease?

Retrospective analysis shows that women who took estrogen replacement therapy may have less risk of cognitive decline and of developing Alzheimer's disease (AD). The greater risk associated with female gender and these observations suggest that estrogen may be implicated in the aetiology of AD. Estrogen is one of a family of sex steroids that exerts many of its genomic effects through the activation of the nuclear estrogen receptors, ERalpha and ERbeta. Previously, increased risk for AD has been reported for polymorphisms in the ERalpha gene in a Japanese cohort, however, this association has not been systematically replicated. We have further investigated polymorphisms in the ERalpha and have extended this to investigate an association with a polymorphism within the ERbeta gene in an independent UK Caucasian population. We found no independent association of these polymorphisms with the risk of developing AD in the total sample nor within either gender. However, we did detect a significant interaction between the ERalpha and ERbeta polymorphisms and the risk for AD (OR=0.22 95% CI (0.05-0.88), P=0.02). If this finding can be supported in other independent studies, it may suggest that the risk for AD may be modulated only when both ERalpha and ERbeta have particular variations in their expression and/or biological activities.

Aged↗

PubMed2001

Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C.

Poly(ethyleneglycol) or PEG has proven to be of great value for a range of biomedical applications. A review the properties of PEG that lead to these applications is reported. Emphasis is placed on pharmaceutical uses of PEG--proteins, with specific discussion of the attributes of PEGylated alpha-interferon for treatment of hepatitis C. In this latter case the choice of PEG reagent is critical to the properties of the drug, and therefore a brief presentation of PEG reagents for protein PEGylation will be given. PEGylation chemistries can be divided into first- and second-generation approaches. The first-generation chemistries are generally restricted to low-molecular-weight methoxy-PEGs because of the problem of diol contamination and resulting difunctional reagents. Problems with weak linkages and side reactions are also encountered. Second-generation PEGylation reagents avoid weak linkages and side reactions. Also they can be purified to remove diol contaminants, and as a consequence, high-molecular-weight PEGs can be used. These relatively simple chemical advances have given new vigor to PEGylation as a technology. The benefits of using high-molecular-weight, second-generation PEG reagents are demonstrated by using PEG--alpha-interferon as an example. In this case it is observed that a greatly improved drug is provided for treatment of hepatitis C.

Animals↗

PubMed2001

In situ ATR-FT-IR kinetic studies of molecular transport and surface binding in thin sol-gel films: reactions of chlorosilane reagents in porous silica materials.

ATR-FT-IR spectroscopy was employed to study the kinetics of transport and binding within thin silica sol-gel films. Studies of transport of several nonbinding probe molecules n-heptane, toluene, and 2-propanol, showed that slow diffusion occurs within the micropores of the sol-gel films which could be modeled as a single-exponential accumulation in agreement with numerical models for diffusion in constricted pores. The rate of transport into the film was found to decrease for molecules that interact strongly with the silica surface, which is consistent with adsorption inhibiting the transport of molecules through the pores. In situ spectroscopic studies of surface reactions with diphenylchlorosilane (DP-SiCl) reveal that DPSiCl reacts quickly with surface water to form diphenylhydroxysilane (DPSiOH), the reactive species detected within the film. Analysis of the time-dependent infrared spectra reveals both transport and surface-binding steps in the reaction kinetics. From the magnitudes of the rate constants and the corresponding pure component spectra, it is determined that the surface-binding component is responsible for accumulation of most of the silane at the silica surface. Ex situ spectroscopic studies confirm that Si-O-Si bond formation occurs at room temperature in these sol-gel films. Studies of chlorosilane reactions at silica surfaces pretreated with triethylamine were conducted to investigate the influence of amines on this chemistry; it was determined that the amine enhances the transport of more reagent molecules to the silica surface while the intrinsic rate of the binding reaction is not significantly changed.

Journal Article↗

PubMed2001

A binocular site for contrast-modulated masking.

Contrast-modulated (CM) gratings, composed of two luminance-modulated sinusoids of similar spatial frequency, mask the detection of test sinusoids at the difference frequency. However, the mechanism underlying masking by CM gratings remains poorly understood. In this paper, we aimed to determine whether the masking of 1 cycle deg(-1) LM test gratings by a 1 cycle deg(-1) beat (formed from a pair of carriers at 8 and 9 cycles deg(-1)) occurs in monocular channels or after the site of binocular combination, or both. Threshold elevations for the detection of a 1 cycle deg(-1) test grating were obtained for a number of stimulus conditions, including: (1) dichoptic CM (both 8 and 9 cycles deg(-1) mask components presented to one eye, with the 1 cycle deg(-1) test grating to the other); (2) dichoptic variant (8 and 9 cycles deg(-1) mask gratings presented to separate eyes, with the 1 cycle deg(-1) test grating presented to one eye); (3) binocular CM (all mask and test gratings presented to both eyes). As a control, masking magnitude was also measured for LM mask gratings of similar frequency (1 cycle deg(-1)) and effective contrast (3%) to that of the beat. For both LM and CM masks, the dichoptic condition yielded threshold elevations that were similar or greater than the binocular condition. When 8 and 9 cycles deg(-1) mask components were presented to separate eyes (the dichoptic variant condition), no beat pattern was visible and no elevations in detection threshold occurred. The results demonstrate that, like LM masking, detection of a target in the presence of a CM mask does not involve purely monocular mechanisms. Further, that the site of CM masking must occur beyond the stage at which monocular matching for stereopsis takes place. This is consistent with other studies which suggest that dichoptic masking is contingent on stereo matching, and thus occurs relatively late in the hierarchy of binocular visual processing.

Contrast Sensitivity↗

PubMed2001

Filling-in the details on perceptual fading.

We examined the perceptual disappearance (or 'filling in') of a peripheral target surrounded by dynamic texture. Targets defined by different visual attributes were used to explore the importance of target properties in determining the time-course of fading. Introducing luminance-, motion- or direction-contrast between the target and background increased the time-to-fade. For motion contrast, this was related to target visibility. Targets defined by a difference of texture from the background took longer to fade than those defined by a difference of motion. This might correspond to activity in different visual areas, or could be due to different visibilities in each case.

Adaptation, Physiological↗

PubMed2001

Environmental associations with eczema in early life.

BACKGROUND: Although atopic eczema (AE) is a common disease, little is known about its causes. OBJECTIVES: To investigate the role of dietary and environmental factors associated with the development of AE by the age of 2 years. METHODS: A cohort of children was recruited before birth from a consecutive series of newly pregnant mothers presenting for antenatal care at three general practices in Ashford, Kent, U.K. Data up to the age of 2 years were available for 624 (97%) of the original cohort. AE was defined using components of the U.K. diagnostic criteria for AE, maternal report of doctor-diagnosed eczema and maternally reported eczema. Exposures of interest were family history of allergic disease, dietary and breastfeeding patterns, family size and exposure to indoor domestic allergens. RESULTS: The cumulative prevalence of AE using the U.K. diagnostic criteria was 14% (95% confidence interval, CI 11-17%). The prevalence of maternally reported doctor-diagnosed eczema was much higher (31%, 95% CI 27-35%) and almost half (45%) the mothers reported that their child had ever had eczema (95% CI 41-49%). The relationship between parental atopy, parental history of allergic disease and the child's eczema was consistently stronger for the mothers than the fathers. There was a marked increase in the prevalence of eczema with increasing maternal education and in less crowded homes, associations that remained significant after controlling for other factors. CONCLUSIONS: The associations with environmental factors are consistent with the hypothesis that more crowded houses, increased family size and birth order, which may possibly increase early exposure to infections, may offer protection from subsequent development of eczema.

Adult↗

PubMed2001

The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain.

Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A -48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the -48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Abeta(40), Abeta(42(43)), and total Abeta load in AD brains. The -48 CC genotype was associated with 47% greater total Abeta load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Abeta load.

Age of Onset↗

PubMed2001

Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function.

The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse target tissues. Here we report AR gene mutations identified in human prostate cancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues (668)QPIF(671) at the boundary of the hinge and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fold increased activity compared with wild-type AR in response to dihydrotestosterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand binding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of patients. Homology modeling indicates that amino acid residues (668)QPIF(671) form a ridge bordering a potential protein-protein interaction surface. The naturally occurring AR gene mutations reported in this study result in decreased hydrophobicity of this surface, suggesting that altered receptor-protein interaction mediates the precocious activity of the AR variants.

Adenocarcinoma↗

PubMed2001

Occupational distribution and geographic clustering of deaths certified to be cryptogenic fibrosing alveolitis in england and wales.

STUDY OBJECTIVES: The etiology of cryptogenic fibrosing alveolitis (CFA) remains largely obscure, although a 1996 report suggested an increased risk from occupational exposure to metal and wood dusts. Using data from death certificates in England and Wales, we sought evidence of any relationship between occupation and CFA and of the extent of any temporospatial clustering of place of birth and place of death as possible evidence of a geographically related environmental factor. DESIGN AND SETTING: Data on occupation and address (postal code) were obtained from certificates of men and women dying as a result of CFA between 1981 and 1990 and were compared with national mortality statistics. Place of birth data were extracted from certificates for deaths between 1993 and 1995, the only available years, and were compared with national birth statistics. MEASUREMENTS AND RESULTS: Standardized mortality ratios (SMRs) were raised (p<0.05) in the following four occupational groups: members of the armed forces (SMR, 217.8); miners and quarrymen (SMR, 142.0); service, sports, and recreation workers (SMR, 118.6); and electrical and electronic workers (SMR, 146.6). Of these four groups, the latter group might be worth testing in a future study. There was statistical evidence of geographic clustering in postal code sectors for the recorded place of death, but the high-rate areas were different in men and women. Deaths were increased for those subjects born in urban areas, although these did not follow a clear geographic pattern. CONCLUSIONS: Overall, these analyses provide little evidence of any important contribution from environmental factors to the etiology of CFA and suggest that more consideration be given to alternative concepts of causation.

Adolescent↗

PubMed2001

Pegylation: a novel process for modifying pharmacokinetics.

The use of liposomal carriers and the modification of therapeutic molecules through the attachment of poly(ethylene glycol) [PEG] moieties ('pegylation') are the most common approaches for enhancing the delivery of parenteral agents. Although 'classical' liposomes (i.e. phospholipid bilayer vehicles) have been effective in decreasing the clearance of encapsulated agents and in passively targeting specific tissues, they are associated with considerable limitations. Pegylation may be an effective method of delivering therapeutic proteins and modifying their pharmacokinetic properties, in turn modifying pharmacodynamics, via a mechanism dependent on altered binding properties of the native protein. Pegylation reduces renal clearance and, for some products, results in a more sustained absorption after subcutaneous administration as well as restricted distribution. These pharmacokinetic changes may result in more constant and sustained plasma concentrations, which can lead to increases in clinical effectiveness when the desired effects are concentration-dependent. Maintaining drug concentrations at or near a target concentration for an extended period of time is often clinically advantageous, and is particularly useful in antiviral therapy, since constant antiviral pressure should prevent replication and may thereby suppress the emergence of resistant variants. Additionally, PEG modification may decrease adverse effects caused by the large variations in peak-to-trough plasma drug concentrations associated with frequent administration and by the immunogenicity of unmodified proteins. Pegylated proteins may have reduced immunogenicity because PEG-induced steric hindrance can prevent immune recognition. Two PEG-modified proteins are currently approved by the US Food and Drug Administration; several others, including cytokines such as interferon-alpha (IFNalpha), growth factors and free radical scavengers, are under development. Careful assessment of various pegylated IFNalpha products suggests that pegylated molecules can be differentiated on the basis of their pharmacokinetic properties and related changes in pharmacodynamics. Because the size, geometry and attachment site of the PEG moiety play a crucial role in determining these properties, therapeutically optimised agents must be designed on a protein-by-protein basis.

Drug Delivery Systems↗

PubMed2001

Development of pegylated interferons for the treatment of chronic hepatitis C.

The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound. A PEG-protein conjugate is formed by first activating the PEG moiety so that it will react with, and couple to, the protein. PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent innovation in PEG technology, involves the coupling of a 30kD (or less) mPEG to lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weight may account for the restricted volume of distribution seen with drugs utilising these reagents. Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatment of severe combined immunodeficiency disease, pegaspargase for the treatment of various leukaemias, and pegylated interferon-alpha for chronic hepatitis C virus infections. As illustrated in the case of the 2 pegylated interferon-alphas, all pegylated proteins are not equal. The choice of PEG reagent and coupling chemistry is critical to the properties of the PEG-protein conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the strength of the covalent attachment of PEG to therapeutic protein.

Antiviral Agents↗

PubMed2001

Can Internet-based continuing medical education improve physicians' skin cancer knowledge and skills?

We sought to determine whether an Internet-based continuing medical education (CME) program could improve physician confidence, knowledge, and clinical skills in managing pigmented skin lesions. The CME program provided an interactive, customized learning experience and incorporated well-established guidelines for recognizing malignant melanoma. During a 6-week evaluation period, 354 physicians completed the on-line program as well as a pretest and an identical posttest. Use of the CME program was associated with significant improvements in physician confidence, correct answers to a 10-question knowledge test (52% vs 85% correct), and correct answers to a 15-question clinical skills test (81% vs 90% correct). We found that the overall improvement in clinical skills was due to a marked increase in specificity and a small decrease in sensitivity for evaluating pigmented lesions. User satisfaction was extremely high. This popular and easily distributed online CME program increased physicians' confidence and knowledge of skin cancer. Remaining challenges include improving the program to increase physician sensitivity for evaluating pigmented lesions while preserving the enhanced specificity.

Computer-Assisted Instruction↗

PubMed2001

Stereotactic breast biopsy: a six-year surgical experience.

A retrospective review was done of all stereotactic breast biopsies performed at the Central Baptist Hospital Breast Center from February 1994 through December 1999. A total of 1,080 biopsies were performed in 1,026 patients, all by surgeons working independently. Masses were biopsied in 54% and calcifications in 40%. Eighteen percent of biopsies were malignant. The most common benign diagnosis was fibrocystic disease (72%), followed by fibroadenoma (19%), lymph node (2%), and papilloma (2%). The most common malignant diagnosis was invasive ductal carcinoma (40%) followed by ductal carcinoma in situ (32%) and mixed invasive and in situ ductal carcinoma (19%). A prebiopsy BI-RADS mammographic Category III was associated with a 2% incidence of malignancy; Category IV--17%; Category V--90%. Atypical ductal hyperplasia on stereotactic biopsy was upgraded to a malignant diagnosis after reexcision in 19% of the cases. The false-negative rate was 0.4% (sensitivity 99%) and the complication rate was 3%, mostly related to bleeding. Stereotactic biopsy is a safe and accurate technique for the minimally-invasive diagnosis of abnormal mammograms.

Adult↗

PubMed2001

Collocation of androgen receptor gene mutations in prostate cancer.

Consistent with both the development of the normal prostate gland and prostate tumorigenesis being dependent on testicular androgens, targeting the androgen-signaling axis (i.e., androgen ablation therapy) remains the predominant treatment regime for patients with metastatic prostate cancer. Although there is a very good initial response to androgen ablation, these treatments are essentially palliative. Recent evidence suggests that treatment failure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. A consistent finding is that androgen receptor (AR) gene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result in decreased specificity of ligand-binding and inappropriate receptor activation by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence and AF-2, two discrete regions of the ligand-binding domain critical for androgen signaling, we recently proposed that collocation of mutations identified in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-amino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. AR gene mutations have also been identified that collocate to areas in the DNA-binding domain, to the NH(2)-terminal transactivation domain, and to the hinge region in prostate tumors. In nearly every case, missense mutations in the AR gene identified in prostate cancer that collocate to discrete regions of the receptor contribute to altered androgen signaling and provide a potential mechanism to explain the reemergence of tumor growth during the course of hormone ablation therapies.

Androgens↗

PubMed2000

Founder's Award, Society for Biomaterials. Sixth World Biomaterials Congress 2000, Kamuela, HI,May 15-20, 2000. Really smart bioconjugates of smart polymers and receptor proteins.

Over the past 18 years we have been deeply involved with the synthesis and applications of stimuli-responsive polymer systems, especially polymer-biomolecule conjugates. This article summarizes our work with one of these conjugate systems, specifically polymer-protein conjugates. We include conjugates prepared by random polymer conjugation to lysine amino groups, and also those prepared by site-specific conjugation of the polymer to specific amino acid sites that are genetically engineered into the known amino acid sequence of the protein. We describe the preparation and properties of thermally sensitive random conjugates to enzymes and several affinity recognition proteins. We have also prepared site-specific conjugates to streptavidin with temperature-sensitive polymers, pH-sensitive polymers, and light-sensitive polymers. The preparation of these conjugates and their many fascinating applications are reviewed in this article.

Acrylamides↗

PubMed2000

An outbreak of asthma in a modern detergent factory.

The striking decrease in the occurrence of protease-induced occupational asthma in the detergent Industry has been attributed to enzyme encapsulation. We report an outbreak of asthma, at least equal in size to those reported in the 1960s, in a modem European factory which has exclusively used encapsulated enzymes. A survey revealed that enzyme sensitisation and work-related respiratory symptoms were positively correlated with airborne enzyme exposure. We suggest that encapsulation alone is insufficient to prevent enzyme-Induced allergy and asthma.

Adolescent↗