Biomedical subjects

Richard Jones

Publications and source records attributed to Richard Jones.

At least 19 recordsLinked to original sources

PubMed2006

Recoverable cognitive dysfunction at hospital admission in older persons during acute illness.

BACKGROUND: While acute illness and hospitalization represent pivotal events for older persons, their contribution to recoverable cognitive dysfunction (RCD) has not been well examined. OBJECTIVE: Our goals were to estimate the frequency and degree of RCD in an older hospitalized cohort; to examine the relationship of RCD with delirium and dementia; and to determine 1-year cognitive outcomes. DESIGN: Prospective cohort study. PARTICIPANTS: Four hundred and sixty patients aged > or =70 years drawn from consecutive admissions to an academic hospital. MEASUREMENTS: Patients underwent interviews daily during hospitalization and at 1 year. The primary outcome was RCD, defined as an admission Mini-Mental State Examination (MMSE) score that improved by 3 or more points by discharge. RESULTS: Recoverable cognitive dysfunction occurred in 179 of 460 (39%) patients, with MMSE impairment at baseline ranging from 3 to 13 points (median=5.0 points). The majority of cases were not characteristic of either delirium or dementia, as 144 of 179 (80%) cases did not meet criteria for delirium, and 133 of 164 (81%) cases did not meet criteria for dementia at baseline. In multivariable analysis controlling for baseline MMSE level, 3 factors were predictive of RCD: higher educational level, preadmission functional impairment, and higher illness severity. At 1 year, further improvement in MMSE score occurred in 38 of 92 (41%) patients with RCD. Recoverable cognitive dysfunction was independently predictive of 1-year mortality with an adjusted odds ratio of 1.82 (95% confidence interval [95% CI] 1.03 to 3.20). CONCLUSIONS: Acute illness is accompanied by a high rate of RCD that is neither characteristic of delirium or dementia. Our observations underscore the reversible nature of this cognitive dysfunction with continued improvement over the ensuing year, and highlight the potential clinical implications of this under-recognized phenomenon.

Activities of Daily Living↗

PubMed2006

The effects of the ACTIVE cognitive training trial on clinically relevant declines in health-related quality of life.

OBJECTIVES: The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study used three cognitive interventions (memory, reasoning, or speed of processing) in order to improve cognitive abilities. In this article, we evaluate ACTIVE's ability to avoid extensive decline in health-related quality of life (HRQoL). METHODS: ACTIVE enrolled 2,802 adults aged 65 or older and randomized them into one of three cognitive interventions or a no-contact control group. Researchers obtained data on 2,147 participants at the 24-month follow-up. We measured HRQoL by using the eight Short Form-36 scales, and we defined clinically relevant decline on each as a drop of 0.5 standard deviations from baseline. We defined extensive HRQoL decline as clinically relevant drops on four or more Short Form-36 scales, and we assessed this by using multiple logistic regression methods that adjusted for sociodemographic, cognitive, and health status covariates, and incorporated propensity score derived weights in order to adjust for potential attrition bias. RESULTS: We found that 25.0% of ACTIVE participants had extensive HRQoL decline. Participants in the speed-of-processing intervention arm were less likely to have extensive HRQoL decline (adjusted odds ratio = 0.643; p =.004) compared with controls, and participants in the memory and reasoning arms were equivalent to controls (adjusted odds ratios = 1.149 and 1.014, respectively; ps =.322 and.919, respectively). DISCUSSION: Although all three intervention arms improved cognitive ability, only the speed-of-processing arm protected against extensive clinically relevant decline in HRQoL.

Aged↗

PubMed2006

Evaluation of proinflammatory cytokines and inflammation markers as biomarkers for the action of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers.

AIMS: Thiazolidinediones (TZDs) not only enhance cellular glucose transport but are reported to have potent anti-inflammatory effects. These effects may play an important role in the insulin sensitizing mechanism, and possibly precede the effects on parameters of glucoregulation. We sought to investigate whether these anti-inflammatory effects could yield early responding biomarkers for TZD action in Type 2 diabetes mellitus (T2DM) patients and healthy volunteers (HV) to expedite early clinical development of novel compounds. METHODS: We investigated the timing of treatment effects on several proinflammatory cytokines and markers of inflammation in comparison with effects on typical measures of glucoregulation in T2DM patients and HV receiving rosiglitazone 4 mg or placebo twice daily for 6 weeks. RESULTS: We found a significant reduction in interleukin (IL)-6 [-39.4%, confidence interval (CI) - 60.0, - 8.2] and white blood cell count (-18.4%, CI - 30.2, - 4.5) after 4 weeks of treatment in the T2DM group. These anti-inflammatory effects did not precede the effects on typical parameters of glucoregulation in the T2DM group and there was no significant anti-inflammatory response in the HV group. CONCLUSION: We could not identify biomarkers that precede the effects of rosiglitazone on parameters of glucoregulation in T2DM or that have a significant response in HV. However, the IL-6 response observed in this study indicates a potential role for this cytokine as complementary biomarker in clinical 'proof of concept' studies with novel TZDs.

Adult↗

PubMed2005

Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.

Case-Control Studies↗

PubMed2005

Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials.

Melatonin has been proposed as a treatment for Alzheimer's disease based on the demonstration of antioxidant and "anti-amyloid" effects in vitro and in vivo. Chronic melatonin therapy in old, amyloid plaque-bearing transgenic mice was studied. Tg2576 mice started melatonin treatment at 14 months of age. After 4 months of treatment, there were no differences between untreated and melatonin-treated mice in cortical levels of soluble, formic acid extracted, or histologically detectable beta amyloid (Abeta), nor in brain levels of lipid peroxidation product (total 8,12-isoprostane F(2alpha)-VI), despite marked elevations in plasma melatonin. We conclude that melatonin fails to produce anti-amyloid or antioxidant effects when initiated after the age of amyloid plaque deposition. These findings diminish the possibility that melatonin will be useful for the treatment of established Alzheimer's disease.

Aging↗

PubMed2005

A continuous-wave Raman silicon laser.

Achieving optical gain and/or lasing in silicon has been one of the most challenging goals in silicon-based photonics because bulk silicon is an indirect bandgap semiconductor and therefore has a very low light emission efficiency. Recently, stimulated Raman scattering has been used to demonstrate light amplification and lasing in silicon. However, because of the nonlinear optical loss associated with two-photon absorption (TPA)-induced free carrier absorption (FCA), until now lasing has been limited to pulsed operation. Here we demonstrate a continuous-wave silicon Raman laser. Specifically, we show that TPA-induced FCA in silicon can be significantly reduced by introducing a reverse-biased p-i-n diode embedded in a silicon waveguide. The laser cavity is formed by coating the facets of the silicon waveguide with multilayer dielectric films. We have demonstrated stable single mode laser output with side-mode suppression of over 55 dB and linewidth of less than 80 MHz. The lasing threshold depends on the p-i-n reverse bias voltage and the laser wavelength can be tuned by adjusting the wavelength of the pump laser. The demonstration of a continuous-wave silicon laser represents a significant milestone for silicon-based optoelectronic devices.

Journal Article↗

PubMed2005

An all-silicon Raman laser.

The possibility of light generation and/or amplification in silicon has attracted a great deal of attention for silicon-based optoelectronic applications owing to the potential for forming inexpensive, monolithic integrated optical components. Because of its indirect bandgap, bulk silicon shows very inefficient band-to-band radiative electron-hole recombination. Light emission in silicon has thus focused on the use of silicon engineered materials such as nanocrystals, Si/SiO2 superlattices, erbium-doped silicon-rich oxides, surface-textured bulk silicon and Si/SiGe quantum cascade structures. Stimulated Raman scattering (SRS) has recently been demonstrated as a mechanism to generate optical gain in planar silicon waveguide structures. In fact, net optical gain in the range 2-11 dB due to SRS has been reported in centimetre-sized silicon waveguides using pulsed pumping. Recently, a lasing experiment involving silicon as the gain medium by way of SRS was reported, where the ring laser cavity was formed by an 8-m-long optical fibre. Here we report the experimental demonstration of Raman lasing in a compact, all-silicon, waveguide cavity on a single silicon chip. This demonstration represents an important step towards producing practical continuous-wave optical amplifiers and lasers that could be integrated with other optoelectronic components onto CMOS-compatible silicon chips.

Journal Article↗

PubMed2005

The search for genenotype/phenotype associations and the phenome scan.

All the approaches to the search for genotype/phenotype associations have their share of problems. Comparing the genome scan and candidate gene approaches, the former makes fewer assumptions at the genetic level or about mechanism but has greater statistical difficulties while the latter partially solves the statistical problem but makes more assumptions at both genetic and mechanistic levels. Among current difficulties is a lack of information about the nature of gene variant/phenotype associations: the frequency with which different classes of gene or sequence are involved; the type of genetic variation most commonly involved; the appropriate genetic models to apply to analysis. The overarching problem is that of multiple testing, one solution to which is to integrate genetic information to create a smaller number of compound variables. At the other end of the scale, decisions about the level of complexity at which to pitch the identification of phenotypes also affect the multiple testing problem: whether to pitch them at the level of disease outcomes, or at any of the multiple levels of intermediate phenotypes or traits. The third issue is how best to deal with gene/gene or gene/environment interactions, or whether to ignore them. Only as more genotype/phenotype associations emerge, by whatever means, will the numbers of results allow these questions to be answered. We describe here a new approach to genotype/phenotype association studies, the phenome scan, in which dense phenotypic information in human cohorts is scanned for associations with individual genetic variants. We believe that this approach can generate data that will be useful in answering generic questions about genotype/phenotype associations as well as in discovering novel ones.

Environmental Exposure↗

PubMed2005

Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent Actimid (CC-4047) and their relationship with venous thrombosis.

We evaluated the serum/plasma levels of cytokines [interleukin (IL)-6, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta2] and markers of coagulation, fibrinolysis, endothelial and platelet activation during the first 4 wk of treatment with the thalidomide analogue Actimid (CC-4047) in 15 patients with relapsed/refractory myeloma. There was evidence of activation of endothelium (soluble vascular cell adhesion molecule, sVCAM), coagulation (prothrombin fragment 1 + 2, PF1 + 2) and fibrinolysis (D-dimers) but no evidence of platelet activation or endothelial cell damage in myeloma patients. These parameters were not affected by the use of CC-4047. Three of four patients with baseline D-dimers levels >500 microg/L subsequently developed deep vein thrombosis (DVT). The hypothesis that D-dimer level >500 microg/L may predict for those patients most at risk of thromboembolism with multiple myeloma undergoing treatment is worthy of further study.

Aged↗

PubMed2005

Excess post-exercise oxygen consumption following continuous and interval cycling exercise.

The purpose of this investigation was to examine the effect of interval (INT) and continuous (CON) cycle exercise on excess post-exercise oxygen consumption (EPOC). Twelve males first completed a graded exercise test for VO2max and then the two exercise challenges in random order on separate days approximately 1 wk apart. The INT challenge consisted of seven 2 min work intervals at 90% VO2max, each followed by 3 min of relief at 30% VO2max. The CON exercise consisted of 30 to 32 min of continuous cycling at 65% VO2max. Gas exchange and heart rate (HR) were measured for 30 min before, during, and for 2 h post-exercise. Three methods were used to analyze post-exercise oxygen consumption and all produced similar results. There were no significant differences in either the magnitude or duration of EPOC between the CON and INT protocols. HR, however, was higher (P < 0.05) while respiratory exchange ratio (RER) was lower (P < 0.05) following INT. These results indicate that when total work was similar, the magnitude and duration of EPOC were similar following CON or INT exercise. The differences in HR and RER during recovery suggest differential physiological responses to the exercise challenges.

Adult↗

PubMed2005

Inhaled nitric oxide treatment of patients with pulmonary tuberculosis evidenced by positive sputum smears.

Endogenous nitric oxide (NO) has antimycobacterial properties. We tested the hypothesis that exogenous (inhaled) NO can be safely delivered and can accelerate airway disinfection for pulmonary tuberculosis patients treated with standard therapy. Exogenous NO administered at 80 ppm for 72 h can be safely delivered but does not accelerate airway disinfection.

Administration, Inhalation↗

PubMed2005

Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.

Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK beta-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight.

Adult↗

PubMed2004

Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch.

Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-A(s)/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 x SJL)F(1) mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 x SJL/J)F(1) mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-beta3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.

Amino Acid Sequence↗

PubMed2004

A high-speed silicon optical modulator based on a metal-oxide-semiconductor capacitor.

Silicon has long been the optimal material for electronics, but it is only relatively recently that it has been considered as a material option for photonics. One of the key limitations for using silicon as a photonic material has been the relatively low speed of silicon optical modulators compared to those fabricated from III-V semiconductor compounds and/or electro-optic materials such as lithium niobate. To date, the fastest silicon-waveguide-based optical modulator that has been demonstrated experimentally has a modulation frequency of only approximately 20 MHz (refs 10, 11), although it has been predicted theoretically that a approximately 1-GHz modulation frequency might be achievable in some device structures. Here we describe an approach based on a metal-oxide-semiconductor (MOS) capacitor structure embedded in a silicon waveguide that can produce high-speed optical phase modulation: we demonstrate an all-silicon optical modulator with a modulation bandwidth exceeding 1 GHz. As this technology is compatible with conventional complementary MOS (CMOS) processing, monolithic integration of the silicon modulator with advanced electronics on a single silicon substrate becomes possible.

Journal Article↗

PubMed2004

Myelin oligodendrocyte glycoprotein-35-55 peptide induces severe chronic experimental autoimmune encephalomyelitis in HLA-DR2-transgenic mice.

The use of HLA class II-transgenic (Tg) mice has facilitated identification of antigenic T cell epitopes that may contribute to inflammation in T cell-mediated diseases such as rheumatoid arthritis and multiple sclerosis (MS). In this study, we compared the encephalitogenic activity of three DR2-restricted myelin determinants [mouse (m) myelin oligodendrocyte glycoprotein (MOG)-35-55, human (h)MOG-35-55 and myelin basic protein (MBP)-87-99] in Tg mice expressing the MS-associated DR2 allele, DRB1*1501. We found that mMOG-35-55 peptide was strongly immunogenic and induced moderately severe chronic experimental autoimmune encephalomyelitis (EAE) with white matter lesions after a single injection in Freund's complete adjuvant followed by pertussis toxin. hMOG-35-55 peptide,which differs from mMOG-35-55 peptide by a proline for serine substitution at position 42, was also immunogenic, but not encephalitogenic, and was only partially cross-reactive with mMOG-35-55. In contrast, MBP-87-99, which can induce EAE in double-Tg mice expressing both HLA-DR2 and a human MBP-specific TCR, was completely non-encephalitogenic in HLA-DR2-Tg mice lacking the human TCR transgene. These findings demonstrate potent encephalitogenic activity of the mMOG-35-55 peptide in association with HLA-DR2, thus providing a strong rationale for further study of hMOG-35-55 peptide as a potential pathogenic determinant in humans.

Animals↗

PubMed2004

In utero hematopoietic stem cell transplantation with haploidentical donor adult bone marrow in a canine model.

OBJECTIVE: Chimerism can be achieved in a canine model of in utero bone marrow transplantation with > or =1 x 10(8) CD34(+) haploidentical donor cells per kilogram without graft-versus-host disease. STUDY DESIGN: In utero bone marrow transplantation was performed by ultrasound-guided intraperitoneal infusion in 30- to 41-day-old canines with CD34(+) selected cells from paternal bone marrow at doses of 1.3 x 10(8) to 2.5 x 10(10) CD34(+) cells/kg. A method for marking control littermates was developed with intraperitoneal ethiodol. Postnatal studies included histologic, fluorescent in situ hybridization canine Y probe, and polymerase chain reaction-based chimerism analyses. RESULTS: Term survival was 86% to 100% for transplantations > or =34 days versus 14% and 43% at 30 and 31 days. Microchimerism (<1%) was demonstrated in tissues from 4 informative litters that included thymus, liver, skin, spleen, and intestine. Neither gestational age nor donor CD34 cell dosage altered the level of engraftment in these experiments. There was no evidence of graft-versus-host disease. CONCLUSION: In utero bone marrow transplantation in a canine model achieves microchimerism with high CD34(+) cell doses.

Animals↗

PubMed2004

Home care quality indicators (HCQIs) based on the MDS-HC.

PURPOSE: This study aimed to develop home care quality indicators (HCQIs) to be used by a variety of audiences including consumers, agencies, regulators, and policy makers to support evidence-based decision making related to the quality of home care services. DESIGN AND METHODS: Data from 3,041 Canadian and 11,252 U.S. home care clients assessed with the Minimum Data Set-Home Care (MDS-HC) were used to evaluate a series of indicators suggested by international experts and by focus groups conducted in Canada and the United States. Risk adjustment methods were derived and validated using data from Ontario and Michigan. RESULTS: Of the 73 original candidate HCQIs, 22 were retained for the final list of recommended indicators. All but three indicators include risk adjusters based on individual-level covariates. An agency-level risk adjustment was developed to correct for selection and ascertainment bias. IMPLICATIONS: The HCQIs are new tools providing a first step along the path of quality improvement for home care. These indicators can provide high-quality evidence on performance at the agency level and on a regional basis.

Aged↗

PubMed2004

Isolated soy protein consumption reduces urinary albumin excretion and improves the serum lipid profile in men with type 2 diabetes mellitus and nephropathy.

Soy protein was shown to exhibit several beneficial effects on renal function in nondiabetic patients with nephropathy, and to improve serum lipids. This study examined the effects of isolated soy protein consumption on urinary albumin excretion, serum lipids, plasma amino acids, and isoflavones in diabetic patients with nephropathy. Male patients (n = 14) with type 2 diabetes and nephropathy were followed in a crossover design for 7 mo. The study comprised two 8-wk intervention periods, placed between a 4-wk lead-in and two 4-wk washout periods. In the 2 intervention periods, 0.5 g/(kg. d) of the dietary protein was provided as either isolated soy protein (ISP) or casein, in random order. Blood and urine samples were collected at the beginning and end of each period. Data were analyzed by multiple linear regression for a repeated-measure design. ISP consumption led to changes of -9.5% in urinary albumin excretion (P < 0.0001), -0.45 in the total-to-HDL-cholesterol ratio (P < 0.05), -0.20 in the LDL-to-HDL cholesterol ratio (P < 0.05), and +4.3% in HDL cholesterol (P = 0.0040). Plasma arginine concentrations, the arginine-to-lysine ratio, and plasma isoflavone concentrations were higher after ISP consumption (P < 0.05). Urinary albumin excretion was negatively correlated with plasma total isoflavones (rho = -0.441), daidzein (rho = -0.326), and O-desmethylangolesin (rho = -0.389) (P < 0.05). The findings indicate that isolated soy protein consumption improves several markers that may be beneficial for type 2 diabetic patients with nephropathy.

Aged↗