Search PubMed⌕ Search

Biomedical subjects

J A Knight

Publications and source records attributed to J A Knight.

At least 19 recordsLinked to original sources
PubMed2006

Functional characterization of novel presenilin-2 variants identified in human breast cancers.

We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer's disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Abeta(42)/Abeta(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.

Alleles↗
PubMed2006

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

Adolescent↗
PubMed2006

The role of self-defined race/ethnicity in population structure control.

Population-based association studies are powerful tools for the genetic mapping of complex diseases. However, this method is sensitive to potential confounding by population structure. While statistical methods that use genetic markers to detect and control for population structure have been the focus of current literature, the utility of self-defined race/ethnicity in controlling for population structure has been controversial. In this study of 1334 individuals, who self-identified as either African American, European American or Hispanic, we demonstrated that when the true underlying genetic structure and the self-defined racial/ethnic groups were roughly in agreement with each other, the self-defined race/ethnicity information was useful in the control of population structure.

Black or African American↗
PubMed2005

Variation of long-lived free radicals responsible for the EPR native signal in bone of aged or diseased human females and ovariectomized adult rats.

The purpose of this study was to gain insights into the variations seen in the electron paramagnetic resonance (EPR) spectroscopy of the native signals of teeth and bones used for retrospective dosimetry measurements. We determined that changes occur in the long-lived free radicals responsible for the native signal of cortical bone in aging or diseased human females and aged ovariectomized rats. This was done by measuring the magnitude of the broad (BC) and narrow (NC) components of the native EPR signal of bone following chemical extraction, aging, crushing and thermal annealing. Bone from the upper midshaft of femora of young (17-34 years old, n=5) and elderly (70-92 years old, n=18) females was examined. The results showed that the elderly women had significantly higher BC than the younger women (P<0.01). A similar interpretation was made of the data from an aging female rat osteoporosis model. The results for the NC signals were similar. Finally, dramatic decreases in both NC and BC signals were seen in HIV positive and uncontrolled diabetic (one each) patients indicating the need for studying this signal for a broad spectrum of metabolic disorders. Experiments were performed which strongly indicate that iron liganded with organic molecules is the source of the BC signal. Finally, the accuracy achieved in this study indicates that resolving the dosimetric signal (g=2.0018) should be improved by subtraction of the deconvoluted NC and BC signals from the original spectrum.

Adolescent↗
PubMed2003

Changes in median nerve somatosensory transmission and motor output following transient deafferentation of the radial nerve in humans.

OBJECTIVE: To determine if transient anaesthetic deafferentation of the radial nerve would lead to alterations in processing of early somatosensory evoked potentials (SEPs) from the median nerve or alter cortico-motor output to the median nerve innervated abductor pollicis brevis (APB) muscle. METHODS: Spinal, brainstem, and cortical SEPs to median nerve stimulation were recorded before, during and after ipsilateral radial nerve block with local anaesthesia. Motor evoked potentials (MEPs) and motor cortex output maps were recorded from the APB muscle. RESULTS: There were no significant changes to most early SEP peaks. The N30 peak, however, showed a significant increase in amplitude, which remained elevated throughout the anaesthetic period, returning to baseline once the anaesthetic had completely worn off. MEP amplitude of the median nerve innervated APB muscle was significantly decreased during the radial nerve blockade. There was also a significant alteration in the APB optimal site location, and a small but significant decrease in the silent period during the radial nerve blockade. CONCLUSIONS: Transient anaesthetic deafferentation of the radial nerve at the elbow leads to a rapid modulation of cortical processing of median nerve input and output. These changes suggest an overall decrease in motor cortex output to a median nerve innervated muscle not affected by the radial nerve block, occurring concomitantly with an increased amplitude of the median nerve generated N30 SEP peak, thought to represent processing in the supplementary motor area (SMA). Independent subcortical connections to the SMA are thought to contribute to the N30 response observed in this study. Unmasking of pre-existing but latent cortico-cortical and/or thalamo-cortical connections may be the mechanism underlying the cortical SEP increases observed following radial nerve deafferentation. SIGNIFICANCE: Transient deafferentation of the radial nerve, which supplies wrist and hand extensor muscles, has been shown to alter sensory processing from and motor output to the median nerve innervated thenar muscles.

Adult↗
PubMed2000

The biochemistry of aging.

Although philosophers and scientists have long been interested in the aging process, general interest in this fascinating and highly important topic was minimal before the 1960s. In recent decades, however, interest in aging has greatly accelerated, not only since the elderly form an ever-increasing percentage of the population, but because they utilize a significant proportion of the national expenditures. In addition, many people have come to the realization that one can now lead a very happy, active, and productive life well beyond the usual retirement age. Scientifically, aging is an extremely complex, multifactorial process, and numerous aging theories have been proposed; the most important of these are probably the genomic and free radical theories. Although it is abundantly clear that our genes influence aging and longevity, exactly how this takes place on a chemical level is only partially understood. For example, what kinds of genes are these, and what proteins do they control? Certainly they include, among others, those that regulate the processes of somatic maintenance and repair, such as the stress-response systems. The accelerated aging syndromes (i.e., Hutchinson-Gilford, Werner's, and Down's syndromes) are genetically controlled, and studies of them have decidedly increased our understanding of aging. In addition, C. elegans and D. melanogaster are important systems for studying aging. This is especially true for the former, in which the age-1 mutant has been shown to greatly increase the life span over the wild-type strain. This genetic mutation results in increased activities of the antioxidative enzymes, Cu-Zn superoxide dismutase and catalase. Thus, the genomic and free radical theories are closely linked. In addition, trisomy 21 (Down's syndrome) is characterized by a significantly shortened life span; it is also plagued by increased oxidative stress which results in various free radical-related disturbances. Exactly how this extra chromosome results in an increased production of reactive oxygen species is, however, only partially understood. There is considerable additional indirect evidence supporting the free radical theory of aging. Not only are several major age-associated diseases clearly affected by increased oxidative stress (atherosclerosis, cancer, etc.), but the fact that there are numerous natural protective mechanisms to prevent oxyradical-induced cellular damage speaks loudly that this theory has a key role in aging [the presence of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, among others; various important intrinsic (uric acid, bilirubin, -SH proteins, glutathione, etc.) and extrinsic (vitamins C, E, carotenoids, flavonoids, etc.) antioxidants; and metal chelating proteins to prevent Fenton and Haber-Weiss chemistry]. In addition, a major part of the free radical theory involves the damaging role of reactive oxygen species and various toxins on mitochondria. These lead to numerous mitochondrial DNA mutations which result in a progressive reduction in energy output, significantly below that needed in body tissues. This can result in various signs of aging, such as loss of memory, hearing, vision, and stamina. Oxidative stress also inactivates critical enzymes and other proteins. In addition to these factors, caloric restriction is the only known method that increases the life span of rodents; studies currently underway suggest that this also applies to primates, and presumably to humans. Certainly, oxidative stress plays an important role here, although other, as yet unknown, factors are also presumably involved. Exactly how the other major theories (i.e., immune, neuroendocrine, somatic mutation, error catastrophe) control aging is more difficult to define. The immune and neuroendocrine systems clearly deteriorate with age. (ABSTRACT TRUNCATED)

Aging↗
PubMed2000

Wellness assessment: A role for laboratory medicine.

Within the next 20-25 years, 20% of the U.S. population is expected to be 65 years old or older. Unless significant changes are made (ie, increased research, improved treatment, and promotion of health and disease prevention), medical costs will continue to rise but with fewer citizens to finance them. However, this need not be the case. The 10 most common causes of death in the U.S. are all, to a significant degree, lifestyle-related. Most of these diseases take years or even decades to develop. By the time a physician makes a diagnosis, the disease is already present. However, with a panel of laboratory tests, combined with age, sex, family history, body mass index, blood pressure, and information regarding lifestyle (diet, exercise, smoking, alcohol), an estimate can be made regarding the relative risk for developing the major diseases/disorders. If recommendations are followed, these conditions will decline, medical costs will be reduced, and people will enjoy longer, healthier, and more productive lives.

Aging↗
PubMed2000

Review: Free radicals, antioxidants, and the immune system.

Oxygen-derived free radicals are important in both natural and acquired immunity. Neutrophil and macrophage phagocytosis stimulates various cellular processes including the "respiratory burst" whereby increased cellular oxygen uptake results in the production of the potent oxidant bactericidal agents, hypochlorous acid and hydroxyl radical. In addition, nitric oxide, a gaseous radical produced by macrophages, reacts with superoxide to form peroxynitrite, also a potent bactericidal agent. Conversely, oxidative stress may be detrimental in acquired immunity by activation of nuclear factor kappa B, which governs gene expression involving various cytokines, chemokines, and cell adhesion molecules, among others. However, antioxidant supplementation essentially reverses several age-associated immune deficiencies, resulting in increased levels of interleukin-2, elevated numbers of total lymphocytes and T-cell subsets, enhanced mitogen responsiveness, increased killer cell activity, augmented antibody response to antigen stimulation, decreased lipid peroxidation, and decreased prostaglandin synthesis.

Animals↗
PubMed1999

Mammographic densities and risk of breast cancer among subjects with a family history of this disease.

BACKGROUND: A family history of breast cancer is known to increase risk of the disease, but other genetic and environmental factors that modify this risk are likely to exist. One of these factors is mammographic density, and we have sought evidence that it is associated with increased risk of breast cancer among women with a family history of breast cancer. METHODS: We used data from a nested case-control study based on the Canadian National Breast Screening Study (NBSS). From 354 case patients with incident breast cancer detected at least 12 months after entry into the NBSS and 354 matched control subjects, we analyzed subjects who were identified as having a family history of breast cancer according to one of three, nonmutually exclusive, criteria. We compared the mammographic densities of case patients and control subjects by radiologic and computer-assisted methods of measurement. RESULTS: After adjustment for other risk factors for breast cancer, the relative risks (RRs) between the most and least extensive categories of breast density were as follows: For at least one first-degree relative with breast cancer, RR = 11.14 (95% confidence interval [CI] = 1.54-80.39); for at least two affected first- or second-degree relatives, RR = 2.57 (95% CI = 0.23-28.22); for at least one first- or second-degree relative with breast cancer, RR = 5.43 (95% CI = 1.85-15.88). CONCLUSIONS: These results suggest that mammographic density may be strongly associated with risk of breast cancer among women with a family history of the disease. Because mammographic densities can be modified by dietary and hormonal interventions, the results suggest potential approaches to the prevention of breast cancer in women with a family history of breast cancer.

Adult↗
PubMed1999

Macronutrient intake and change in mammographic density at menopause: results from a randomized trial.

To examine the effects of dietary fat intake on breast cancer risk, we are conducting a randomized trial of dietary intervention in women with extensive areas of radiologically dense breast tissue on mammography, a risk factor for breast cancer. Early results show that after 2 years on a low-fat, high-carbohydrate diet there is a significant reduction in area of density, particularly in women going through menopause. In women who went through menopause during the 2-year follow-up, the mean decreases in area of density and percentage of density in the intervention group were 11.0 cm2 and 11.0%, respectively, whereas the control group decreased 4.5 cm2 and 5.2%. The purpose of this analysis was to determine whether changes in intake of specific macronutrients could account for the observed reduction in breast density in these women. Differences between 2-year and baseline values of macronutrients (averaged over 3 nonconsecutive days of food intake) were calculated. We examined the effect of dietary variables, adjusted for changes in total calorie intake and weight and for family history of breast cancer, on changes in area of density and percentage of density using linear regression. Reduction in total or saturated fat intake or cholesterol intake was significantly associated with decreased dense area (p < or = .004). The most significant dietary variable associated with reduction in percentage of density was reduction in dietary cholesterol intake (P = 0.001), although reducing saturated fat intake was of borderline significance (P = 0.05). The effect of the membership in the intervention and control groups on change in area of density or percentage of density was reduced by models that included changes in intake of any fat, or cholesterol, or carbohydrates. The observation of an effect of diet at menopause on breast density, a marker of increased risk of breast cancer, may be an indication that exposures at this time have an enhanced effect on subsequent risk.

Body Weight↗
PubMed1998

An assessment of the influence of clinical breast examination reports on the interpretation of mammograms in a breast screening program. Ontario Breast Screening Program Radiologists Research Group.

The population-based Ontario Breast Screening Program (OBSP) provides two-yearly screening by both nurse examiner clinical breast examination (CBE) and two-view mammography to women aged 50 to 69. CBE alone accounts for about 5% of cancer detection. The purpose of this study was to determine whether CBE information affects radiologists' interpretation of mammography. Interpretation was defined by 1) radiologists' referral rates for diagnostic evaluation and 2) radiologists' accuracy in distinguishing cancer from non-cancer on mammograms. Mammograms were obtained from women randomly selected from those screened in the OBSP between 1990 and 1992. Selection was stratified by whether or not the nurse examiner had independently referred for diagnostic evaluation. Additional women diagnosed with breast cancer were selected to increase the precision of the receiver-operating characteristic (ROC) curve. Each participating OBSP radiologist read a set of mammograms twice, approximately three weeks apart. The first reading was based on mammograms alone. At the second reading, the CBE report was included on the reporting form. Among 620 women referred by the nurse, radiologist referral rate increased from 37.7% to 40.8% (p = 0.079) when CBE information was available. Among the 637 not referred by the nurse, radiologist referral rate decreased from 29.8% to 25.6% (p = 0.005). There was little effect on the sensitivity and specificity of radiologist referral and the areas under the two ROC curves (with and without CBE information) were not significantly different (p = 0.571). Although there was some effect of CBE information on radiologists' pattern of referral, there was no effect on accuracy of cancer detection.

Breast Neoplasms↗
PubMed1998

Mammographic densities and breast cancer risk.

Variations between individuals in the radiographic appearance, or mammographic pattern, of the female breast arise because of differences in the relative amounts and X-ray attenuation characteristics of fat and connective and epithelial tissue. Studies using quantitative methods of assessment have consistently shown these variations to be strongly related to risk of breast cancer. Individuals with extensive areas of radiologically dense breast tissue on the mammogram have been found to have a risk of breast cancer that is four to six times higher than women with little or no density. In this paper, we propose a model for the relationship of mammographic densities to risk of breast cancer. We propose that the risk of breast cancer associated with mammographically dense breast tissue is due to the combined effects of two processes: cell proliferation (mitogenesis), induced by growth factors and sex hormones and influenced by reproductive risk factors for breast cancer; and damage to the DNA of dividing cells (mutagenesis) by mutagens generated by lipid peroxidation. We review the evidence that each of these processes is associated with mammographic densities and propose further work that we believe should be done to clarify these relationships.

Journal Article↗
PubMed1997

Spurious hypophosphatemia in a patient with multiple myeloma.

We report a patient with multiple myeloma and a prolonged history of hypophosphatemia who had remained asymptomatic. Extensive evaluation for a cause, including the search for a renal tubular disorder, oncogenous osteomalacia, or a parathyroid hormone (PTH)-related protein was unproductive. Renal biopsy showed no evidence of myeloma kidney. Subsequent mixing of the immunoglobulin G (IgG) fraction from the patient's serum with normal human serum, confirmed that the observed hypophosphatemia was spurious, resulting from interference of large amounts of an abnormal IgG with a standard automated laboratory assay for phosphate.

Autoanalysis↗
PubMed1997

Parental occupational exposure and the risk of testicular cancer in Ontario.

The incidence of germ cell testicular cancer is increasing, but its etiology remains largely unknown. Initiation may occur in a parental germ cell. In a case-control study in Ontario, jobs and industries of mothers (before and during pregnancy) and fathers (before pregnancy) of 343 case subjects and 524 control subjects were analyzed. Significantly increased risk was associated with fathers who were wood processors (odds ratio [OR] = 10.46; 95% confidence interval [CI], 1.20 to 91.14), metalworkers (OR = 3.28; 95% CI, 1.03 to 10.52), stationary engineers (OR = 1.05; 95% CI, 1.05 to 11.87), or employees of the food products (OR = 2.79; 95% CI, 1.34 to 5.79), metal products (OR = 5.77, 95% CI, 1.53 to 21.77), or food and beverage services (OR = 4.36; 95% CI, 1.50 to 12.63) industries. There was little evidence of risk associated with maternal employment. Paternal employment before conception in jobs related particularly to metal or food and beverages may be related to testicular cancer risk in sons.

Adolescent↗
PubMed1996

Pathophysiologic role of alpha 4 integrins in the lung.

Evidence for a central role for the integrins alpha 4 beta 1 and alpha 4 beta 7 in leukocyte pathophysiology is rapidly accumulating. Five distinct alpha 4 mAbs, each able to block alpha 4-dependent adhesion in vitro, show beneficial effects in vivo in six different species, and in a wide variety of organ systems, including colon, lung, skin, neural tissue, pancreas, peritoneum, and the vessel wall. In particular, a clear role for these integrins in lung pathophysiology is implied on the basis of in vivo studies in four different species. Although several issues remain to be resolved, including the relative importance of alpha 4 beta 1 and alpha 4 beta 7, and the relative roles of their counterligands, VCAM1, fibronectin, and MAdCAM, the data argue that alpha 4 integrins will likely be critical to both the normal physiology and pathology of the lung in man. To this end, we (Adams, Lin, Lobb, and Gill, unpublished data) and others have generated peptidomimetic small molecule antagonists of VLA4 based on the connecting segment 1 (CS1) peptide sequence of fibronectin that are potent blockers of integrin adhesive function in vitro and show efficacy in vivo. We have found that our inhibitors are excellent blockers of both murine contact hypersensitivity, and of the LPR and AHR in the sheep allergic airways model (Abraham, Lobb, Adams, and Gill, unpublished data), and are therefore possible candidates for clinical intervention in human asthma. The use of the VCAM-Ig fusion protein as a probe for high-affinity alpha 4 integrins has further enhanced our understanding of alpha 4 integrin function in the lung. While integrin upregulation in vitro has been observed many times, and high affinity (as opposed to avidity) of integrins seen in vitro in several systems, in vivo proof of integrin upregulation to a high-affinity state has been difficult to obtain in the absence of selective probes. Our data provide key information in this regard and strongly argue not only that integrin upregulation does indeed occur in vivo, but also that it is in fact obligatory for the leukocyte pathologies we have examined to date. Further studies are clearly warranted to further examine mechanisms of action, and to confirm and extend these studies, both with the alpha 4 integrins and with other integrin families. In summary, our studies of alpha 4 integrins continue to provide novel insights into the pathophysiology of integrin function and into future directions for drug discovery.

Animals↗
PubMed1996

Occupation and risk of germ cell testicular cancer by histologic type in Ontario.

Incidence of both major histologic subgroups of germ cell testicular cancer, seminoma and nonseminoma, is increasing, but the etiology is largely unknown. Occupational clusters have been observed. In a case-control study in Ontario with 495 incident cases and 974 population control subjects, jobs and industries were coded and analyzed. There is little evidence of occupational risk for all cases or for seminoma. Significantly increased risk of nonseminoma was associated with: miners (odds ratio [OR] = 12.39; 95% confidence interval [CI], 2.22 to 69.27), food and beverage processors (OR = 3.20; 95% CI, 1.39 to 7.35), utilities employees (OR = 3.15; 95% CI, 1.15 to 8.61), and other service workers (OR = 1.05; 95% CI, 1.05 to 4.56). Leather-industry employees had elevated risk of nonseminoma (OR = 4.60; 95% CI, 0.75 to 28.28) consistent with a leather tannery cluster. Increased risk of nonseminoma among some workers can be explained if an additional event is required for converting seminoma to nonseminoma.

Adolescent↗