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Biomedical subjects

R Klein

Publications and source records attributed to R Klein.

At least 325 records · Page 18Linked to original sources
PubMed1997

The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study.

BACKGROUND PURPOSE: The objective was to investigate the relationship of systemic hypertension to the incidence of various retinal vascular lesions in the population-based Beaver Dam Eye Study. METHODS: Subjects aged 43 through 86 years who lived in Beaver Dam, Wisconsin between 1987 and 1988 were examined between 1988 and 1990 and 5 years later, 1993-1995. Blood pressure was measured using standardized protocols. Stereoscopic color fundus photographs were graded in a masked fashion using standardized protocols to determine the presence of retinopathy (blot hemorrhages, microaneurysms, hard and soft exudates, intraretinal microvascular abnormalities, and venous beading), retinal arteriolar narrowing, and arterio-venous nicking. People with diabetes or retinal vascular occlusions were excluded from the analyses. RESULTS: Among those examined, 2,151 (69.1%) were normotensive and 963 (30.9%) were hypertensive at baseline. Over the five-year period, retinopathy developed in 175 (6.0%), arteriolar narrowing in 282 (9.9%) and arterio-venous nicking in 201 (6.5%) nondiabetic subjects. After adjusting for age, hypertension was associated with the incidence of retinopathy (in men: relative risk [RR] 2.31, 95% confidence interval [CI] 1.54 to 3.48; in women: RR 1.61, 95% CI 1.07 to 2.43) and with arteriolar narrowing (in men: RR 1.82, 95% CI 1.25 to 2.66; in women: RR 1.36, 95% CI 1.05 to 1.77), but not with arterio-venous nicking (in men: RR 1.01, 95% CI 0.69 to 1.48; in women: RR 1.37, 95% CI 0.95 to 1.97). The five-year incidence of retinopathy and of arteriolar narrowing was higher in those subjects whose blood pressure was elevated despite use of antihypertensive medications compared with those subjects whose blood pressure was controlled with antihypertensive medications or those who were normotensive. CONCLUSIONS: These data show a relation of hypertension to an increased incidence of retinopathy and arteriolar narrowing. Furthermore, these data suggest that pharmacologic control of blood pressure is related to a lower incidence of these anatomic retinal lesions relative to uncontrolled blood pressure.

Adult↗
PubMed1997

[Vaccination rates in childhood and adolescents are improved].

Improvement of Children's Immunisation Coverage: Only the branches for infants, children and adolescents in the public health departments carry out regular data collections concerning the protection given by vaccination of children and adolescents. These immunisation records as well as selected studies show a lack of vaccination and immunisation in these age groups. The analysis of these immunisation records by the public health departments shows specific vaccination deficits which are basic for specific strategies that must be taken to improve the immunisation coverage. The main objective of the branches for infants, children and adolescents in the public health departments is to make these data available for all persons who are regionally responsible for children. All these persons together have to develop strategies to improve the immunisation coverage in the short as well as in the long run. The public health department coordinate these strategies, validate coverage data and and evaluate them. The central points of such a concept are here presented.

Adolescent↗
PubMed1996

Longitudinal patterns of glycemic control and diabetes care from diagnosis in a population-based cohort with type 1 diabetes. The Wisconsin Diabetes Registry.

Glycosylated hemoglobin is an indicator of long-term glycemic control and a strong predictor of diabetic complications. This paper provides a comprehensive description of glycemic control (total glycosylated hemoglobin (GHb)) up to 4.5 years duration of diabetes by age, duration, and sex in a population-based cohort (n = 507) aged less than 20 years followed from diagnosis of Type 1 diabetes in Wisconsin during 1987-1994 Important aspects of demographics and diabetes care are described to allow comparison with other populations. Since large variations between laboratories are known to exist in the measurement of GHb, levels are also interpreted relative to the frequency of short-term complications. GHb increased after diagnosis, but leveled off after 2-3 years. Peak GHb values occurred in the age group 12-15 years. The within-individual standard deviation in GHb between tests, adjusted for age and duration was 1.6%. The mean GHb at last testing was 11.3%, with a standard deviation across individuals of 2.9%. The majority (74%) of individuals saw a diabetes specialist at least once. The mean number of insulin injections per day increased from 2.2 to 2.5 across the 4.5-year duration, and the insulin dose increased from 0.6 to 0.9 units per day per kg body weight. Despite the quite satisfactory level of care, 38% of subjects had GHb levels associated with significant short-term complications.

Adolescent↗
PubMed1996

TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons.

The Trk family of protein tyrosine kinases (TrkA/B/C) are receptors for neurotrophins, a family of closely related proteins that are important physiological regulators of the survival of specific neurons within the peripheral nervous system (PNS) of vertebrates. In contrast to the PNS, brains of mutant mice deficient in a single neurotrophin or Trk receptor species do not show signs of major cell loss. However, in double mutant mice, we now show that reducing the expression of both TrkB and TrkC causes massive cell death of postnatal hippocampal and cerebellar granule neurons. Kinetic analysis of neuronal death in the hippocampus showed that dentate gyrus granule neurons become dependent on TrkB and TrkC after the first postnatal week, shortly after the period of naturally occurring cell death, indicating a role of these receptors in supporting postmitotic neurons. Correlating with the loss of granule cells, the number of mossy fibers projecting to CA3 pyramidal neurons was markedly reduced in mice carrying mutant trkB/trkC alleles, demonstrating impairment of excitatory pathways in the hippocampus. In the cerebellum, TrkB and TrkC receptors were specifically required for premigratory granule neurons located in the external granule layer. In contrast, cerebellar Purkinje cells were found to be poorly differentiated, but showed no signs of increased cell death. These results provide in vivo evidence that neurotrophins are essential physiological survival factors for specific central neurons. Moreover, they suggest that central, in contrast to peripheral, neurons are capable of using more than one neurotrophin/Trk receptor signaling pathway to stay alive.

Animals↗
PubMed1996

Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation.

Sek4 and Nuk are members of the Eph-related family of receptor protein-tyrosine kinases. These receptors interact with a set of cell surface ligands that have recently been implicated in axon guidance and fasciculation. We now demonstrate that the formation of the corpus callosum and anterior commissure, two major commissural axon tracts that connect the two cerebral hemispheres, is critically dependent on Sek4 and Nuk. While mice deficient in Nuk exhibit defects in pathfinding of anterior commissure axons, sek4 mutants have defects in corpus callosum formation. The phenotype in both axon tracts is markedly more severe in sek4/nuk1 double mutants, indicating that the two receptors act in a partially redundant fashion. sek4/nuk1 double mutants also exhibit specific guidance and fasciculation defects of diencephalic axon tracts. Moreover, while mice singly deficient in either Sek4 or Nuk are viable, most sek4/nuk1 double mutants die immediately after birth primarily due to a cleft palate. These results demonstrate essential and cooperative functions for Sek4 and Nuk in establishing axon pathways in the developing brain, and during the development of facial structures.

Animals↗
PubMed1996

Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development.

Hepatocyte growth factor (HGF) and its receptor, the Met tyrosine kinase, are determinants of placenta, liver, and muscle development. Here, we show that Met function in vivo requires signaling via two carboxy-terminal tyrosines. Mutation of both residues in the mouse genome caused embryonal death, with placenta, liver, and limb muscle defects, mimicking the phenotype of met null mutants. In contrast, disrupting the consensus for Grb2 binding allowed development to proceed to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers. These data show that the requirements for Met signaling vary depending on the tissue and reveal a novel role for HGF/ Met in late myogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Nuk controls pathfinding of commissural axons in the mammalian central nervous system.

Eph family receptor tyrosine kinases have been proposed to control axon guidance and fasciculation. To address the biological functions of the Eph family member Nuk, two mutations in the mouse germline have been generated: a protein null allele (Nuk1) and an allele that encodes a Nuk-beta gal fusion receptor lacking the tyrosine kinase and C-terminal domains (Nuk(lacZ)). In Nuk1 homozygous brains, the majority of axons forming the posterior tract of the anterior commissure migrate aberrantly to the floor of the brain, resulting in a failure of cortical neurons to link the two temporal lobes. These results indicate that Nuk, a receptor that binds transmembrane ligands, plays a critical and unique role in the pathfinding of specific axons in the mammalian central nervous system.

Alleles↗
PubMed1996

Sialosyl-Tn antigen as a marker of gastric cancer progression: an international study.

Sialosyl-Tn, a mucin-associated carbohydrate antigen, is not expressed by normal mucus-producing cells of the stomach but becomes expressed in metaplastic, pre-malignant and malignant gastric tissues. Reports vary as to the frequency of STn expression and its prognostic role in gastric cancer. To determine whether these differences might be due to inter-country variations in gastric cancer biology, we immunohistochemically analyzed 340 gastric cancers from 2 countries at high-risk (high incidence) for gastric cancer (Japan and Chile), one with intermediate risk (Brazil) and one with low-risk (USA). Expression of STn was correlated with clinico-pathological features of the tumors and with cancer-related survival. Regardless of country, the frequency of STn-positive tumors was lower in non-invasive ("early") than in advanced gastric cancer. Consequently, high-risk countries where early gastric cancer is more common demonstrated a lower overall frequency of STn-positive tumors. In all 4 countries, STn expression directly correlated with depth of invasion, stage, and lymph node involvement. In addition, STn expression correlated with a poor prognosis in all 4 countries, but the effect of STn on survival was not independent of tumor stage. Our findings indicate the need to consider the inherent gastric cancer risk and prevalence of early gastric cancer in the study population when reporting frequency of STn expression in gastric cancer. Regardless of country, however, STn expression is a marker of gastric cancer progression suggesting that cancer-associated mucins play a role in the malignant behavior of this tumor.

Aged↗
PubMed1996

The incidence of hypertension in insulin-dependent diabetes.

BACKGROUND: There are few epidemiologic data describing the long-term incidence of hypertension in people with diabetes. METHODS: In a population-based study performed in southern Wisconsin, 765 individuals diagnosed as having diabetes when they were younger than 30 years and taking insulin participated in baseline, 4-year, and 10-year examinations. Blood pressure was measured by standardized protocols,and hypertension was defined as a mean systolic blood pressure of 160 mm Hg or more ( > or = 140 mm Hg in those younger than 25 years) and/or mean diastolic blood pressure of 95 mm Hg or more ( > or = 90 mm Hg in those younger than 25 years) and/or history of hypertension with the use of antihypertensive medication. RESULTS: The prevalence of hypertension at baseline was 17.3%. The 10-year incidence of hypertension was 25.9%. The incidence of hypertension was greater with older age, longer duration of diabetes, higher glycosylated hemoglobin level, proteinuria, more severe retinopathy, and male gender. After other risk factors were controlled for, the 10-year incidence of hypertension was significantly related to higher glycosylated hemoglobin level (odds ratio, 1.23 per percentage increase; 95% confidence interval, 1.13 to 1.34) presence of gross proteinuria (odds ratio, 3.64; 95% confidence interval, 2.26 to 5.85), longer duration of diabetes (odds ratio, 1.03 per year of diabetes; 95% confidence interval, 1.01 to 1.04), and being male (odds ratio, 1.93; 95% confidence interval, 1.34 to 2.77). CONCLUSION: These data suggest that control of hyperglycemia and prevention of gross proteinuria may lead to a reduction in the long-term incidence of hypertension.

Adult↗
PubMed1996

Autoantibody reactivity in serum of patients with Alzheimer's disease and other age-related dementias.

Serum antibodies against a series of antigens, including an organ-specific central nervous system (CNS) antigen and the neurotransmitter serotonin, were investigated in 22 patients with Alzheimer's Disease (n=15) and other age-related dementias (n=7) by indirect immunofluorescence assay and enzyme-linked immunosorbent assay. Patients with dementia showed an increase of antibody-positive sera against nuclear antigen, gastric parietal cells, CNS antigen, gangliosides (Gm1), laminin, and keratin. Alzheimer's Disease patients alone exhibited antibodies against CNS antigen. However, the results do not show sufficient specificity and sensitivity for use as a diagnostic indicator.

Aged↗
PubMed1996

Bacterial ghosts: non-living candidate vaccines.

Expression of cloned PhiX174 gene E in bacteria results in lysis of bacteria. It is unique among phage lysis systems as it introduces a transmembrane tunnel structure through the cell envelope complex of Gram-negative bacteria. The resulting bacterial ghosts have intact envelope structures devoid of cytoplasmic contents. E-mediated lysis has been achieved in a variety of Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Vibrio cholerae, Klebsiella pneumoniae, and Actinobacillus pleuropneumoniae. Such ghosts, derived from human or animal pathogens, have been proposed as non-living candidate vaccines and represent an alternative to heat or chemically inactivated bacteria. In 'recombinant ghosts', foreign proteins (e.g., viral proteins) are inserted into the inner membrane via specific N-, or C-, or N- and C-terminal anchor sequences prior to lysis. Relevant advantages of (recombinant) bacterial ghosts as immunogens include: (i) inactivation procedures that denature relevant immunogenic determinants are not employed in the production of ghosts used as vaccines or as carriers of relevant antigens; (ii) the recombinant proteins are inserted into a highly immune stimulatory environment; (iii) there is no size limitation of the foreign protein moieties: multiple antigenic determinants can be presented simultaneously; (iv) bacterial ghosts can be produced inexpensively in large quantities; (v) (recombinant) ghosts are stable for long periods of time and do not require the cold chain storage system. Intraperitoneal, subcutaneous or intramuscular applications of recombinant ghosts in experimental animals induced specific humoral and cellular immune responses against bacterial and viral components. Initial aerosol vaccinations of swine with ghosts from Actinobacillus pleuropneumoniae showed that protective immunity can be established by this route of application and that the well-preserved surface structures of ghosts obtained by E-mediated lysis are able to target the mucosal immune system.

Animals↗
PubMed1996

Relation of glycemic control to diabetic microvascular complications in diabetes mellitus.

OBJECTIVE: To describe the relation between glycated hemoglobin and the incidence or progression, or both, of diabetic microvascular complications in persons with insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: Population-based on cohort study. SETTING: An 11-county area in southern Wisconsin. PATIENTS: All persons with IDDM diagnosed before age 30 and taking insulin (n = 996) and a probability sample (based on duration of disease) of persons diagnosed with diabetes at age 30 or older who were either taking insulin (n = 674) or not taking insulin (n = 696) and who participated in a baseline examination from 1980 to 1982. Survivors of the cohort were re-examined again in 1984 to 1986 and 1990 to 1992. MEASUREMENTS: The incidence and progression of diabetic retinopathy was determined by masked grading of stereoscopic color fundus photographs using the modified Early Treatment Diabetic Retinopathy Study severity scale. Gross proteinuria was determined using a dipstick. Ten-year incidence of renal dialysis or transplantation or loss of tactile sensation or of temperature sensitivity was based on self-reported history. RESULTS: The glycated hemoglobin level at baseline was strongly related to the incidence or progression, or both, of diabetic retinopathy, the incidence of gross proteinuria, and the incidence of loss of tactile sensation or temperature sensitivity in persons with either IDDM or NIDDM. CONCLUSIONS: These prospective epidemiologic data suggest that glycemic control is similarly related to the incidence and progression of diabetic microvascular complications in both IDDM and NIDDM. However, further evidence from clinical trials in persons with NIDDM is necessary to assess the risks and benefits of such treatment in preventing these complications.

Age of Onset↗
PubMed1996

Association of zinc and antioxidant nutrients with age-related maculopathy.

OBJECTIVE: To quantify relationships between dietary intake of zinc and antioxidant nutrients and early and late age-related maculopathy (ARM). DESIGN: A retrospective longitudinal cohort design using data pertaining to diets in the past (1978-1980), which were assessed retrospectively using a food frequency questionnaire. SETTING: Beaver Dam, Wis. PATIENTS: A 50% random sample of free-living Beaver Dam Eye Study participants, 43 to 86 years of age (N = 1968). MAIN OUTCOME MEASURE: The presence of early and late ARM determined from fundus photography. RESULTS: People in the highest vs lowest quintiles for intake of zinc from foods had lower risk for early ARM (odds ratio = 0.6, 95% confidence interval, 0.4-1.0, P for trend < .05). This relationship appeared to be stronger for some types of early ARM (increased retinal pigment) than for others. Zinc intake was unrelated to late ARM. However, small numbers (n = 30) of people with this condition limit the ability to draw conclusions about this later stage. Levels of carotenoids were unrelated to early or late ARM. Odds for early ARM were lower in people in the highest vs lowest quintiles for the intake of vitamins C or E. However, these associations were not statistically significant. CONCLUSIONS: The data are weakly supportive of a protective effect of zinc on the development of some forms of early ARM. Prospective studies are needed to further evaluate the potential influence of these and other nutritional factors on different types and stages of age-related macular degeneration.

Adult↗
PubMed1996

Qualitative and quantitative analysis of orthotopic bone regeneration by marrow.

A rat model of a femoral segmental defect was used to specifically test the hypothesis that autogenous marrow has the osteogenic capability to heal a bone defect. The variables analyzed included the ratio of the marrow volume to the defect, implantation of live or dead marrow, and remodeling of established nonunions by implantation of live marrow. The uniqueness of this model allows biomechanical evaluation of the new bone formed by the implant. When live marrow was implanted, woven bone formed at 3 weeks, progressing to early lamellar bone at 6 weeks, with subsequent remodeling for as long as 12 weeks in a volumetric fashion (p < 0.05). Bone marrow, when placed in a fresh femoral defect and given in sufficient amounts, produced a rate of union comparable with that of autologous bone grafts. Mature lamellar bone formed by marrow was evaluated biomechanically; the results were statistically comparable with those of cancellous bone grafts at 12 weeks. Significant bone formation occurred when marrow was percutaneously injected in femoral nonunions, although union and remodeling did not take place in this rat model. Implantation of dead marrow resulted in rare cellular infiltration and minimal bone formation in a manner comparable with that of autogenous cancellous bone grafts. These results indicate that bone marrow can lead to structurally functional bone regeneration in an orthotopic location.

Analysis of Variance↗
PubMed1996

Similarities and differences in the way transmembrane-type ligands interact with the Elk subclass of Eph receptors.

The Eph family of receptor tyrosine kinases and their cell surface bound ligands have been implicated in a number of developmental processes, including axon pathfinding and fasciculation, as well as patterning in the central nervous system. To better understand the complex signaling events taking place, we have undertaken a comparative analysis of ligand-receptor interactions between a subset of ligands, those that are tethered to the cell surface via a transmembrane domain, and a subset of Eph receptors, the so-called Elk subclass. Based on binding characteristics, receptor autophosphorylation, and cellular transformation assays, we find that the transmembrane-type ligands Lerk2 and Elf2 have common and specific receptors within the Elk subclass of receptors. The common receptors Cek10 and Elk bind and signal in response to Lerk2 and Elf2, whereas the Myk1 receptor is specific for Elf2. Elf2, however, fails to signal through Cek5 in a cellular transformation assay, suggesting that Lerk2 may be the preferred Cek5 ligand in vivo. A recently identified third transmembrane-type ligand, Elf3, specifically, but weakly, binds Cek10 and only induces focus formation when activated by C-terminal truncation. This suggests that the physiological Elf3 receptor may have yet to be identified. Knowledge regarding functional ligand-receptor interactions as presented in this study will be important for the design and interpretation of in vivo experiments, e.g., loss-of-function studies in transgenic mice.

3T3 Cells↗