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Biomedical subjects

R Hiller

Publications and source records attributed to R Hiller.

At least 37 records · Page 2Linked to original sources
PubMed1995

Serum zinc and serum lipid profiles in 778 adults.

There has been increasing use of high-dosage zinc supplementation in the population, in particular as a potential treatment for age-related macular degeneration. We examined the relationship between fasting serum zinc and serum lipid levels in 778 adults, aged 22 to 80 years, who were control subjects in a multicenter, clinic-based case-control study. The samples were taken during 1987 to 1990, a time when vitamin/mineral supplementation was becoming increasingly common. We found that higher serum zinc levels, most notably those above the highest quintile, were associated with higher levels of total serum cholesterol, low-density-lipoprotein cholesterol, and triglycerides. No significant trend was noted for high-density-lipoprotein cholesterol. Previous studies demonstrated that high-dosage zinc supplements raise serum zinc levels. The possibility that use of such supplements can adversely affect serum lipid profiles suggests that chronic ingestion of such supplements should not be done without adequate medical supervision.

Adult↗
PubMed1995

NMR observation of interactions in the combining site region of an antibody using a spin-labeled peptide antigen and NOESY difference spectroscopy.

A spin-labeled peptide antigen (TEMPOVEVPGSQHIDSQ) was used to measure NOESY difference spectra that show interactions in the binding site region of the Fab fragment of the anti-cholera toxin peptide antibody TE33. In addition to identification of peptide-Fab interactions and interactions within the bound peptide, these difference spectra show well-resolved cross peaks due to interactions within the large Fab fragment (50 kDa). These difference spectra indicate that the conformational changes in the Fab upon peptide binding are confined to the combining site region of the antibody. The NOESY difference spectra of selectively deuterated Fab molecules were used in combination with HOHAHA measurements to assign the interactions to amino acid type and to identify the interactions within the Fab as either inter- or intraresidue interactions. The assignment of interactions within the Fab to corresponding aromatic residues in the Fab sequence was facilitated by an earlier NMR-derived model calculated on the basis of NOE restraints on Fab-peptide and intra-bound-peptide distances. The new restraints on distances within the Fab, combined with the previously obtained restraints, were used to generate a refined NMR-derived model for the TE33-peptide complex.

Amino Acid Sequence↗
PubMed1994

Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group.

OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. DESIGN--The multicenter Eye Disease Case-Control Study. SETTING--Five ophthalmology centers in the United States. PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of vitamin C, particularly from foods. CONCLUSION--Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship.

Aged↗
PubMed1994

The barriers in protein folding.

Elimination of an interaction which forms in denatured cytochrome c enables the majority of the molecules to fold to the native state on a 15 ms time scale, without populating observable intermediates. These results are contrary to the current view that particular steps in protein folding, including the supposedly rate-limiting molten globule to native transition, are intrinsically slow. Instead it appears that intermediates characterized so far may be kinetically trapped by barriers that are optional rather than integral to the folding process. Major barriers may result from misorganization of the chain in the initial condensation step.

Animals↗
PubMed1993

Two-dimensional NMR investigations of the interactions of antibodies with peptide antigens.

To increase our understanding of the molecular basis for antibody specificity and for the cross-reactivity of anti-peptide antibodies with native proteins it is important to study the three-dimensional structure of antibody complexes with their peptide antigens. For this purpose it may not be necessary to solve the structure of the whole antibody complex but rather to concentrate on elucidating the combining site structure, the interactions of the antibody with its antigen and the bound peptide conformation. We have developed an NMR methodology based on two-dimensional difference spectrum measurements which extract the information concerning antibody-peptide interactions and intramolecular interactions in the bound ligand from the crowded and unresolved spectrum of the Fab complex. These measurements yield restraints on interproton distances in the complex which are used to dock the peptide into calculated models for the antibodies' combining sites. Comparison of the interactions of three antibodies against a cholera toxin peptide (CTP3), which differ in their cross-reactivity with the toxin, yields information about the size and conformation of antigenic determinants recognized by antibodies, the structure of their combining sites and relationships between antibodies' primary structure, and their interactions with peptide antigens.

Amino Acid Sequence↗
PubMed1992

Induced peptide conformations in different antibody complexes: molecular modeling of the three-dimensional structure of peptide-antibody complexes using NMR-derived distance restraints.

Intramolecular interactions in bound cholera toxin peptide (CTP3) in three antibody complexes were studied by two-dimensional transferred NOE spectroscopy. These measurements together with previously recorded spectra that show intermolecular interactions in these complexes were used to obtain restraints on interproton distances in two of these complexes (TE32 and TE33). The NMR-derived distance restraints were used to dock the peptide into calculated models for the three-dimensional structure of the antibody combining site. It was found that TE32 and TE33 recognize a loop comprising the sequence VPGSQHID and a beta-turn formed by the sequence VPGS. The third antibody, TE34, recognizes a different epitope within the same peptide and a beta-turn formed by the sequence IDSQ. Neither of these two turns was observed in the free peptide. The formation of a beta-turn in the bound peptide gives a compact conformation that maximizes the contact with the antibody and that has greater conformational freedom than alpha-helix or beta-sheet secondary structure. A total of 15 antibody residues are involved in peptide contacts in the TE33 complex, and 73% of the contact area in the antibody combining site consists of the side chains of aromatic amino acids. A comparison of the NMR-derived models for CTP3 interacting with TE32 and TE33 with the previously derived model for TE34 reveals a relationship between amino acid sequence and combining site structure and function. (a) The three aromatic residues that interact with the peptide in TE32 and TE33 complexes, Tyr 32L, Tyr 32H, and Trp 50H, are invariant in all light chains sharing at least 65% identity with TE33 and TE32 and in all heavy chains sharing at least 75% identity with TE33. Although TE34 differs from TE32 and TE33 in its fine specificity, these aromatic residues are conserved in TE34 and interact with its antigen. Therefore, we conclude that the role of these three aromatic residues is to participate in nonspecific hydrophobic interactions with the antigen. (b) Residues 31, 31c, and 31e of CDR1 of the light chain interact with the antigen in all three antibodies that we have studied. The amino acids in these positions in TE34 differ from those in TE32 and TE33, and they are involved in specific polar interactions with the antigen. (c) CDR3 of the heavy chain varies considerably both in length and in sequence between TE34 and the two other anti-CTP3 antibodies. These changes modify the shape of the combining site and the hydrophobic and polar interactions of CDR3 with the peptide antigen.

Amino Acid Sequence↗
PubMed1992

Solution conformation of a peptide corresponding to the principal neutralizing determinant of HIV-1IIIB: a two-dimensional NMR study.

The 24 amino acid peptide RP135 corresponds in its amino acid sequence to the principal neutralizing determinant (PND) of the IIIB isolate of HIV-1. Although the sequence of the PND is highly variable, its central part, containing the sequence GPGR, is conserved in most HIV isolates. Using 2D NMR and CD spectroscopy, we have studied the conformation of RP135 and of two shorter versions: one (P547) that includes the GPGR sequence with the N-terminal part of the peptide and the other (P344) that includes GPGR and the C-terminal segment of RP135. In water, the C-terminal part of RP135 was found to exist in several transient turnlike conformations ("nascent helix"). A helical conformation was found to be stabilized by the addition of TFE. A transient turn was observed also in the GPGR sequence, both in water and in aqueous TFE solutions. While no nascent helix conformations could be observed in the N-terminal part of RP135 in water, a helical conformation was partially stabilized by the addition of TFE. The conformations of the two shorter versions of the peptide were similar to those of the corresponding parts of RP135, except that the transient turn in GPGR could not be detected in P547 dissolved in water. The turn in GPGR was previously predicted by Larosa et al. (1990) and was observed by Chandrasekhar et al. (1991) in the PND peptide of HIV-1MN (RP142), which shares only 56% identity with RP135. However, nascent helix conformations were not observed in aqueous solutions of RP142.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1990

Kinetic analysis of cooperative interactions induced by Mn2+ binding to the chloroplast H(+)-ATPase.

The kinetics of Mn2+ binding to three cooperatively interacting sites in chloroplast H(+)-ATPase (CF1) were measured by EPR following rapid mixing of the enzyme with MnCl2 with a time resolution of 8 ms. Mixing of the enzyme-bound Mn2+ with MgCl2 gave a measure of the rate of exchange. The data could be best fitted to a kinetic model assuming three sequential, positively cooperative binding sites. (1) In the latent CF1, the binding to all three sites had a similar on-rate constants of (1.1 +/- 0.04) X 10(4) M-1s-1. (2) Site segregation was found in the release of ions with off-rate constants of 0.69 +/- 0.04 s-1 for the first two and 0.055 +/- 0.003 s-1 for the third. (3) Addition of one ADP per CF1 caused a decrease in the off-rate constants to 0.31 +/- 0.02 and 0.033 +/- 0.008 s-1 for the first two and the third sites, respectively. (4) Heat activation of CF1 increased the on-rate constant to (4.2 +/- 0.92) X 10(4) M-1s-1 and the off-rate constants of the first two and the third site to 1.34 +/- 0.08 and 0.16 +/- 0.07 s-1, respectively. (5) The calculated thermodynamic dissociation constants were similar to those previously obtained from equilibrium binding studies. These findings were correlated to the rate constants obtained from studies of the catalysis and regulation of the H(+)-ATPase. The data support the suggestion that regulation induces sequential progress of catalysis through the three active sites of the enzyme.

Binding Sites↗
PubMed1989

Measurement error in assessing the size of posterior subcapsular cataracts from retroillumination photographs.

Twenty-six eyes with posterior subcapsular opacities of various sizes were photographed with the Neitz-Kawara Retroillumination camera. The outline of the opacity in a single photograph of each opacity was traced onto a transparent plastic overlay twice by two independent outliners. Two methods were used to estimate the area within the outlines of the opacities. In the first, a transparent overlay with a standard grid was used to count the number of boxes within the outlines. The second method used computer planimetry to estimate the area within the tracings. We estimated the measurement error associated with a single outlining of an opacity and the contribution of the measurement error to overall sample size requirements in studies comparing the mean areas of posterior subcapsular opacities. Variability in the measurement techniques contributed fewer than 20 additional subjects to overall sample size estimates, a small contribution to total sample size requirements in most studies. An outliner's inherent variability in outlining an opacity was a much larger contributor to the measurement error than was variability in assessing the area of the outline of the opacity. While within outliner variability was similar for the two persons outlining the opacities, there were systematic differences in the way the two traced the outlines. Variability from the use of separate photographs of the same opacity taken by different photographers was minimal.

Cataract↗
PubMed1988

Diabetic retinopathy and cardiovascular disease in type II diabetics. The Framingham Heart Study and the Framingham Eye Study.

Data from the Framingham Heart Study and the Framingham Eye Study were used to examine the association between diabetic retinopathy and the occurrence of cardiovascular events (coronary heart disease, intermittent claudication, congestive heart failure, and stroke). Among the 206 persons with Type II diabetes in the Framingham Eye Study, the odds ratios for diabetic retinopathy and cardiovascular disease were 14.3 (95% confidence interval (CI) = 2.7-101.9), 2.0 (95% CI = 0.5-8.1), and 0.3 (95% CI = 0.05-1.3) for ages 52-64, 65-74, and 75-85 years, respectively. The test for homogeneity indicated highly significant differences for the odds ratios across age groups. The associations were similar when sex, duration of diabetes, age at diagnosis of diabetes, and history of insulin treatment were accounted for by logistic regression. Our data suggest an association in younger diabetics between diabetic retinopathy, a small vessel complication of diabetes, and a group of cardiovascular events commonly thought to result from large vessel disease. The finding may merely indicate that diabetics with large vessel disease are also more likely to have small vessel disease. However, it is also consistent with the hypothesis, suggested by histologic data, that a more generalized microangiopathy affecting not only the eye but also organs such as the heart may play a role in the pathogenesis of cardiovascular disease in diabetics.

Age Factors↗
PubMed1986

Systemic hypertension and age-related maculopathy in the Framingham Study.

Analysis of data on 1,828 subjects from the Framingham Heart and Eye Studies shows a small and consistent significant association between age-related maculopathy and systemic hypertension. The association was found using blood pressure and medical history data collected both 25 years before the eye examination and concurrently with the eye examination. Prevalence of age-related maculopathy progressively increases with increasing duration of systemic hypertension. Previous epidemiologic studies of the association between systemic blood pressure and age-related maculopathy have produced conflicting results. The failure of some studies to detect an association may have resulted from inadequate sample sizes to detect the small relative risks and problems in determining the duration of the systemic hypertension.

Aged↗
PubMed1986

Epidemiologic associations with nuclear, cortical, and posterior subcapsular cataracts.

Data from the 1971-1972 National Health and Nutrition Examination Survey were used to examine the associations between specific cataract types and age, race, sex, number of years spent in school, diabetes, systolic blood pressure, urban versus rural residence, and average daily ultraviolet spectrum B (UV-B) radiation counts at the site of examination. Separate comparisons were made of persons with no lens changes (n = 1,299) and persons with cortical (n = 55), nuclear (n = 104), and posterior subcapsular cataracts (n = 18). Persons with more than one type of cataract were excluded from the analysis. Cortical cataracts were associated with age (relative risk (RR) = 11.4 for age 70 years vs. age 50 years), race (RR = 3.5 for blacks vs. whites), sex (RR = 3.0 for women vs. men), educational achievement (RR = 1.8 for less than nine years of schooling vs. college), and UV-B count (RR = 3.6 for 6.0 X 10(3) counts vs. (2.6 X 10(3) counts). Nuclear cataracts were associated with age (RR = 38.6 for age 70 years vs. age 50 years), race (RR = 1.8 for black vs. white), and residence (RR = 1.6 for rural vs. urban). Posterior subcapsular cataracts were associated with diabetes (RR = 6.6 for diabetes present vs. diabetes absent) and systolic blood pressure (RR = 2.2 for 160 mmHg vs. 120 mmHg). Cortical cataracts were more common in women and more often found in locations with increased UV-B radiation counts than either nuclear or posterior subcapsular cataracts. In diabetics, the risk of posterior subcapsular cataracts was greater than the risk of nuclear cataracts (p less than 0.05) and also appeared to be greater than the risk of cortical cataracts (p = 0.06).

Age Factors↗
PubMed1986

Comparability of ophthalmic diagnoses by clinical and Reading Center examiners in the Visual Acuity Impairment Survey Pilot Study.

Technologic advances in ophthalmic equipment offer the possibility of replacing direct clinical examinations with Reading Center evaluations of data recorded in epidemiologic studies. Clinical and Reading Center examiners made independent ophthalmic diagnoses of 133 right and 132 left eyes of 138 adults in the Visual Acuity Impairment Survey Pilot Study, carried out in three US cities, Boston, Detroit, and Minneapolis, in August 1981-December 1982. The Reading Center diagnosed eye conditions using only photographic and visual field data collected at the time of the clinical examination. In the comparisons of clinical and Reading Center evaluations reported here, only eyes judged by the examiners to have pathology severe enough to reduce visual acuity to 6/9 or worse were classified as having pathology. (No visual acuity criterion was required for the diagnosis of glaucoma or diabetic retinopathy.) There was agreement in diagnostic assessments between clinical and Reading Center examiners in about 80% of eyes. The kappa statistic, which adjusts for chance agreement, was in the fair to good range: 0.60 for 133 right eyes and 0.62 for 132 left eyes. When the Reading Center examiners were provided with additional information on medical history, refractive error and best corrected visual acuity, the agreement between clinical and Reading Center assessments among the subset of eyes with 6/9 or worse vision again was in the fair to good range, with kappas of 0.61 for 45 right eyes and 0.68 for 48 left eyes. Inter-observer agreement between Reading Center examiners in diagnosing pathology was in the good to excellent range. Use of Reading Centers in future epidemiologic studies should be considered, but elimination of the clinical examinations is not recommended until modifications in the protocol described here have been made and shown to improve levels of agreement between clinical and Reading Center examiners.

Eye Diseases↗
PubMed1985

Cooperativity among manganese-binding sites in the H+-ATPase of chloroplasts.

Coupling factor, isolated from lettuce chloroplasts, contained several binding sites for Mn2+ ions. Three of these sites showed strong cooperative interactions having a Hill coefficient of 2.9 +/- 0.20 and a Kd of 14.7 +/- 0.44 microM. Three additional non-interacting Mn2+-binding sites were found with a Kd of 46.7 +/- 2.3 microM. Chemical modification with naphthylglyoxal of 1 arginyl residue/chloroplast coupling factor 1, which inhibited ATPase activity, inhibited the cooperativity among the sites but did not prevent Mn2+ binding to the enzyme. It is suggested that the cooperative interaction among the Mn2+-binding sites is an expression of the interaction among the active sites of the enzyme which is required for catalysis.

Adenosine Triphosphate↗
PubMed1984

The prevalence of nuclear, cortical, and posterior subcapsular lens opacities in a general population sample.

Data from the 1973 to 1975 Framingham Eye Study were used to estimate the prevalence rates of nuclear, cortical, and posterior subcapsular lens opacities in persons between ages 52 and 85 years. The rates for each of the opacities increased rapidly with age, so that for the oldest age group, 75 years and over, nuclear, cortical, and posterior subcapsular opacities were found in 65.5%, 27.7% and 19.7% of persons, respectively. Nuclear opacities were the most commonly diagnosed lens change. Each of the opacities was found more often in women than in men. Among persons with senile lens changes, the proportion with more than one type of change increased from 26.5% for ages 52 to 64 years, to 47.1% for ages 75 to 85 years. The high prevalence rates for senile lens opacities (over 75% for persons aged 75 to 85 years) and the frequent occurrence of opacities in combination create methodological problems for epidemiologic studies of lens opacities.

Age Factors↗