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Biomedical subjects

R C Williams

Publications and source records attributed to R C Williams.

At least 19 recordsLinked to original sources

A 3D quantitative comparison of trapezium and trapezoid relative articular and nonarticular surface areas in modern humans and great apes.

The structure and functions of the modern human hand are critical components of what distinguishes Homo sapiens from the great apes (Gorilla, Pan, and Pongo). In this study, attention is focused on the trapezium and trapezoid, the two most lateral bones of the distal carpal row, in the four extant hominid genera, representing the first time they have been quantified and analyzed together as a morphological-functional complex. Our objective is to quantify the relative articular and nonarticular surface areas of these two bones and to test whether modern humans exhibit significant shape differences from the great apes, as predicted by previous qualitative analyses and the functional demands of differing manipulative and locomotor strategies. Modern humans were predicted to show larger relative first metacarpal and scaphoid surfaces on the trapezium because of the regular recruitment of the thumb during manipulative behaviors; alternatively, great apes were predicted to show larger relative second metacarpal and scaphoid surfaces on the trapezoid because of the functional demands on the hands during locomotor behaviors. Modern humans were also expected to exhibit larger relative mutual joint surfaces between the trapezoid and adjacent carpals than do the great apes because of assumed transverse loads generated by the functional demands of the modern human power grip. Using 3D bone models acquired through laser digitizing, the relative articular and nonarticular areas on each bone are quantified and compared. Multivariate analyses of these data clearly distinguish modern humans from the great apes. In total, the observed differences between modern humans and the great apes support morphological predictions based on the fact that this region of the human wrist is no longer involved in weight-bearing during locomotor behavior and is instead recruited solely for manipulative behaviors. The results provide the beginnings of a 3D comparative standard against which further extant and fossil primate wrist bones can be compared within the contexts of manipulative and locomotor behaviors.

Anatomy, Comparative↗

Periodontal disease -- the emergence of a risk for systemic conditions: pre-term low birth weight.

This paper addresses the problem of adverse pregnancy outcome in relation to periodontal disease. There is compelling evidence that a link exists between pre-term low birth weight (PLBW) and periodontitis. Although 25% to 50% of PLBW deliveries occur without any known aetiology, there is increasing evidence that infection may play a significant role in pre-term delivery. A model explaining the plausible relationship is proposed based upon the concept of infection leading to a cascade of inflammatory reactions associated with pre-term labour and periodontal disease. Current evidence has pointed to an interest in dental intervention studies to control periodontal disease as one of the potential strategies to reduce pre-term labour. This paper reviews the potential association between periodontal infection and adverse pregnancy outcomes.

Animals↗

Clinical relevance of adjunctive minocycline microspheres in patients with chronic periodontitis: secondary analysis of a phase 3 trial.

BACKGROUND: A recent Phase 3 trial demonstrated that adjunctive treatment with minocycline microspheres resulted in significant reductions in patient mean probing depths as compared to scaling and root planing (SRP) alone. The objective of the present study was to evaluate clinical relevance of these changes within the trial using proposed site-based criteria. METHODS: A total of 499 patients with moderate to advanced chronic periodontitis were enrolled in a multi-center trial and randomized to either: 1) SRP alone or 2) SRP plus minocycline microspheres. Subjects received complete probing examinations including the measurement of probing depths at baseline, and 1 and 3 months. Probing depth reductions were tabulated by treatment, examination time, and baseline depths, and inter-group differences were evaluated with logistic regression models for correlated data. RESULTS: Significantly more sites treated with adjunctive minocycline microspheres exhibited probing depths < 5 mm at 1 (P = 0.0009) and 3 (P = 0.01) months as compared to sites treated with SRP alone, both in the overall population and in smokers. In addition, significantly more sites decreased by 1, 2, or 3 mm in the adjunctive minocycline group than in the SRP alone group at 1 and 3 months, both overall as well as in smokers (P < 0.05). CONCLUSION: This secondary analysis indicates that treatment with SRP plus minocycline microspheres is consistently more effective than SRP alone in providing clinically relevant site-based responses in patients with chronic periodontitis.

Anti-Bacterial Agents↗

Optimal reconstruction of historical water supply to a distribution system: A. Methodology.

The New Jersey Department of Health and Senior Services (NJDHSS), with support from the Agency for Toxic Substances and Disease Registry (ATSDR) conducted an epidemiological study of childhood leukaemia and nervous system cancers that occurred in the period 1979 through 1996 in Dover Township, Ocean County, New Jersey. The epidemiological study explored a wide variety of possible risk factors, including environmental exposures. ATSDR and NJDHSS determined that completed human exposure pathways to groundwater contaminants occurred in the past through private and community water supplies (i.e. the water distribution system serving the area). To investigate this exposure, a model of the water distribution system was developed and calibrated through an extensive field investigation. The components of this water distribution system, such as number of pipes, number of tanks, and number of supply wells in the network, changed significantly over a 35-year period (1962--1996), the time frame established for the epidemiological study. Data on the historical management of this system was limited. Thus, it was necessary to investigate alternative ways to reconstruct the operation of the system and test the sensitivity of the system to various alternative operations. Manual reconstruction of the historical water supply to the system in order to provide this sensitivity analysis was time-consuming and labour intensive, given the complexity of the system and the time constraints imposed on the study. To address these issues, the problem was formulated as an optimization problem, where it was assumed that the water distribution system was operated in an optimum manner at all times to satisfy the constraints in the system. The solution to the optimization problem provided the historical water supply strategy in a consistent manner for each month of the study period. The non-uniqueness of the selected historical water supply strategy was addressed by the formulation of a second model, which was based on the first solution. Numerous other sensitivity analyses were also conducted using these two models. Both models are solved using a two-stage progressive optimality algorithm along with genetic algorithms (GAs) and the EPANET2 water distribution network solver. This process reduced the required solution time and generated a historically consistent water supply strategy for the water distribution system.

Algorithms↗

Optimal reconstruction of historical water supply to a distribution system: B. Applications.

In a recently completed case-control epidemiological study, the New Jersey Department of Health and Senior Services (NJDHSS) with support from the Agency for Toxic Substances and Disease Registry (ATSDR) documented an association between prenatal exposure to a specific contaminated community water source and leukaemia in female children. An important and necessary step in the epidemiological study was the reconstruction of the historical water supply strategy of the water distribution system serving the Dover Township area, New Jersey. The sensitivity of solutions to: (1) pressure and pattern factor constraints, (2) allowable operational extremes of water levels in the storage tanks, and (3) the non-uniqueness of the water supply solution are analysed in detail. The computational results show that the proposed approach yields satisfactory results for the complete set of monthly simulations and sensitivity analyses, providing a consistent approach for identifying the historical water supply strategy of the water distribution system. Sensitivity analyses indicated that the alternative strategy obtained from the revised objective function and the variation of constraints did not yield significantly different water supply characteristics. The overall analysis demonstrates that the progressive optimality genetic algorithm (POGA) developed to solve the optimization problem is an effective and efficient algorithm for the reconstruction of water supply strategies in water distribution systems.

Algorithms↗

Functional capabilities of modern and fossil hominid hands: three-dimensional analysis of trapezia.

Three-dimensional (3D) trapezium models from Homo sapiens, Gorilla gorilla, Pan troglodytes, Australopithecus afarensis (A.L.333-80), and Homo habilis (O.H.7-NNQ) were acquired through laser digitizing. Least-square planes were generated for each articular surface, and the angles between the planes were compared. Each extant species displays an overall pattern that distinguishes it from the others. The observed angles in G. gorilla and P. troglodytes are more similar to one other than either is to H. sapiens. Our results, obtained from using new 3D modeling and analytical tools, raise interesting questions about the functional capabilities of the fossil trapezia. Multivariate statistical analyses indicate that A.L.333-80 is morphologically more similar to that of modern humans, whereas the O.H.7 trapezium is more similar to that of the gorilla. Significant differences between A.L.333-80 and the extant species occur, but some similarities to humans suggest the ability to form the distinctively human forceful pad-to-side and three-jaw chuck grips. Some key morphological differences from humans highlighted and quantified by our research suggest limitations in the functional capabilities of the O.H.7 trapezium, particularly in those that facilitate pronation at the base of the second metacarpal. If the O.H.7 trapezium represents part of the hand responsible for manufacturing and using the stone tools found at Olduvai, our results suggest that the hand manipulated the stones in a way for which we have no modern analog. Alternative considerations are that the O.H.7 trapezium is not representative of other trapezia from its species (i.e., N=1), or that it represents another primate or hominid species.

Animals↗

Serum elevations of soluble Fas (CD95/apo-I) concur in deregulating T cell apoptosis during active lupus disease.

Apoptosis is deregulated in active systemic lupus erythematosus and Fas is overexpressed by T cells, although the role of its soluble form (sFas) is unclear. We have explored both the biological significance and structure of sFas in relation to the disease activity. Serum levels of both sFas and sFas-L were correlated with T cell apoptosis in 26 systemic lupus eythematosus patients along with measurement of poly (ADP) ribose polymerase and CK18. In addition, both proliferative rate and change of ploidy were measured in CD3+ cells after treatment with sFas. Both sFas and sFas-L correlated with apoptosis in patients with active systemic lupus eythematosus. Incubation with sFas greatly suppressed proliferation of CD3+ cells from inactive patients and healthy donors, whereas immunoprecipitation revealed both the 48-kDa full-length Fas and the 26-kDa splicing variant in sera from active patients. We postulate that sFas is released to exert a pro-apoptogen effect. It seems possible that the apoptosis program itself includes the shedding/secretion of different forms of Fas to spread a death signal.

Apoptosis↗

Safety and clinical effects of topical histatin gels in humans with experimental gingivitis.

BACKGROUND: Our research group has recently reported that exogenously applied histatins can inhibit plaque accumulation and gingival inflammation in a preclinical canine model (Paquette et al. 1997). OBJECTIVES: The aims of the present double-blinded, randomized, controlled clinical trial were to evaluate the safety and toxicity of three histatin (P-113) concentrations in gel formulations, and to assess potential clinical benefit on the development of gingivitis (partial mouth design). MATERIAL AND METHODS: One hundred and six healthy subjects were recruited and brought to optimal gingival health (GI < 0.5) prior to treatment initiation. At baseline, eligible subjects were randomized for one of the following treatments: (1) placebo; (2) 0.0625% P-113; (3) 0.125% P-113; and (4) 0.375% P-113. Patients self-applied gels twice daily for 29 days to the maxillary right quadrant with the use of customized stents. In addition, patients deferred all oral hygiene procedures within this quadrant for the duration of the treatment period. Safety was assessed in terms of physical and oral examinations, clinical laboratory testing and recording of adverse events. Clinical indices were measured weekly and included gingival index (GI), plaque index (PI) and %BOP. RESULTS: All study formulations were well tolerated by patients, and no differences in adverse event occurrences were noted among treatment groups, including taste alteration or staining. For the intent-to-treat population, significantly smaller %BOP changes were noted in subjects treated with 0.0625, 0.125 and 0.375% P-113 gels (17.4, 18.18 and 17.9%, respectively) versus placebo (28.0%) (p < 0.05) at day 29. When groups were compared in terms of per cent responders (change in %BOP < 15 or < 20%), P-113 treatment groups exhibited a higher frequency of response, especially for the 0.0625 and 0.125% P-113 formulations (p < 0.05). Although no statistically significant intergroup differences were noted for changes in GI or PI among all subjects (intent-to-treat population), significantly smaller changes in PI at day 22 were observed among compliant individuals (defined as subjects using > 60% of the target gel mass) administering P-113 gels as compared with compliant placebo subjects (p < 0.05). CONCLUSIONS: These data indicate safety and tolerance of P-113 gels for topical oral use in human subjects. These data also suggest that P-113 gels administered twice daily may reduce experimental gingivitis as measured with bleeding on probing in humans.

Adult↗

Column selection and method development for the determination of the enantiomeric purity of investigational non-nucleoside reverse transcriptase inhibitors.

DPC 961 and DPC 083 are investigational non-nucleoside reversed transcriptase inhibitors (NNRTI) being evaluated for the treatment of HIV infections (Corbett et al., Antimicrob Agents Chemother 1999;43:2893-2897). Both compounds are chiral and are synthesized as single enantiomers by an asymmetric synthetic pathway (Magnus et al., Tetrahedron Lett 2000;41:3015-3019). A chiral method was developed to control the enantiomeric purity of the drug substance and to monitor for any chiral inversion in the drug substance and in the tablet formulation during stability studies. Three columns were evaluated: Chiralpak AD, Chirobiotic V, and Whelk-O. All three columns have broad applicability and can resolve enantiomers of compounds of very diverse molecular structure and polarity. The three columns were evaluated with various mobile phase compositions for their ability to resolve the racemic mixtures of DPC 083, DPC 961, and their respective enantiomers and for their selectivity toward the synthetic impurities of the two drug substances. Nonaqueous mobile phases were selected because the two drugs are poorly water soluble. The separation between the unwanted enantiomer of DPC 083 and DPC 961, which is a major impurity of DPC 083, in particular, was closely monitored. The final method was fully validated and is used for the routine testing of the drug substance and tablets.

Anti-HIV Agents↗

Influence of modified atmospheric storage, lactic acid, and NaCl on survival of sublethally heat-injured Listeria monocytogenes.

The effect of package atmosphere on survival of uninjured and sublethally heat-injured Listeria monocytogenes, inoculated onto tryptose phosphate agar containing 0.85% lactic acid and 2% NaCl (TPALAS) was investigated. Inoculated TPALAS plates were packaged in air, 100% N2 (N2), 30% CO2-70% N2 (CO2-N2), and vacuum and stored at 4 and 20 degrees C for up to 31 days. Recovery of L. monocytogenes from TPALAS was influenced by the injury status (i.e., injured and uninjured) of the inoculum, storage atmosphere (air, N2, CO2-N2, and vacuum), storage temperature (4 and 20 degrees C), and recovery media [tryptose phosphate agar (TPA) and modified Oxford agar (MOX)] (P <0.05). Overall, storage at 4 degrees C supported greater survival than storage at 20 degrees C (P< 0.05). Uninjured L. monocytogenes stored at 4 degrees C was recovered on TPA better than sublethally heat-injured L. monocytogenes stored at 40 degrees C (P < 0.05). Recovery of sublethally heat-injured L. monocytogenes stored at 4 degrees C followed the order N2 > CO2-N2 > air > vacuum (P < 0.05), whereas recovery of uninjured L. monocyrogenes stored at 4 degrees C followed the order N2 > CO2-N2 > vacuum > air (P < 0.05). Air and vacuum atmospheres supported greater survival of uninjured and heat-injured L. monocytogenes than N2 and CO2-N2 atmospheres at 20 degrees C (P < 0.05). Recovery of sublethally heat-injured L. monocytogenes stored at 20 degrees C followed the order vacuum > air> CO2-N2 = N2 (P <0.05), whereas recovery of uninjured L. monocytogenes stored at 20 degrees C followed the order vacuum > air> CO2-N2 > N2 (P<0.05). Uninjured L. monocytogenes stored under N2 at 4 degrees C was recovered best, whereas sublethally heat-injured L. monocytogenes stored under N2 at 20 degrees C was recovered poorest (P < 0.05). Factors such as package atmosphere and storage temperature, involved in the production, storage, and distribution of fermented foods must be thoroughly evaluated when determining strategies for control and detection of L. monocytogenes in such products.

Air↗

Chiral analysis of drug substance in clinical plasma extracts using achiral HPLC with circular dichroism detection.

A circular dichroism (CD) detector in series with a UV detector was used with reversed-phase gradient HPLC to do the chiral analysis of unresolved enantiomers of a single stereoisomer drug substance in extracts of clinical plasma samples. The CD/UV peak area ratio of the unresolved enantiomers in the plasma extracts was calculated and compared with pure drug substance standards to show that there was no racemization of the chiral center during pharmacokinetic studies. The CD detector can be used only with chiral compounds with a UV chromophore and the limit of detection was approximately 5 ng with the drug substance and chromatographic conditions used in this study.

Chromatography, High Pressure Liquid↗

Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives.

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.

Adolescent↗

Amphipathic variable region heavy chain peptides derived from monoclonal human Wegener's anti-PR3 antibodies stimulate lymphocytes from patients with Wegener's granulomatosis and microscopic polyangiitis.

Amphipathic variable-region heavy chain 11-mer peptides from monoclonal human IgM antiproteinase-3 antibodies were studied for peripheral blood lymphocyte stimulation in 21 patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), connective tissue disease controls and normal control subjects. Positive T-cell activation was observed in most experiments with WG patients' lymphocytes using amphipathic VH-region peptides from four different human monoclonal anti-PR3 antibodies. Control peptides of the same length but without amphipathic characteristics along with other amphipathic peptides not derived from monoclonal anti-PR3 sequence were employed as controls. No significant lymphocyte stimulation was observed with normal controls, but positive stimulation with amphipathic VH peptides was also recorded in other connective tissue disease controls mainly patients with rheumatoid arthritis. Amphipathic peptides not derived from anti-PR3 sequence did not stimulate WG lymphocytes. Our findings indicate that lymphocyte reactivity as an element of cell-mediated immunity may be activated by amphipathic VH-region amino acid sequences of autoantibodies which are themselves associated with diseases such as WG.

Adult↗

Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial.

BACKGROUND: Periodontitis is an inflammatory condition of tooth-supporting tissues that is usually treated by mechanical removal of plaque and microorganisms that adhere to teeth. This treatment, known as scaling and root planing, is not optimally effective. Adjunctive therapy with locally delivered antimicrobials has resulted in improved clinical outcomes such as probing depth reduction. This article reports on the efficacy and safety of locally administered microencapsulated minocycline. METHODS: Seven hundred forty-eight (748) patients with moderate to advanced periodontitis were enrolled in a multi-center trial and randomized to 1 of 3 treatment arms: 1) scaling and root planing (SRP) alone; 2) SRP plus vehicle; or 3) SRP plus minocycline microspheres. The primary outcome measure was probing depth reduction at 9 months. Clinical assessments were performed at baseline and 1, 3, 6, and 9 months. RESULTS: Minocycline microspheres plus scaling and root planing provided substantially more probing depth reduction than either SRP alone or SRP plus vehicle. The difference reached statistical significance after the first month and was maintained throughout the trial. The improved outcome was observed to be independent of patients' smoking status, age, gender, or baseline disease level. There was no difference in the incidence of adverse effects among treatment groups. CONCLUSIONS: Scaling and root planing plus minocycline microspheres is more effective than scaling and root planing alone in reducing probing depths in periodontitis patients.

Administration, Topical↗

Detection of nucleosome particles in serum and plasma from patients with systemic lupus erythematosus using monoclonal antibody 4H7.

OBJECTIVE: To develop a monoclonal antibody reagent that would react with nucleosomes but not directly with constituent double stranded DNA (dsDNA) or with histones. METHODS: Mice were immunized with highly purified chicken mononucleosomes and hybridomas employed to produce Mab that did not react with dsDNA or histones but still showed reactivity with nucleosomes. RESULTS: Murine monoclonal IgG antibody 4H7, generated from a mouse immunized with highly purified chicken erythrocyte nucleosomes, showed no direct ELISA reactivity with either dsDNA or isolated histones or with Sm and RNP antigens or combinations of any of these components. Mab 4H7 did show strong ELISA reactivity for chicken erythrocyte and calf thymus nucleosomes as well as for human leukocyte nucleosomes. The Mab did show strong ELISA reactions with peptides 1-25 of histone H2B and 1-21 of H3, which correspond to sequences known to be located at the surface of nucleosomes. We then measured relative serum levels of 4H7 reactive nucleosome antigen in 140 patients with systemic lupus erythematosus (SLE) in parallel with 50 non-SLE patients with other types of connective tissue disease and 92 healthy subjects. Occasional low levels of serum nucleosomal antigen were seen in 4 of 92 controls, but many patients with SLE (66/140) showed marked elevations of serum nucleosomal antigen. No difference was observed when serum or plasma samples were studied. A marked correlation (R = 0.401, p < 0.0001) was noted when disease activity score (SLEDAI) was plotted against optical density value measured with 4H7 in ELISA. Further, the levels of circulating nucleosomes were raised in SLE patients with very active central nervous system and renal involvement. CONCLUSION: Presence of nucleosome related antigen in sera from patients with SLE may provide insight into the sequence of disease related antigenic stimuli in active SLE.

Adult↗

Cold adaptation of microtubule assembly and dynamics. Structural interpretation of primary sequence changes present in the alpha- and beta-tubulins of Antarctic fishes.

The microtubules of Antarctic fishes, unlike those of homeotherms, assemble at very low temperatures (-1.8 degrees C). The adaptations that enhance assembly of these microtubules are intrinsic to the tubulin dimer and reduce its critical concentration for polymerization at 0 degrees C to approximately 0.9 mg/ml (Williams, R. C., Jr., Correia, J. J., and DeVries, A. L. (1985) Biochemistry 24, 2790-2798). Here we demonstrate that microtubules formed by pure brain tubulins of Antarctic fishes exhibit slow dynamics at both low (5 degrees C) and high (25 degrees C) temperatures; the rates of polymer growth and shortening and the frequencies of interconversion between these states are small relative to those observed for mammalian microtubules (37 degrees C). To investigate the contribution of tubulin primary sequence variation to the functional properties of the microtubules of Antarctic fishes, we have sequenced brain cDNAs that encode 9 alpha-tubulins and 4 beta-tubulins from the yellowbelly rockcod Notothenia coriiceps and 4 alpha-tubulins and 2 beta-tubulins from the ocellated icefish Chionodraco rastrospinosus. The tubulins of these fishes were found to contain small sets of unique or rare residue substitutions that mapped to the lateral, interprotofilament surfaces or to the interiors of the alpha- and beta-polypeptides; longitudinal interaction surfaces are not altered in the fish tubulins. Four changes (A278T and S287T in alpha; S280G and A285S in beta) were present in the S7-H9 interprotofilament "M" loops of some monomers and would be expected to increase the flexibility of these regions. A fifth lateral substitution specific to the alpha-chain (M302L or M302F) may increase the hydrophobicity of the interprotofilament interaction. Two hydrophobic substitutions (alpha:S187A in helix H5 and beta:Y202F in sheet S6) may act to stabilize the monomers in conformations favorable to polymerization. We propose that cold adaptation of microtubule assembly in Antarctic fishes has occurred in part by evolutionary restructuring of the lateral surfaces and the cores of the tubulin monomers.

Adaptation, Physiological↗

What you should know about PR3-ANCA. Structural aspects of antibodies to proteinase 3 (PR3).

Reactive antigenic epitopes on presumed autoantigens of biologic interest have been examined by many researchers. The central third complementarity-determining region (CDR3) residues of a human monoclonal anti-proteinase 3 (PR3) antibody contained many negatively charged aspartic acid residues, perhaps contributing to its reactivity with positively charged PR3 regions. Examination of four other human monoclonal anti-PR3 antibodies shows a number of negatively charged residues within their CDR3 regions. Mapping of segments of linear PR3-epitopes reacting with anti-neutrophil cytoplasmic antibodies (ANCA) demonstrated a preliminary estimate of structures contributing to antigenic determinants. T-cell epitopes on PR3 are reported in studies of chronic myeloid leukemia. These T-cell epitopes appear to be human leukocyte antigen (HLA) A2.1 restricted.

Animals↗