Biomedical subjects
Publications and source records attributed to D Williams.
Medical devices are often subjected to repetitive stresses, the magnitude and frequency of which means that they are susceptible to fatigue. This article discusses some of the implications of fatigue and methods for its avoidance.
For as long as biomaterials have been designed, there has been a strong interest in certain water-containing substances known as hydrogels. These have been assumed to be "biocompatible" because of certain similarities they have with tissues of the body, but they also offer a variety of other desirable characteristics. For several reasons, however, hydrogels have not fully realized their potential. This article addresses some of the issues involved.
Medical devices often need some form of protection from their immediate environment. However, with small, complex, and sensitive components, the application of a protective coating is not a trivial matter. This article discusses the problem and describes a solution.
The inherent variability in the responses of the human body to stimuli means that it is often necessary to utilize statistical methods to evaluate causal relationships in clinical research. It is necessary, however, to be cautious with statistical methods and it is imperative that scientific plausibility is included in the analysis. This article addresses some of these issues in relation to the assessment of so-called adverse effects associated with medical devices.
There is no doubt that body composition changes with aging. Some general trends have been described, including an increase in body weight and fat mass in middle age followed by a decrease in stature, weight, FFM, and body cell mass at older ages. Losses in muscle, protein, and bone mineral contribute to the decline in FFM; however, the onset and rates of decline remain controversial. Most data are available for men and women < 80 yr and we know relatively little about the normal status and the changes that occur in body composition in elderly men and women. This situation has developed in part because the changes that occur in various body constituents with aging confound the estimation of body composition by traditional techniques. Hence, there is a need for longitudinal reference data in persons 80 yr of age, both to describe the normal status and to develop valid prediction equations for estimating body composition in older men and women in settings outside the laboratory. This should be possible using new technologies and approaches based on multiple component models of body composition. An understanding of the normal changes in body composition with increasing age, the normal variation in these changes, and their health implications is important for the health, nutritional support, and pharmacologic treatment of elderly men and women in the United States. The information is especially important because elderly men and women, in terms of both numbers and health care dollars, represent the most rapidly expanding segment of the U.S. population.
The metabolism of clozapine by human liver has been investigated in vitro. Irreversible protein-binding and conjunction with model nucleophiles have been used as markers for bioactivation of clozapine, while stable metabolite formation has been assessed using radiometric HPLC. In all nine liver microsomal preparations investigated, clozapine was extensively metabolized to the stable products desmethylclozapine (range 19%-27.2%), N-oxide (1.5-20.5%) and three polar metabolites (0-20.8%), and was bioactivated to a protein-reactive metabolite (0.6-2.1%). The CYP2D6 genotype did not influence the capacity of the livers to form these metabolites. All metabolic pathways were inhibited by ketoconazole, indicating the involvement of the cytochrome P450 enzymes. Isozyme-selective inhibitor studies demonstrated that whereas demethylation was performed by CYP1A2, N-oxidation and chemically reactive metabolite formation were dependent upon multiple forms of P450. The N-oxide was readily reduced back to clozapine in the presence of NADPH, this conversion being inhibited by ascorbic acid. Glutathione (1 mM) decreased covalent binding by 70%. The amount of putative adduct formed in the presence of glutathione (13.4 +/- 0.9%) was much greater than the covalent binding (mean 1.1 +/- 0.2%). The bioactivation of clozapine was, like the N-oxidation of clozapine, a reversible process. In summary, our results indicate clozapine undergoes extensive metabolism by human liver to both stable and chemically reactive metabolites, the formation of which is catalyzed by the cytochrome P450 enzymes. The role of the reactive metabolite, which may be a free radical, in the pathogenesis of clozapine agranulocytosis and hepatotoxicity requires further study.
Clozapine, a dibenzodiazepine antipsychotic, is associated with a 0.8% incidence of agranulocytosis. This clinically restrictive toxicity has been attributed to its chemically reactive metabolites. The generation of such metabolites--assessed via covalent binding and formation of thioether adducts--was investigated using human, rat and mouse liver microsomes and human neutrophils and bone marrow cells. In every instance, one major glutathione adduct of clozapine--C-6 glutathionyl clozapine--was formed in the presence of added glutathione. Adduct formation by the neutrophils and myeloid cells was dependent on cell activation by phorbol myristate acetate. Small fractions of drug underwent covalent binding to microsomes (1-6.8%) and to protein coincubated with neutrophils (0.47%) and myeloid cells (0.21%). Clozapine did not deplete intracellular glutathione in activated neutrophils. Clozapine was also metabolized in vivo to glutathione conjugates in rats and mice, the conjugates eliminated in bile over a 3-hr period representing 38% and 33% of the dose, respectively. In addition to the principal clozapine adduct found in vitro, the C-8 glutathionyl derivative of deschloroclozapine was excreted by both species. It is concluded that clozapine undergoes bioactivation in several tissues and considerable bioactivation in vivo. The reactive metabolites generated by neutrophils and myeloid cells may play an important role in the metabolic causation of clozapine-induced agranuiocytosis.
Interleukin 6 (IL-6) is a pleiotropic cytokine produced by cells in response to injurious stimuli including viral infections and UV light. Numerous human keratinocyte-derived lines overexpress IL-6 and have been shown to respond to IL-6 as a mitogen. In a survey of such lines, we discovered that two lines, SiHa and Caski, which harbor human papillomavirus (HPV) type 16 genomes, showed the highest levels of secretion. We have, therefore, asked whether immortalization of human keratinocytes with HPV 16 could result in elevated secretion of IL-6. Oral keratinocytes were transfected with a plasmid expressing the entire HPV type 16 early region under the control of the Moloney leukemia virus long terminal repeat promoter. Three immortal lines were derived and tested for their ability to secrete biologically active IL-6. These lines showed 2-, 3-, and 9-fold increases in detectable IL-6 when compared with parental strains of keratinocytes. Cells from one of these lines, T103C, showed a negative growth response to IL-6-neutralizing antisera, suggesting that the secreted IL-6 acted as an autocrine growth stimulator.
2'-Fluoro- and 2'-amino-2'-deoxynucleoside triphosphates have been used for in vitro transcription of 2'-modified luciferase mRNA. The 2'-modified deoxynucleoside-containing transcripts were tested for the expression of luciferase in X.Laevis oocytes as well as in rabbit reticulocyte lysate. Only 2'-fluoro-2'-deoxy-adenosine-modified mRNA gave rise to luciferase as shown by SDS gel as well as by enzyme activity measurements in vivo as well as in vitro. 2'-Fluoro-2'-deoxy-pyrimidine nucleoside-modified mRNA did not give rise to luciferase activity. However, they directed incorporation of 35S-labeled methionine into peptide fragments in rabbit reticulocyte lysate indicating premature termination of translation. No or only extremely little of such incorporation could be detected with 2'-amino modified transcripts.
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Using a newly developed in vitro sheep hair culture system, we found that the pattern of sheath growth is a function of the level at which the follicle is transected. Two patterns are observed. The type 1 pattern, which occurs after the follicle is transected below the sebaceous gland, shows an equal elongation of the sheath and shaft. The type 2 pattern, which occurs when the follicle is cultured either after transection above the sebaceous gland or with an intact attached epidermis, is characterized by growth of hair shaft clean of sheath. These growth patterns, dictated by the transection level, are observed in both sheep and human follicles, are not dependent on the presence of the sebaceous gland itself, and are not influenced by the presence of co-cultured epidermis or infundibulum. Thymidine autoradiography demonstrates that transecting follicles beneath the sebaceous gland leads to an increase in DNA synthesis of the cells in the external root sheath, but does not alter DNA synthesis of the cells in the follicle matrix. Besides the obvious implications to wound closure, these findings indicate that the sebaceous gland demarcates a significant region of the follicle which influences sheath-shaft interactions and that the sheath and the shaft constitute coordinated cell populations which nevertheless respond distinctly to proliferative signals.
In a randomized prospective study ampicillin/sulbactam and cefamandole were compared in the therapy of patients hospitalized with community acquired pneumonia. Patients receiving ampicillin/sulbactam (n = 37) and cefamandole (n = 38) were similar with respect to age (mean age 70 vs. 76 years respectively), clinical characteristics, severity of illness and underlying disease. Pathogens isolated from patients in the cefamandole and ampicillin/sulbactam group, respectively, were Streptococcus pneumoniae (7 vs. 7 patients), Haemophilus parainfluenzae (7 vs. 6 patients), Haemophilus influenzae (5 vs. 5 patients), Staphylococcus aureus (5 vs. 4 patients), Escherichia coli (4 vs. 4 patients), Klebsiella pneumoniae (3 vs. 3 patients), Enterobacter spp. (2 vs. 3 patients), Moraxella catarrhalis (1 vs. 2 patients), and organisms of the oral flora (4 vs. 3 patients). The rate of resistance to penicillin was 80%, to clindamycin 76%, to erythromycin 45%, to ampicillin 43%, and to cefazolin 18%. Overall successful treatment rates of 81% for cefamandole and 97% for ampicillin/sulbactam (p = 0.05) were observed. Both cefamandole and ampicillin/sulbactam were shown to be effective agents for therapy of community acquired pneumonia; however ampicillin/sulbactam demonstrated superior overall clinical efficacy.
Transrectal ultrasonic examinations were made in 31 pregnant pony mares once a week during Months 6 to 11. Each uterine horn was divided into 3 approximately equal segments (caudal, middle, cranial). The percentage of examinations with cranial fetal presentation increased (P<0.05) progressively from 58% at Month 6 to 99% at Month 9 and was followed in all mares by entry of the fetal hind limbs into one uterine horn. The mean number of uterinehorn segments with limb parts increased (P<0.05) between each set of consecutive months from Month 6 to Month 10. Initially (Months 7 and 8), retraction of limbs after entry into the caudal and middle segments of the horn was common (31% incidence). The mean day of final entry of the limbs without detection of subsequent retraction was Day 230 +/- 2.2. Both uterine horns were closed during the examination preceding final entry of the hind limbs into one horn in 25 of 29 (86%) mares. The limbs reached the cranial segment in most examinations by Months 9 and 10 (73% and 98%). The cross-sectional height, as seen on the ultrasound screen, of both uterine horns increased (P<0.05) progressively during Months 7 to 10. Between Months 10 and 11, the height of the horn containing the limbs decreased (P<0.05); this result was attributable to a flattening of the horn and thinning (P<0.05) of the horn wall above a hoof and metatarsal bone. Apparent placental fluid (nonechogenic areas >5 mm in height) between the hind limbs and the cornual wall was detected in 0, 10, 25, and 63% (P<0.01) of examinations for Months 8 to 11, respectively. Results indicated that entry of the fetal hind limbs into a uterine horn was initially tentative and became final during a mean of Month 8. The apposition between the cornual wall and limbs was close during Months 7 to 11. By Month 11, the fetal-limb horn became flatter and thin-walled and usually contained placental fluid.
BACKGROUND/AIMS: To investigate whether healing of the esophagitis was associated with an improvement in esophageal clearance function, 15 patients with endoscopic and histologically confirmed erosive esophagitis were studied both before and after 1-month treatment with 40 mg/day of omeprazole. METHODS: All patients were studied before and after treatment by perfusion manometry to measure esophageal pressures, and a traction measuring device was used to record aboral forces generated by graded intraluminal distension. RESULTS: Before treatment, standard manometry showed reduced lower esophageal sphincter pressures (4 mm Hg [range, 2-9] vs. a control of 12 mm Hg [range, 5-25]; P < 0.01) and distal peristaltic amplitudes (29 mm Hg [range, 5-57] vs. a control of 55 mg Hg [range, 32-90]; P < 0.01). Responses to distension were also abnormal with a higher threshold for induction of contractile activity (12 mL [range, 8.5-14] vs. control values of 5 mL [range, 3-10]; P < 0.01) and weaker clearance forces (5 g [range, 0-80] vs. control values of 20 g [range, 8-90]; P < 0.01). After treatment, all patients showed endoscopic and histological evidence of healing, but not consistent improvement in either lower esophageal sphincter pressure (5 mm Hg [range, 3-7]; P > 0.05 vs. pretreatment) or peristaltic amplitude (35 mm Hg [range, 10-55]) was found. However, responses to distension did improve, with a decrease in distension threshold to 10 mL (range, 7-14; P = 0.04) and enhancement of traction force to 14 g (range, 0-95; P < 0.01). Patients with the worst pretreatment distension responses showed the least improvement with therapy. CONCLUSIONS: Improvement in esophageal clearance can be achieved by the healing of esophagitis, although the capacity for functional benefit appears to be related to the degree of dysfunction present before therapy.
OBJECTIVE: Both zinc (Zn) and magnesium (Mg) are widely used as nutritional supplements and the possibility was considered that Zn may interfere with the absorption of Mg, similar to previously reported results [1,2] obtained with the same dose of supplemental Zn on the absorption of calcium (Ca). METHODS: Mg absorption studies and metabolic balances of Mg and of Zn were carried out in three groups of adult males in a metabolic research unit during the intake of supplemental doses of 142 mg Zn as Zn sulfate (ZnSO4) during Ca intakes of 230, 500 and 800 mg/day. RESULTS: The Zn intake of 142 mg/day decreased the Mg balance and Mg absorption only during the 500 mg Ca intake compared to control values. However, the overall effect of the high Zn intake of the three groups combined, regardless of the Ca intake, was a highly significant decrease of Mg absorption and of the Mg balance. CONCLUSION: Zn supplements of 142 mg/day decreased Mg absorption and the Mg balance significantly during all Ca intakes for the three groups combined.
OBJECTIVE: In view of the widespread use of magnesium (Mg) as a nutritional supplement, we investigated whether Mg would affect the absorption of calcium (Ca) as the intestinal absorption sites for Mg and Ca differ. METHODS: The intestinal absorption of Ca, using 47CaCl2 as the tracer, and metabolic balances of Ca, phosphorus (P) and Mg were determined in five adult males under strictly controlled dietary conditions in control studies and during Mg supplementation. Mg was given as magnesium oxide (MgO) in 10 studies during two Ca intakes: five studies during a low Ca intake of 241 mg/day and five studies during a normal Ca intake of 812 mg/day. Dietary Mg intake ranged from 241 to 264 mg/day in control studies. During Mg supplementation, the total Mg intake ranged from 789 to 826 mg/day. RESULTS: There was no change of the intestinal Ca absorption during Mg supplementation during the two Ca intakes. The only change was the higher 1-hour 47Ca plasma level in the 47Ca absorption studies during the high Mg intake. Urinary Ca increased during Mg supplementation only during the low Ca intake, the Ca balance became more negative but this difference was not significant. There was also no change in Ca excretion or Ca balance during the high Mg intake at the normal Ca intake of 800 mg/day. P balance studies showed a slight decrease in urinary P and an increase in fecal P, but the P balances did not change. Mg balances were negative in control studies during the two Ca intakes. Supplemental Mg increased both urinary and fecal Mg excretion and the Mg balance became positive, but these differences were not significant. CONCLUSION: The increased Mg intake of 826 mg did not affect intestinal Ca absorption determined with tracer doses of 47Ca during Ca intakes of 241 and 812 mg/day.
The recent successes in culturing follicular papilla cells have afforded a rapid advance in our understanding of hair biology. Although the experimental manipulation of the papilla is briefly described in the original reports, a detailed description for workers starting in the field is not yet available. In this report we give a brief review of hair biology relevant to the papilla, and illustrate the method we have found successful for isolating and growing papilla cells.