Biomedical subjects
S D Kirby
Publications and source records attributed to S D Kirby.
Progress on the road to new nerve agent treatments.
In the 50 years since nerve agents were developed a great deal has been learned about their acute toxicity, treatment and prophylactic strategies. However, the currently fielded treatments are not significantly different from those available at the end of World War II. Reasons for this lack of progress and strategies to circumvent those intrinsic problems that have impeded progress are discussed, with emphasis on the development of scavengers to be introduced as prophylactics that will significantly reduce the effective dose and thus protect against multiple times the normal LD50.
Issues in evaluating mass-media health communication campaigns.
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Technical modifications of the latissimus dorsi pedicled flap to increase versatility and viability.
OBJECTIVE: Describe the elevation and insetting of the pedicled latissimus dorsi musculocutaneous flap. Review history of this flap's evolution and personal series of 68 consecutive cases since 1984. STUDY DESIGN: Retrospective review. SETTING: Tertiary, referral, academic center. METHODS: Retrospective review of 68 consecutive patient records in which the pedicled latissimus dorsi musculocutaneous flap was used to reconstruct head and neck defects. Overall flap survival and postoperative complications were used as outcome measures. RESULTS: Thirty-one women and 37 men underwent reconstruction with the latissimus dorsi pedicled flap between 1984 to 1998. The mean age was 61 years. Sixty-three cases followed postoncologic ablation and 5 cases addressed traumatic tissue loss. Forty-three patients had prior radiotherapy and 26 patients had undergone prior reconstructive surgery. The overall flap survival rate was 67/68 (98.5%), with one case of complete flap necrosis. Six cases of partial flap necrosis occurred. There were 8 other minor complications including fistula, wound dehiscence, hematoma and cerebrospinal fluid accumulation. Fifty-six donor sites were closed primarily resulting in 2 dehiscences and 17 seromatas. Three of 12 skin grafts to the donor sites were compromised. CONCLUSION: The excellent flap survival rate (98.5%) is the result of proper patient selection and adherence to three technical fundamentals: skin paddle design, pedicle dissection, and pedicle stabilization. The minimal donor site morbidity also demonstrated in this series supports the continued use of the latissimus dorsi pedicled flap for reconstruction of head and neck defects.
Neural network prediction of obstructive sleep apnea from clinical criteria.
STUDY OBJECTIVES: Clinical prediction models for the diagnosis of obstructive sleep apnea (OSA) have lacked the accuracy necessary to confidently replace polysomnography (PSG). Artificial neural networks are computer programs that can be trained to predict outcomes based on experience. This study was conducted to test the hypothesis that a generalized regression neural network (GRNN) could accurately classify patients with OSA from clinical data. STUDY DESIGN: Retrospective review. SETTING: Regional sleep referral center. PATIENTS: Randomly selected records of patients referred for possible OSA. MEASUREMENTS: The neural network was trained using 23 clinical variables from 255 patients, and the predictive performance was evaluated using 150 other patients. RESULTS: The prevalence of OSA in this series of 405 patients (293 men and 112 women) was 69%. The trained GRNN had an accuracy of 91.3% (95% confidence interval [CI], 86.8 to 95.8). The sensitivity was 98.9% for having OSA (95% CI, 96.7 to 100), and the specificity was 80% (95% CI, 70 to 90). The positive predictive value that the patient would have OSA was 88.1% (95% CI, 81.8 to 94.4), whereas the negative predictive value that the patient would not have OSA (if so classified) was 98% (95% CI, 94 to 100). CONCLUSIONS: Appropriately trained GRNN has the ability to accurately rule in OSA from clinical data, and GRNN did not misclassify patients with moderate to severe OSA. In this study, use of the neural network could have reduced the number of PSG studies performed. Prospective validation of the neural network for the diagnosis of OSA is now required.
Consideration of three arenas of social control for the treatment and management of sexual offenders.
This paper sets out to explore the influences of social control upon the discourse relating to treatment and management of sexual offenders. This discussion takes as its foci three environmental arenas (social, penal/judicial and health care), and examines their influences and culpability within this context. It is not the intention of this article to present, nor does it arrive at, any answers to the perpetual concerns of treatment and management of this offender group, preferring to leave it to the individual reader to draw their own conclusions. It is accepted that there is no gender demarcation amongst sexual offenders, though in this paper, the masculine tense is used.
The Pasteurella haemolytica 35 kDa iron-regulated protein is an FbpA homologue.
In a previous investigation, a 35 kDa iron-regulated protein was identified from total cellular proteins of Pasteurella haemolytica grown under iron-depleted conditions. This study reports identification of the gene (fbpA) encoding the 35 kDa protein based on complementation of an entA Escherichia coli strain transformed with a plasmid derived from a P. haemolytica lambda ZAP II library. Cross-reactivity was demonstrated between an anti-35 kDa mAb and a 35 kDa protein expressed in this strain. Furthermore, a translated ORF identified on the recombinant plasmid corresponded with the N-terminal amino acid sequence of the intact and a CNBr-cleaved fragment of the 35 kDa iron-regulated protein. Nucleotide sequence analysis of the gene encoding the 35 kDa protein demonstrated homology with the cluster 1 group of extracellular solute-binding proteins, especially to the iron-binding proteins of this family. Complete sequence analysis of the recombinant plasmid insert identified three other predominant ORFs, two of which appeared to be in an operonic organization with fbpA. These latter components (fbpB and fbpC) showed homology to the transmembrane and ATPase components of ATP-binding cassette (ABC)-type uptake systems, respectively. Based on amino acid/DNA sequencing, citrate competition assay of iron affinity and visible wavelength spectra, it was concluded that the P. haemolytica 35 kDa protein functions as an FbpA homologue (referred to as PFbpA) and that the gene encoding this protein is part of an operon comprising a member of the FbpABC family of iron uptake systems. Primary sequence analysis revealed rather surprisingly that PFbpA is more closely related to the intracellular Mn/Fe-binding protein IdiA found in cyanobacteria than to any of the homologous FbpA proteins currently known in commensal or pathogenic members of the Pasteurellaceae or Neisseriaceae.
A Neisseria meningitidis fbpABC mutant is incapable of using nonheme iron for growth.
The neisserial fbpABC locus has been proposed to act as an iron-specific ABC transporter system. To confirm this assigned function, we constructed an fbpABC mutant in Neisseria meningitidis by insertional inactivation of fbpABC with a selectable antibiotic marker. The mutant was unable to use iron supplied from human transferrin, human lactoferrin, or iron chelates. However, the use of iron from heme and human hemoglobin was unimpaired. These results support the obligatory participation of fbpABC in neisserial periplasmic iron transport and do not indicate a role for this genetic locus in the heme iron pathway.
Nonlinear, three-dimensional finite-element model of skin biomechanics.
OBJECTIVE: The aim of this study was to expand the rigour and scope of soft-tissue finite-element modelling through the introduction of nonlinear biomechanics. The capability to simulate "tissue" movement in three-dimensional space was a priority. METHOD: A computer-based finite-element technique was used to approximate the exact solution to the governing differential equations. Common fusiform defects were "closed" in two- and three-dimensional space. Strains of approximately 17% were introduced. Skin was modelled as a nonlinear elastic anisotropic material in a laminated-composite structure undergoing large deformations and large strain. The finite-element software package for nonlinear biomechanical analysis was run on a university-based, multi-user workstation. Repeated simulations were performed. The key independent variables were the magnitude of the subcutaneous adhesion and the degree of undermining. The two dependent variables were the "closure" force and the distortion field. RESULTS: The absolute values computed for "closure" force, ranging from 4.4 N to 5.2 N, were consistent with previous animal studies. The periphery of the distortion field varied from 4.7 to 5.9 cm from the defect midline. The force of subcutaneous adhesion was varied from 2 to 20 kN/m (+900%) and led to a -19% and +16% change in the distortion field width and "closure" force, respectively. Undermining was progressively increased from 1 to 5 cm (+400%) and produced a +5% and -12% change in the width of the distortion field and the "closure" force, respectively. CONCLUSIONS: The application of nonlinear biomechanics to soft-tissue finite-element modelling has been rewarding. The results correlate well with surgical experience. With specific regard to undermining, additional insight has been gained. Undermining broad-based soft-tissue flaps has progressively limited benefits. The computational demonstration of this result, consistent with prior animal studies, has not been previously published. Future application of this technology may permit the development of more complex flaps. Animal experimentation may be reduced and/or deferred until postulated flap designs have been simulated and refined.
Characterization of a ferric-binding protein mutant in Haemophilus influenzae.
Ferric-binding proteins (FbpA) have been implicated in the transferrin receptor-mediated iron acquisition pathways of Haemophilus influenzae and Neisseria spp. These proteins are believed to function by shuttling iron from outer membrane transferrin receptors to a specific inner membrane permease complex. However, the role of these proteins has not been conclusively resolved, as attempts at creating isogenic mutants in the fbpA genes of both species have been unsuccessful, prompting the hypothesis that FbpA may play a critical role in H. influenzae and Neisseria spp. This study describes the construction and characterization of an H. influenzae isogenic fbpA mutant. It is demonstrated that this mutant is deficient in its ability to use human transferrin as a sole iron source, even though the strain is still competent for binding human transferrin. It is also demonstrated that this mutant is impaired in its ability to use ferric citrate as an iron source, and grows at a reduced rate relative to wild type in broth supplemented with protoporphyrin rather than haemin.
Biochemical characterization of a Haemophilus influenzae periplasmic iron transport operon.
Bacterial iron transport is critical for growth of pathogens in the host environment, where iron is limited as a form of nonspecific immunity. For Gram-negative bacteria such as Haemophilus influenzae, iron first must be transported across the outer membrane and into the periplasmic space, then from the periplasm to the cytosol. H. influenzae express a periplasmic iron-binding protein encoded by the hitA gene. This gene is organized as the first of a three-gene operon purported to encode a classic high affinity iron acquisition system that includes hitA, a cytoplasmic permease (hitB), and a nucleotide binding protein (hitC). In this study we describe the cloning, overexpression, and purification of the H. influenzae hitA gene product. The function of this protein is unambiguously assigned by demonstrating its ability to compete for iron bound to the chemical iron chelator 2,2'-dipyridyl, both in vitro and within the periplasmic space of a siderophore-deficient strain of Escherichia coli. Finally, the importance of a functional hitABC operon for iron acquisition is demonstrated by complementation of this siderophore-deficient E. coli to growth on dipyridyl-containing medium. These studies represent a detailed genetic, biochemical, and physiologic description of an active transport system that has evolved to efficiently transport iron and consequently is widely distributed among Gram-negative pathogenic bacteria.
The relationship between a medium secure environment and occupational stress in forensic psychiatric nurses.
The present study investigated occupational stress levels in forensic psychiatric nurses within a medium secure unit for mentally disordered offenders and examined the possible relationships between aspects of the ward environment and identified stress levels. Data were obtained through self-report measures and unit statistics using a sample of 38 nurses on two secure (high and medium) wards. No significant differences in levels of occupational stress or perception of ward environment were observed between nurses on the two wards. Global ward atmosphere scores were compared with those of a maximum secure facility in the USA, showing the unit to be highly therapeutic. Occupational stress scores for all nurses were compared with normative regional data and showed elevated scores on broad view of control, satisfaction and type A behaviour. No demographic or ward environment variables were found to be associated with these high scores. Interpretations and implications are discussed.
Phosgene effects on F-actin organization and concentration in cells cultured from sheep and rat lung.
Pulmonary edema and immunosuppression of the lung are primary causes of debilitation and death from phosgene gas exposure. The pathophysiology that gives rise to these conditions shares a common clinical pathway. However, the target cells and lesions that disrupt normal barrier function and immune response of the lung are complex and poorly understood. Using confocal laser microscopy and FITC-conjugated phalloidin, we have studied the effects of phosgene on F-actin in endothelial cells from sheep pulmonary arteries and epithelial cells from rat tracheal explants. Image analyses from attached culture systems indicate that F-actin was a sensitive target molecule in both species. Exposures ranging from 0.15 to 1.0 x LCt50 for sheep in vivo (3300 ppm.min) produced immediate, dose-dependent decreases in average F-actin content of cultured endothelial cells. Dense peripheral bands and stress fibers were diminished and partially disrupted but were not destroyed by these doses. Changes in ultrastructure and the permeability barrier of endothelial tissues included separation of basal lamina and development of paracellular leakage paths. Phosgene also decreased the F-actin in airway epithelial cells and potentiated phenotypic transformations that gave rise to progeny with dendritic processes. Differences in endothelial and airway epithelial response indicate that the cytoskeletal effects of phosgene were cell-type specific. Disruption of basal lamina, depletion of F-actin, and development of endothelial leakage paths may contribute to decreased barrier function and increased permeability of vascular tissues. Phosgene-induced transformations that involved F-actin reorganization and appearance of dendritic cells among airway epithelial may affect other functions of the lung.
Reactive oxygen species produced in metal-catalyzed oxidation of bis(trifluoromethyl)disulfide and protection by ZE.
Bis(trifluoromethyl)disulfide (TFD), used as an industrial fumigant, was found to generate a thiyl free radical as seen by EPR/spin trapping. Oxygen appears to be an absolute requirement for radical production. The results obtained in this investigation implicate the production of thiyl and reactive oxygen species (ROS), superoxide radical anion and hydroxyl radicals, during TFD autoxidation. The rate of production of these free radical intermediates was found to increase in the presence of iron(III) and copper(II). In addition, the metal ion chelator DETAPAC and ROS scavengers ethanol, mannitol, and PEG-SOD/catalase were found to inhibit free radical production. Reactive oxygen species were not formed when a high-potency zinc plus antioxidant, ZE caps, was present. These results provide support for the pro-oxidation of TFD and a protective role for zinc.
Adolescent risk behaviors and the potential for violence: a look at what's coming to campus.
This study analyzed the types and predictors of violent behaviors reported by students in Grades 11 and 12 in South Carolina. Results are based upon responses of 2,299 students from 57 schools, approximately 3% of the total state enrollment in those grades. The 70-item self-report Youth Risk Behavior Survey developed and piloted by the Federal Centers for Disease Control was used to collect data. The authors performed a series of logistic regression analyses to explore the relation of the demographic and potential risk variables to fighting and carrying weapons. Results from the simple logistic analyses, adjusting for race and gender, indicated that alcohol use, binge drinking, sexual activity, and use of any drugs were significantly associated (p < .05) with reported fighting. These variables and poor academic self-image were significantly associated with carrying weapons. Comprehensive multivariable models indicated that, when considered simultaneously, being black, male, sexually active, and engaging in binge drinking and drug use were significant predictors of fighting. Gender, but not race, alcohol use, drug use, or sexual activity, remained a significant predictor of carrying a weapon. Findings suggest that college risk-reduction and health-promotion programs should direct efforts at environmental modification, policy development and enforcement, as well as at personal change, including effective conflict resolution, stress management, and communication skills.
Formation of methemoglobin and metmyoglobin using 8-aminoquinoline derivatives or sodium nitrite and subsequent reaction with cyanide.
The kinetics of the oxidation of hemoglobin (Hb) and myoglobin (Mb) by sodium nitrite, 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-quinoline diphosphate (primaquine), 6-methoxy-8-(6-diethylaminohexylamino)-4-methyl-quinoline dihydrochloride (WR6026) and 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl- 5-[(3-trifluoromethyl)phenoxy]quinoline succinate (WR238,605) were studied at pH values ranging from 7.4 to 7.6 and at 37 +/- 1 degrees C. The reaction between Hb and primaquine, WR6026 and WR238,605 resulted in precipitation, as did the reaction between Mb and WR238,605. The reaction between nitrite ion (NO2-) and Hb showed a lag period followed by an autocatalytic phase. The data in this study are consistent with and substantiate the proposed mechanism for the Hb-NO2- oxidation reaction. The reaction between Mb and NO2- at higher NO2- concentrations also showed a lag period followed by an autocatalytic period, while at lower NO2- concentrations no lag period was seen. The data suggest a shift in rate constant at these lower NO2- concentrations. The reaction between Mb and both WR6026 and primaquine followed a two-term rate law with oxidant-dependent and -independent terms. Concentration-effect curve data, along with these results, suggest the presence of a catalytic pathway. The rates of formation of cyanomethemoglobin and cyanometmyoglobin complexes from cyanide ion and methemoglobin (MHb) and metmyoglobin (MMb), respectively, were followed in the presence of the heme oxidants. The rate constants were all within a narrow range and suggest that complexation of cyanide by MHb and MMb is not affected by the presence of oxidants.
The effect of sodium tetrathionate on cyanide conversion to thiocyanate by enzymatic and non-enzymatic mechanisms.
Sodium tetrathionate has been proposed as a cyanide antidote despite its reported toxicology and inhibitory effect on rhodanese. We investigated the effect of tetrathionate and an analog, dithionite, on rhodanese activity because of their structural similarity to thiosulfate, a known sulfane sulfur donor for this enzyme. Rhodanese activity of guinea pig liver homogenate was assayed by measuring the formation of ferric thiocyanate complex at 460 nm. With thiosulfate as a substrate, the Km for rhodanese was 6.7 mM and the Vmax was 0.67 mumol thiocyanate min-1 mg-1 protein. The conversion of cyanide to thiocyanate by rhodanese was inhibited in the presence of tetrathionate at the millimolar concentration (e.g. 1 mM) range. Dithionite had a negligible effect on rhodanese activity. Neither thiosulfate (1-100 mM) nor dithionite produced significant amounts of thiocyanate from cyanide spontaneously (i.e. non-enzymatically). However, in the absence of rhodanese, tetrathionate (1.0, 10.0 and 100.0 mM) produced a dose-dependent increase in thiocyanate. These data suggest that tetrathionate detoxifies cyanide non-enzymatically, which may, in part, account for its antidotal effects.
The inactivation of rhodanese by nitrite and inhibition by other anions in vitro.
Cyanide detoxification in mammals occurs, in part, by sulfur transfer by rhodanese to form the less toxic thiocyanate. Thiosulfate and nitrite are often used in combination for the treatment of cyanide intoxication. This report shows that nitrite can inhibit the rate of sulfur transfer by rhodanese in vitro. Nitrate, chloride, sulfate, and acetate were also examined as inhibitors. Inhibition by nitrite appeared to be more complex than for the other anions tested. Closer examination showed that nitrite can inactivate the sulfur-free rhodanese. Our observation leads to the suggestion that, in vivo, either rhodanese is maintained in its more stable sulfur-substituted form or cellular compartmentalization prevents inactivation by nitrite.