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Bone circulation in Hemorrhagic Shock was studied in 35 male mongrel dogs. The term hemorrhagic shock is defined in this thesis as persistent profound hypotensive syndrome, due to acute hemorrhage of more than one third of blood volume. The method of induction of shock consisted of removal of one third of estimated blood volume (8% of body weight) at a rate of 25 - 50 ml/min, and subsequently dropping the systemic blood pressure in a stepwise manner until the maintaining level of 30 - 35 mmHg is reached. The central venous pressure, pulse and respiratory rates were also recorded. Bone circulation was studied by (1) recording the blood flow through a cannula inserted into the tibial nutrient vein or artery and (2) recording the intramedullary pressure of tibia. When one third of estimated blood volume was removed, the bone blood flow through the nutrient vessel decreased to 22.5 ± 3.4% of control level. The decreased bone blood flow persisted as long as the hemorrhagic shock was maintained for 4-18 hours. The decreased bone blood flow was also evidenced by a profound and persistent fall of the intramedullary pressure of bone. Reinfusion into the animal of lost blood within fifteen minutes to six hours after hemorrhage resulted in a complete or partial recovery of the control systemic blood pressure as well as the control rate of bone blood flow and the control level of intramedullary pressure of bone. The curve showing relationship between the changes in bone blood flow and the systemic blood pressure is an exponential one with concavity towards the flow axis. This indicates that bone has a vasomotor control mechanism of increasing peripheral resistance during hemorrhagic shock. This was substantiated by the following observations: (1) The severity of decrease in bone blood flow on the side of lumbar sympathectomy was much milder (16% less) compared to the side of the intact sympathetic nerve; (2) Dibenzyline (phenoxybenzamine) a sympatholytic drug or alpha-receptor blocking agent alters the pressure-flow curve of bone circulation in chock to a linear pattern which indicates that the drug blocks the bone vasoconstricting mechanism(s). It is concluded that bone blood flow decreases in hemorrhagic shock and is not merely due to a decrease in circulatory blood volume, but also due to sympathetic and catecholamine hormonal vasoconstrictor mechanisms. / Surgery, Department of / Medicine, Faculty of / Graduate

Toxic shock syndrome toxin-1 (TSST-1), an exoprotein produced by some strains of Staphylococcus aureus, is implicated in the pathogenesis of menstrual TSS. However, its role in nonmenstrual TSS is less certain. In order to study the pathogenetic role of TSST-1 in TSS, three approaches were taken: a) to develop an ELISA for detection of TSST-1 in biologic fluids in order to verify TSST-1 production in vivo in TSS patients, b) to quantitate TSST-1 specific antibodies in the serum of TSS patients and controls to determine whether such antibodies are protective, and c) to attempt to identify other staphylococcal products which may be implicated in some forms of TSS. A sensitive and specific noncompetitive enzyme-linked immunosorbent assay (ELISA) capable of detecting TSST-1 at concentrations from 0.5 to 16 ng/ml was developed. This assay did not detect other staphylococcal enterotoxins including A, B, C₁, C₂, C₃, D and E. Possible interference by protein A was readily eliminated by pretreatment of test samples with 10% nonimmune rabbit serum. The assay was adapted for rapid screening of TSST-1 production by S. aureus isolates in culture supernatants in vitro, and for the detection of TSST-1 in vaginal washings and urine of TSS patients and healthy controls in vivo. All 35 S. aureus isolates confirmed to be TSST-1 positive by Ouchterlony immunodiffusion, and 59 of 60 isolates confirmed to be TSST-1 negative, gave concordant results by ELISA. Interestingly, toxigenic S. aureus strains isolated from TSS patients quantitatively produced significantly more toxin in vitro compared to toxigenic control strains (p<0.05, Mann-Whitney rank sum test). TSST-1 could be detected by ELISA in 3 of 4 vaginal washings collected within 3 days of hospitalization from 3 women with acute menstrual TSS, compared to 0 of 17 washings from 9 TSS women collected greater than 3 days after hospitalization (p=0.003, Fisher's exact test) and 1 of 15 washings from 14 healthy control women (p=0.016). TSST-1 was not detected in the urine of 4 acute TSS patients, 2 convalescent TSS patients or in 3 control urine tested. A sensitive and reproducible ELISA was also developed for the quantitation of TSST-1 specific IgG in serum. Anti-TSST-1 was assessed in acute and convalescent sera from 16 nonmenstrual (9 female, 7 male) and 14 menstrual TSS patients, and from 87 healthy women and 66 healthy men as controls. Quantitative levels of anti-TSST-1 in the study groups were calculated as the percent of standard activity (POSA) relative to a medium titre reference serum standard. ELISA titers in acute sera from menstrual TSS (26.2 ± 5.2, mean POSA ± S.E.M.), but not nonmenstrual TSS women (71.8 ± 18.6), were significantly lower than in healthy controls (78.9 ± 7.3) (p<0.01, Mam-Whitney test). Titers from menstrual TSS patients remained low (25.2 ± 10.7) even during late convalescence (mean duration 20 months after illness onset), compared to healthy female controls (p<0.05). Acute titers in males with TSS (37.0 ± 15.6) were also significantly lower than those in control men (114.6 + 11.0) (p<0.05). An inverse relationship of recovery of toxigenic S. aureus and anti-TSST-1 titers in acute sera of TSS patients was observed. Interestingly, antibody titers in control men were significantly higher than in control women (p<0.001). No age-dependent effects or interactive effects of age and sex on ELISA titers were observed. To enable immunoblot analyses, TSST-1 was produced and partially purified using column chromatography techniques. Percent recovery of TSST-1 from culture supernatant through to the final procedure was approximately 15.5%. The relative purity of TSST-1 (TSST-l/total protein, w/w) was increased from 0.21% in culture supernatants to 94.4% in the final product. Ouchterlony immunoprecipitation against reference rabbit antitoxin demonstrated identity with reference TSST-1 as well as with TSST-1 prepared in other laboratories. Physical characterization demonstrated a molecular weight of 24 kd and a pi of 7.0. Using pooled normal human serum as a first antibody probe, several bands in addition to the 24 kd TSST-1 band were visualized by immunoblot against our partially purified toxin as well as similar preparations obtained from other investigators. To determine whether any of the additional bands might be implicated in TSS, acute and convalescent sera from TSS patients were used to probe for immunoreactive bands in our partially purified TSST-1 as well as a commercially obtained preparation. Seroconversion was demonstrated to the 24 kd TSST-1 protein in 7 of 10 TSS patients from whom toxigenic S. aureus was isolated. In addition, seroconversion was noted to a 49 kd band in 4 patients, to a 21 kd band in 3 patients, to a 28 kd band in 1 patient and to a 32 kd band in 2 patients. In conclusion: 1) the ability to measure TSST-1 in biologic fluids lends stronger support for the role of TSST-1 in menstrual TSS patients; 2) the serologic data support the etiologic role of TSST-1 in menstrual TSS and in nonmenstrual TSS patients from whom toxigenic S. aureus could be cultured, but not for nonmenstrual TSS women from whom toxigenic S. aureus was not isolated; 3) immunoblotting results with acute and convalescent sera from TSS and control patients, not only add further support to the role of TSST-1 in patients from whom toxigenic S. aureus could be isolated, but also indicate that there may be several other staphylococcal products implicated in TSS, particularly in whom antibody to TSST-1 pre-existed in acute sera. The nonresponsiveness or lack of seroconversion to TSST-1 in some patients could suggest either: a) TSST-1 was not the etiologic agent for such patients; b) TSST-1 was the etiologic agent, but the exposure was sufficient for an immune response (similar to tetanus), or; c) some immunologic defect may be present. Future studies are required to clarify these possibilities. / Science, Faculty of / Microbiology and Immunology, Department of / Graduate

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Manipulation of high-speed duct flow by streamwise vorticity concentration that are engendered by interactions of surface-mounted passive and active flow control actuators with the cross flow is investigated experimentally in a small-scale wind tunnel. The controlled formation of these streamwise vortices can be a key element in the mitigation of the adverse flow effects in a number of applications including aero-optical aberrations owing to unsteady local transonic shocks, pressure recovery and distortion due to secondary flows in embedded propulsion system, thrusts reversal and augmentation for aerodynamic control. The effects of the actuation are investigated using various converging-diverging inserts along one of the test section walls. Passive actuation includes micro-vanes and active actuation is effected using high-frequency, surface-mounted fluidic oscillators. Hybrid actuation is demonstrated by combining the passive and active actuation approaches to yield a “fail-safe” device with significant degree of controllability. The investigations consider the effects of the surface actuation in three application areas namely, stabilization of transonic shocks, suppression of total-pressure distortion in offset ducts, and mitigation of separation in internal flow turning.

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