Dual role for macrophages in vivo in pathogenesis and control of murine Salmonella enterica var. Typhimurium infections

Salmonella spp. are regarded as facultative intracellular bacterial pathogens which are found inside macrophages (Mphi) after i. v. infection. It is generally assumed that Mphi restrict the replication of the bacteria during infection. In this study we examined the in vivo activities of Mphi during experimental S. typhimurium infections, using a selective liposome-based Mphi elimination technique. Unexpectedly, elimination of Mphi prior to infection with virulent S. typhimurium decreased morbidity and mortality, suggesting that Mphi mediate the pathology caused by S. typhimurium. Removal of Mphi) during vaccination with attenuated S. typhimurium did not affect protection against challenge with virulent S. typhimurium, suggesting that Mphi are not required for the induction of protective immunity and that other cells must function as antigen-presenting cell to elicit T cell-mediated protection. However, Mphi appeared to be important effectors of protection against challenge infection since elimination of Mphi from vaccinated mice prior to challenge infection with virulent S. typhimurium significantly decreased protection. These results enhance our understanding of the control of S. typhimurium growth in vivo, and moreover suggest that Mphi play a major role in the pathology of virulent S. typhimurium infections. As such, these cells may present a novel target for therapeutic intervention.     

Dactinomycin treatment of murine lupus erythematosus. I. Renal disease and longevity.

Three groups of female (NZB X NZW)F1 hybrid mice were treated with an intermittent regimen of dactinomycin (actinomycin D), 3.5 microgram. daily. Median survival was doubled in two of the groups and increased by more than 75 per cent in the third. Most of the treated animals never had significant proteinuria. When kidneys from 14 treated mice, which died between the ages of 11 and 20 months, were examined by light and fluorescence microscopy, most showed the lesions of normal aged CBA and C57BL/6 mice, some expansion of the mesangial matrix and increased cellularity, consistent with deposition of immunoglobulins and complement components in the mesangium, generally sparing the capillary loops. Four of the 14 animals, three of them long-lived, had advanced renal glomerular disease. These data indicate that dactinomycin, by whatever therapeutic mechanism, permits very extended survival of B/W female mice, the large majority of them without significant renal disease.     

Attenuation and vaccine potential of aroQ mutants of Corynebacterium pseudotuberculosis.

Corynebacterium pseudotuberculosis, a gram-positive intracellular bacterial pathogen, is the etiological agent of the disease caseous lymphadenitis (CLA) in both sheep and goats. Attenuated mutants of C. pseudotuberculosis have the potential to act as novel live veterinary vaccine vectors. We have cloned and sequenced the aroB and aroQ genes from C. pseudotuberculosis C231. By allelic exchange, aroQ mutants of both C231, designated CS100, and a pld mutant strain TB521, designated CS200, were constructed. Infection of BALB/c mice indicated that introduction of the aroQ mutation into C231 and TB521 attenuated both strains. In sublethally infected BALB/c mice, both CS100 and CS200 were cleared from spleens and livers by day 8 postinfection. The in vivo persistence of these strains was increased when the intact aroQ gene was supplied on a plasmid in trans. Mice infected with TB521 harbored bacteria in organs at least till day 8 postinfection without ill effect. When used as a vaccine, only the maximum tolerated dose of CS100 had the capacity to protect mice from homologous challenge. Vaccination with TB521 also elicited protective immunity, and this was associated with gamma interferon (IFN-gamma) production from splenocytes stimulated 7 days postvaccination. The role of IFN-gamma in controlling primary infections with C. pseudotuberculosis was examined in mice deficient for the IFN-gamma receptor (IFN-gammaR(-/-) mice). IFN-gammaR(-/-) mice cleared an infection with CS100 but were significantly more susceptible than control littermates to infection with C231 or TB521. These studies support an important role for IFN-gamma in control of primary C. pseudotuberculosis infections and indicate that aroQ mutants remain attenuated even in immunocompromised animals. This is the first report of an aroQ mutant of a bacterial pathogen, and the results may have implications for the construction of aromatic mutants of Mycobacterium tuberculosis for use as vaccines.     

The role of prolactin and testosterone in mediating seasonal differences in the self-grooming behavior of male meadow voles, Microtus pennsylvanicus

Self-grooming in response to the odors of conspecifics is a form of olfactory communication among meadow voles. The amount of time meadow voles spend self-grooming when they encounter the odors of conspecifics varies seasonally, with males targeting the odors of reproductively active females only during the breeding season. Other odor related behaviors in male voles such as odor preferences for conspecifics and the attractiveness of their odors to conspecifics vary seasonally as well. For male meadow voles, these behaviors are mediated by seasonal variations in testosterone (T) and prolactin (PRL) titers. The objective of this study was to determine whether seasonal differences in the amount of time male meadow voles self-groom in response to odors of conspecifics are mediated by seasonal rhythms in their circulating T and PRL titers. We tested the hypothesis that high titers of both T and PRL are necessary for reproductively active (long-photoperiod; LP) males and sufficient for reproductively quiescent (short-photoperiod; SP) male voles to spend more time self-grooming in response to odors of LP females than to those of other conspecifics. Results of this study demonstrate that high titers of PRL and T are necessary for LP male meadow vole to self-groom more in response to odors of LP females as compared to those of other conspecifics, but were not sufficient to induce SP males to preferentially self-groom to odors of LP females. The endocrine control of self-grooming by LP males appears to depend upon high titers of both PRL and T, which matches the endocrine mediation of other odor related behaviors in male voles. In contrast, the endocrine tissues that underlie self-grooming in SP male meadow voles appear to be refractory to the effects of LP-equivalent titers of PRL and T.     

Endoscopic sphincterotomy in the management of benign and malignant extrahepatic biliary obstruction

One hundred twenty-one patients with extrahepatic biliary obstruction underwent endoscopic sphincterotomy (EST). This was followed by balloon occlusion catheter or dormia basket stone extraction in 106 patients with choledocholithiasis, and by transpapillary biliary endoprosthesis placement in 15 patients with malignant distal common bile duct obstruction. All patients had excellent biliary decompression. Complications not requiring surgical intervention were seen in six patients. This article shows that EST is a low-risk, effective therapy for benign and malignant extrahepatic biliary obstruction.     

Argon laser trabeculoplasty as a means of decreasing intraocular pressure from "normal" levels in glaucomatous eyes

We conducted a retrospective study of 67 patients (85 eyes) with severe glaucoma to determine whether argon laser trabeculoplasty could reduce intraocular pressures below the "normal" range. All patients had initial intraocular pressures of less than or equal to 19 mm Hg. Success was defined as a decrease in intraocular pressure of at least 20%, no increase in medications, stable visual field, and no subsequent glaucoma surgery. After an average follow-up period of 30 months, treatment was successful in 31 cases. One half of the failures occurred by six months and 11 failures (30%) occurred after 12 months. Sixteen patients were able to decrease their medications. Two patients achieved intraocular pressures between 6 and 9 mm Hg and 20 between 10 and 12 mm Hg.     

Helicopter copilot workload during nap-of-the-earth flight

Two automatic navigation systems, a Doppler radar system and a projected map system, and a hand-held map were examined for their effects on copilot/navigator workload and performance. The automatic navigation systems reduced the number of navigation errors and the size of deviations from intended tract. The Doppler system reduced the time devoted to navigating and the number of verbal navigation messages exchanged between the pilot and copilot. The projected map system reduced visual workload. However, with all three navigation systems, more than 80% of the copilots' time was spent on navigation tasks, less than 10% of their time was visual "free time" that could be used for other tasks, and greater than 20% of the aircrew's time was occupied with navigation communications.     

Lymphokine-activated killer (LAK) cells can be focused at sites of tumor growth by products of macrophage activation

Successful adoptive cancer immunotherapy presumably depends on the accumulation of tumoricidal leukocytes at the sites of tumor growth. Large numbers of lymphokine-activated killer (LAK) cells can be generated in vitro by growth in high concentrations of interleukin-2 (IL-2), but relatively few arrive at the tumor site after intravenous injection. We hypothesize that the delivery of LAK cells to tumor sites may be augmented by previously demonstrated lymphocyte-recruiting factors, including activated macrophage products such as interleukin-1 (IL-1) and tumor necrosis factor. 111Indium-labeled LAK cells were injected intravenously into syngeneic mice bearing the macrophage activator endotoxin (LPS) in one hind footpad, and saline solution was injected into the contralateral footpad. Significantly more activity was recovered from the LPS-bearing footpad at all times during a 96-hour period. Recombinant IL-1 also attracted more LAK cells after injection into tumor-free hind footpads. Furthermore, LAK cells preferentially homed to hind footpads that were bearing 3-day established sarcomas after intralesional injections of LPS, IL-1, or tumor necrosis factor when compared with contralateral tumor-bearing footpads injected with saline solution alone. In preliminary experiments, mice with hind-footpad tumors appeared to survive longer after combined systemic IL-2 and LAK therapy if intralesional LPS was administered. These studies demonstrate that macrophage activation factors that have been shown capable of attracting circulating normal lymphocytes can also effectively attract LAK cells from the circulation. By the stimulation of macrophages at the sites of tumor growth, more LAK cells can be attracted. It is hoped that by "focusing" the migration of LAK cells to tumors, LAK cells and IL-2 would effect tumor regression more efficiently and with less toxicity.     

Microbiologic features and treatment of persistent peritonitis in patients in the intensive care unit

The charts of 25 patients who died in the intensive care unit of persistent peritonitis after abdominal operations were reviewed to determine the microbial flora and the efficacy of antibiotic treatment. All patients had undergone two or more surgical procedures for abdominal sepsis and 23 had at least three-system organ failure. The most common organisms cultured were: Staphylococcus epidermidis, 24 cultures from 16 patients, Candida albicans, 19 cultures from 10 patients, Pseudomonas aeruginosa, 16 cultures from 12 patients, Enterobacter, 16 cultures from 8 patients and enterococcus, 14 cultures from 8 patients. The classic isolates, Escherichia coli (11 cultures from six patients) and Bacteroides fragilis (4 cultures from three patients) were found infrequently. To determine the adequacy of antimicrobial therapy for this "new" flora, we examined the ability of appropriate agents to eradicate the micro-organism upon subsequent culture. Candida sp. were eradicated in 54% (6 of 11) of the assessable cases, while enterococcus and S. epidermidis were cleared in only 25% and 28% respectively. The spectrum of intra-abdominal organisms cultured from critically ill surgical patients in the intensive care unit differs from that seen in those with acute peritonitis. Despite administration of appropriate antimicrobial agents, these organisms tend to persist, probably reflecting impaired host defences with multiple-system organ failure rather than antimicrobial failure.