Erythema migrans: a chronicle.

Arvid Afzelius first described and named erythema migrans (EM), a clinical entity that he assumed to be caused by an agent transmitted by the bite of a tick (Ixodes reduvius). Certain neurologic, cutaneous, and other syndromes observed in Europe were recognized in the 1920s and 1930s to be disabling sequelae of EM. In the 1940s and 1950s the effectiveness of penicillin as therapy for EM was demonstrated. In 1968 the first patient with EM and neurologic sequelae in North America benefited from treatment with penicillin. In 1975, an epidemic arthropathy appeared in the area of Lyme, Connecticut. Despite resemblance to EM (the initial appearance of cutaneous lesions), the complex was called Lyme disease because of the occurrence of cardiac, neurologic, and arthritic sequelae. The vector of Lyme disease, Ixodes dammini--a tick that harbors agents that cause Lyme disease and babesiosis--was identified and characterized in 1979. The spirochete that causes Lyme disease was designated Borrelia burgdorferi. The North American and European species of spirochete and the clinical syndromes to which they are related are described.

Seasonal variation of transmission risk of Lyme disease and human babesiosis.

The seasonal host-seeking pattern of nymphal Ixodes dammini infected with Babesia microti or Borrelia burgdorferi was determined on Nantucket Island, Massachusetts, during 1985. The peak period of host-seeking by infected nymphal I. dammini occurred in May and June. On a per person-hour basis, the number of infected ticks collected reached a maximum in May (Babesia = 17.3; Borrelia = 16.2). The number of infected ticks remained high in June, but decreased notably in July, August, and September. Transmission risk of the tick-borne etiologic agents of Lyme disease and human babesiosis in Massachusetts is greatest during the late spring-early summer months of May and June.

Inoculation of guinea pigs with varicella-zoster virus via the respiratory route.

Guinea pigs were inoculated by the respiratory route with wild-type (Cyr) or vaccine (Oka) strain varicella zoster virus (VZV). Wild-type cell-free virus obtained by sonication produced neutralizing antibody responses in steroid-treated animals when given via the intratracheal route, and induced neutralizing antibody as well as a pneumonitis in normal animals when given via the intrabronchial (i.b.) route. A humoral response also followed i.b. instillation of cell-associated wild-type or vaccine strain VZV. Prior i.b. administration of thioglycollate or exposure to hyperoxia altered the number and function of pulmonary macrophages, respectively, but viral susceptibility of the guinea pigs was not enhanced. Both strains of VZV could be isolated from bronchial washings up to 48 hours after i.b. instillation of cell-associated virus, but neither strain was isolated thereafter from cultures of bronchial washings or explanted lung tissues.

Alterations in the pathogenicity of Escherichia coli K-12 after transfer of plasmid and chromosomal genes from Shigella flexneri.

A 140-megadalton plasmid (pWR110), which has previously been associated with virulence in Shigella flexneri, was transferred to Escherichia coli K-12. Segments of S. flexneri chromosomal material were then transferred to the plamid-bearing K-12 strains. The virulence of these transconjugant hybrids was assessed in the HeLa cell model, in ligated rabbit ileal loops, or in the Sereny test. A K-12 strain which harbored only pWR110 invaded HeLa cells, produced minimal lesions in the rabbit ileal mucosa, and was negative in the Sereny test. Plasmid-containing K-12 hybrids which had incorporated various shigella chromosomal regions gave differential reactions in the rabbit ileal loops and in the Sereny test. Analysis of these transconjugants indicated that three regions were linked with virulent phenotypes. These included the his region (when the genes responsible for O-antigen synthesis were cotransferred) and the kcp locus (linked to the lac-gal region). Either of these chromosomal regions was sufficient to allow invasion of the rabbit ileal mucosa. In addition to both of these regions, another shigella chromosomal segment linked to the arg and mtl loci was necessary for fluid production in the rabbit ileal loop and for a positive Sereny reaction. Thus, derivatives of an E. coli K-12 strain, constructed by the stepwise conjugal transfer of a large plasmid and three chromosomal segments from S. flexneri, appeared to contain the necessary determinants for full pathogenicity in a variety of laboratory models.

Enteropathogenicity of Aeromonas hydrophila and Plesiomonas shigelloides: prevalence among individuals with and without diarrhea in Thailand.

To evaluate the enteropathogenicity of Aeromonas hydrophila and Plesiomonas shigelloides, the rate of isolation of these organisms was compared among individuals with and without diarrhea in Thailand. In two groups of American travelers, A. hydrophila, but not P. shigelloides, was associated with episodes of travelers diarrhea more often than when individuals did not have diarrhea (P less than 0.025). Among three populations of Thais, A. hydrophila and P. shigelloides were isolated with similar frequencies from individuals with and without diarrhea. The biochemical characteristics, production of cytotoxin, and ability to distend suckling mouse intestine were similar among A. hydrophila isolates from individuals with and without diarrhea. However, cytotoxic A. hydrophila strains distended rabbit and suckling mouse intestine and produced destructive lesions in intestinal mucosa of both species of animal. P. shigelloides strains produced neither cytotoxin nor distended intestine. Oral administration of whole cultures (10(9)) of cytotoxic A. hydrophila or P. shigelloides failed to cause diarrhea in rhesus monkeys. Volunteer studies or intestinal biopsies of patients with diarrhea may be required to establish whether A. hydrophila is a gastrointestinal pathogen in humans.

Transmissible spongiform encephalopathy (Creutzfeldt-Jakob disease). Atypical clinical and pathological findings.

A middle-aged neurosurgeon had an 18-month illness characterized by abnormal sleep patterns, paresthesias, and necrotizing cutaneous lesions with vasculitis and signs of cerebral, brainstem, vestibulocerebellar, and progressive spinal cord involvement. Biopsy specimens of nerve and skin showed an acute vasculitis with endovascular cellular proliferation in the pattern of a Köhlmeier-Degos lesion and focal epidermal necrosis. Mental changes and cranial-nerve signs developed. Myoclonus occurred occasionally during sleep. Akinetic mutism ensued. At autopsy, major abnormalities were limited to the nervous system and skin. Spongiform encephalopathy typical of Creutzfeldt-Jakob disease was found with amyloid kuru plaques. A cribriform change distinct from the spongiform change was seen focally in the white matter. Scarred skin lesions and a healed, partially obliterative arteritis were noted. Inoculation of brain and lung into nonhuman primates resulted in a spongiform encephalopathy.

Protective effect of low-dose interferon against neonatal murine cytomegalovirus infection.

Mice were injected with 10 to 5,000 reference units of interferon intraperitoneally or subcutaneously within 24 h of birth and reinoculated intraperitoneally 24 h later with 200 plaque-forming units of murine cytomegalovirus. Mock interferon and virus diluent were the control inocula. Infection of mock interferon-treated mice resulted in significant retardation of growth, accompanied by tissue injury and a depressed blastogenic response of splenic lymphocytes. Prophylactic administration of interferon prevented growth retardation and resulted in lower tissue viral titers and diminished injurious effects of the virus. Intraperitoneal inoculation of interferon was more protective than was subcutaneous, and 10 U of interferon was often as effective as 5,000 U. Accelerated maturation and enhanced activity of lymphoid elements were observed histologically in spleens and lymph nodes of interferon-treated mice; supportive of these findings was the greater incorporation of [3H]thymidine of splenocytes from interferon-treated mice. The protective effect of interferon may, therefore, be due to stimulation or accelerated maturation of cellular immune functions.

Effect of exogenous interferon on neonatal infection with murine cytomegalovirus.

One dose of interferon given before inoculation of MCMV to the neonatal mouse resulted in less virus in the submaxillary glands and reduced tissue damage due to MCMV infection, probably by modulating the immune system.

The role of altered intestinal permeability in the pathogenesis of salmonella diarrhea in the rhesus monkey.

The pathogenesis of Salmonella diarrhea is unclear. Bacterial invasion of the ileal and colonic mucosa resulting in an intense ileocolitis regularly occurs in concert with secretion of water and sodium in jejunum, ileum, and colon. To examine the role of altered permeability in Salmonella diarrhea we studied intestinal histology, water and electrolyte transport, clearance of intravenously injected [14C]erythritol and [3H]mannitol, and changes in transmural electrical potential difference in normal and Salmonella-infected rhesus monkeys. In normal animals, absorption of water and sodium occurred in jejunum, ileum, and colon and a gradient of diminishing permeability from jejunum to ileum to colon for both erythritol and mannitol was observed. Permeability as measured by determining permeability coefficients was not increased by Salmonella infection and in fact was significantly reduced for erythritol in the jejunum of infected animals. Perfusion with hypertonic erythritol and mannitol produced the same streaming potentials (deltaPD) in control and infected animals, indicating no differences in transmucosal permeability. As a positive control, perfusion with 25 mM ethylenediaminetetraacetic acid in normal animals increased permeability, resulting in increased plasma-to-lumen isotope flux and no deltaPD in response to hypertonic perfusates. These data show that despite severe alterations in intestinal histology, transmucosal permeability remains unchanged and thus is not a contributing factor in Salmonella diarrhea.

Fluid and electrolyte transport in rhesus monkeys challenged intracecally with Shigella flexneri 2a.

Shigella flexneri 2a is an invasive enteric pathogen that may produce diarrhea when ingested by human beings and subhuman primates. We have previously shown that shigella diarrhea correlates with water and electrolyte transport abnormalities in the jejunum and colon. Dysentery alone is associated only with colonic transport abnormalities. To define the relationship between invasion and inflammation of the colon and the occurrence of jejunal transport abnormalities, we studied water and electrolyte transport, histology, and bacteriology in rhesus monkeys that were infected by introducing S. flexneri 2a directly into the cecum. In contrast to the pattern of disease seen after oral administration, cecal inoculation resulted in clinical disease in 64% of animals, of which 94% manifested dysentery alone, rarely preceded by mild diarrhea. Histologically, invasion and inflammation was limited to the colon. Secretion of water and sodium occurred in the colon of infected monkeys when compared with controls, whereas transport was normal in the jejunum and ileum. These data further demonstrate that severe dysentery can result from cecal injection of shigellae, but also suggest that the occurrence of watery diarrhea requires and may result from an undefined interaction between the jejunal mucosa and the organisms during transit through the small intestine.

Small vessel replacement with gore-tex (expanded polytetrafluoroethylene).

Conduits of expanded, fibrillated polytetrafluoroethylene (PTFE [Gore-tex]) have been evaluated as small vessel prostheses in dogs during a 6-month period. A configuration of high porosity and low density, long fibril Gore-tex was found to yield the best patency in canine arteries (femoral and carotid) and veins (femoral) as compared with more dense, less porous PTFE with shorter fibrils. Host tissue reaction showed minimal inflammation, excellent infiltration, and formation of a smooth neointima, which suggested satisfactory acceptance of the prosthesis.

Immunologic enhancement of rat renal allografts. III. Immunopathologic lesions and rejection in long-surviving passively enhanced grafts.

Immunologic enhancement of renal allografts from (Lewis times Brown Norway) F1 to Lewis rats was achieved by administering a single dose of antidonor serum at the time of transplantation. A series of grafts functioning for 1 to 4 months after transplantation were examined by light and immunofluorescence microscopy to evaluate the long-term protective effects of the enhancing serum and to determine if previously unobserved lesions appeared in long survivors. Despite the absence of detectable circulating cytotoxic alloantibody, long-term allografts showed necrotizing glomerular and arterial lesions which resembled those seen in acutely rejecting grafts and were compatible with humoral rejection. Thus, in this model, there is a late decline in the ability of passive enhancement to inhibit humoral rejection. Long-term grafts also developed tubular lesions with deposition of immunoglobulin and complement on the tubular basement membranes (TBM). Anti-TBM antibodies were demonstrated in recipients' sera and found to be organ specific but not major histocompatibility antigen or species specific. This tubular lesion is therefore a unique form of allograft injury in which the immune response is directed against tissue antigen(s) which are distinct from the major histocompatibility antigens that induce rejection.

Pathophysiology of Shigella diarrhea in the rhesus monkey: intestinal transport, morphological, and bacteriological studies.

In contrast to the "toxigenic diarrheas" caused by Vibrio cholerae and Escherichia coli, the site and mechanism of fluid loss in shigellosis are unknown. The occurrence of watery diarrhea in shigellosis suggests involvement of the small bowel. Therefore, jejunal, ileal, and colonic water and electrolyte transport was studied in Shigella flexneri 2a-infected monkeys. Infected animals fell into three groups: dysentery alone, diarrhea alone, or diarrhea and dysentery. In controls, net water, sodium, and chloride absorption was seen in the jejunum, ileum, and colon. All infected animals demonstrated diminished colonic absorption or net colonic secretion. In monkeys with dysentery alone, this was the only transport defect observed. In contrast, animals with diarrhea either alone or in combination with dysentery, exhibited net jejunum secretion. Ileal transport was normal in all animals. A severe colitis with intramucosal shigellae was seen in all symptomatic animals. In the jejunum or ileum, however, morphological changes were minimal and bacterial invasion was not seen. Therefore, unlike the "toxigenic" diarrheas," shigellosis is both a small and large intestinal disease. Mucosal invasion of the colon is essential to the development of a morphological and transport defect. Dysentery results from a colonic transport defect, while diarrhea is secondary to jejunal secretion superimposed on the defect in colonic absorption.