As the pace of emergence and reemergence of infectious diseases quickens, the International Health Regulations, which have served as the legal and policy framework of epidemic control for 45 years, are being revised by the World Health Organization (WHO). In this article, we review the recent history, legal construction, and application of these regulations and related international treaty-based sanitary measures, especially the General Agreement on Tariffs and Trade and the Agreement on the Application of Sanitary and Phytosanitary Measures, and the history of applying the regulations in the maritime and aviation industries. This review indicates that revision efforts should address 1) the limited scope of disease syndromes (and reporters of these syndromes) now in the regulations and 2) the mismatch between multisectoral factors causing disease emergence and the single agency (WHO) administering the regulations. The revised regulations should expand the scope of reporting and simultaneously broaden international agency coordination.

A unique physical feature of Treponema pallidum, the venereally transmitted agent of human syphilis, is that its outer membrane contains 100-fold less membrane-spanning protein than the outer membranes of typical gram-negative bacteria, a property that has been related to the chronicity of syphilitic infection. These membrane-spanning T. pallidum rare outer membrane proteins, termed TROMPs, represent potential surface-exposed virulence determinants and targets of host immunity. Only recently has the outer membrane of T. pallidum been isolated and its constituent proteins identified. Five proteins of molecular mass 17-, 28-, 31-, 45-, and 65-kDa were outer membrane associated. The 17- and 45-kDa proteins, which are also present in greater amounts with the T. pallidum inner membrane protoplasmic cylinder complex, had been previously characterized lipoproteins and are, therefore, not membrane-spanning but rather membrane-anchored by their lipid moiety. In contrast, the 28-, 31-, and 65-kDa proteins are exclusively associated with the outer membrane. Both the purified native and an Escherichia coli recombinant outer membrane form of the 31-kDa protein, designated Tromp1, exhibit porin activity, thereby confirming the membrane-spanning outer membrane topology of Tromp1. The 28-kDa protein, designated Tromp2, has sequence characteristics in common with membrane-spanning outer membrane proteins and has also been recombinantly expressed in E. coli, where it targets exclusively to the E. coli outer membrane. The 65-kDa protein, designated Tromp3, is present in the least amount relative to Tromps1 and 2. Tromps 1, 2, and 3 were antigenic when tested with serum from infection and immune syphilitic rabbits and humans. These newly identified TROMPs provide a molecular foundation for the future study of syphilis pathogenesis and immunity.

Mycoplasmas are most unusual self-replicating bacteria, possessing very small genomes, lacking cell wall components, requiring cholesterol for membrane function and growth, using UGA codon for tryptophan, passing through "bacterial-retaining" filters, and displaying genetic economy that requires a strict dependence on the host for nutrients and refuge. In addition, many of the mycoplasmas pathogenic for humans and animals possess extraordinary specialized tip organelles that mediate their intimate interaction with eucaryotic cells. This host-adapted survival is achieved through surface parasitism of target cells, acquisition of essential biosynthetic precursors, and in some cases, subsequent entry and survival intracellularly. Misconceptions concerning the role of mycoplasmas in disease pathogenesis can be directly attributed to their biological subtleties and to fundamental deficits in understanding their virulence capabilities. In this review, we highlight the biology and pathogenesis of these procaryotes and provide new evidence that may lead to increased appreciation of their role as human pathogens.

Fluoroquinolones and broad-spectrum cephalosporins are the most effective antimicrobial agents for the treatment of gonorrhea. However, clinically significant resistance to fluoroquinolones has emerged in Neisseria gonorrhoeae. Fluoroquinolone-resistant strains account for approximately 10% of all gonococcal strains in Hong Kong and the Republic of the Philippines. As many as 50% of strains from some Far Eastern countries exhibit decreased susceptibility (intermediate resistance) to fluoroquinolones. Strains with intermediate resistance and clinically significant resistance are being isolated sporadically in North America, where resistant strains have been associated with an outbreak and with failure of infections to respond to treatment with doses of ciprofloxacin and ofloxacin recommended by the Centers for Disease Control and Prevention; strains exhibiting decreased susceptibility to these agents are endemic in at least one metropolitan area. Monitoring for fluoroquinolone resistance is now critical for ensuring adequate treatment of infections with resistant strains and for maximizing the time during which fluoroquinolones may be used to treat gonorrhea.

Human leukocyte antigens (HLAs) are an inherent system of alloantigens, which are the products of genes of the major histocompatibility complex (MHC). These genes span a region of approximately 4 centimorgans on the short arm of human chromosome 6 at band p 21.3 and encode the HLA class I and class II antigens, which play a central role in cell-to-cell interaction in the immune system. These antigens interact with the antigen-specific cell surface receptors of T lymphocytes (TCR) thus causing activation of the lymphocytes and the resulting immune response. Class I antigens restrict cytotoxic T-cell (CD8+) function thus killing viral infected targets, while class II antigens are involved in presentation of exogenous antigens to T-helper cells (CD4+) by antigen presenting cells (APC). The APC processes the antigens, and the immunogenic peptide is then presented at the cell surface along with the MHC molecule for recognition by the TCR. Since the MHC molecules play a central role in regulating the immune response, they may have an important role in controlling resistance and susceptibility to diseases. In this review we have highlighted studies conducted to look for an association between HLA and infectious diseases; such studies have had a variable degree of success because the pathogenesis of different diseases varies widely, and most diseases have a polygenic etiology.

Cryptosporidium parvum, a leading cause of persistent diarrhea in developing countries, is a major threat to the U.S. water supply. Able to infect with as few as 30 microscopic oocysts, Cryptosporidium is found in untreated surface water, as well as in swimming and wade pools, day-care centers, and hospitals. The organism can cause illnesses lasting longer than 1 to 2 weeks in previously healthy persons or indefinitely in immunocompromised patients; furthermore, in young children in developing countries, cryptosporidiosis predisposes to substantially increased diarrheal illnesses. Recent increased awareness of the threat of cryptosporidiosis should improve detection in patients with diarrhea. New methods such as those using polymerase chain reaction may help with detection of Cryptosporidium in water supplies or in asymptomatic carriers. Although treatment is very limited, new approaches that may reduce secretion or enhance repair of the damaged intestinal mucosa are under study.

Three outbreaks of Ebola hemorrhagic fever have recently occurred in Gabon. Virus has been isolated from clinical materials from all three outbreaks, and nucleotide sequence analysis of the glycoprotein gene of the isolates and virus present in clinical samples has been carried out. These data indicate that each of the three outbreaks should be considered an independent emergence of a different Ebola virus of the Zaire subtype. As in earlier Ebola virus outbreaks, no genetic variability was detected between virus samples taken during an individual outbreak.

Creutzfeldt-Jakob disease (CJD), and particularly its transmissibility through blood and blood products, has become a focus of concern in Canada. The recent identification of new variant CJD led to a review of the Canadian mortality database to identify any clustering of CJD by age, sex, or geographic location.

Corynebacterium pseudodiphtheriticum has rarely been reported to cause disease in humans, despite its common presence in the flora of the upper respiratory tract. We report here a case of exudative pharyngitis with pseudomembrane possibly caused by C. pseudodiphtheriticum in a 4-year-old girl. The case initially triggered clinical and laboratory suspicion of diphtheria. Because C. pseudodiphtheriticum can be easily confused with Corynebacterium diphtheriae in Gram stain, clarification of its role in the pathogenesis of exudative pharyngitis in otherwise healthy persons is of public health importance. Simple and rapid screening tests to differentiate C. pseudodiphtheriticum from C. diphtheriae should be performed to prevent unnecessary concern in the community and unnecessary outbreak control measures.

A new mycoplasmal conjunctivitis was first reported in wild house finches (Carpodacus mexicanus) in early 1994. The causative agent was identified as Mycoplasma gallisepticum (MG), a nonzoonotic pathogen of poultry that had not been associated with disease in wild songbirds. Since the initial observations of affected house finches in the mid-Atlantic region, the disease has become widespread and has been reported throughout the eastern United States and Canada. By late 1995, mycoplasmal conjunctivitis had spread to an additional species, the American goldfinch (Carduelis tristis). This new disease exemplifies the rapid spread of a pathogen following introduction into a mobile wildlife population and provides lessons that may apply to emerging human diseases.

Many infectious and parasitic diseases, especially those newly emerging or reemerging, present a difficult diagnostic challenge because of their obscurity and low incidence. Important clues that could lead to an initial diagnosis are often overlooked, misinterpreted, not linked to a disease, or disregarded. We constructed a computer-based decision support system containing 223 infectious and parasitic diseases and used it to conduct a historical intervention study based on field investigation records of 200 cases of human brucellosis and 96 cases of murine typhus that occurred in Texas from 1980 through 1989. Knowledge-based screening showed that the average number of days from the initial patient visit to the time of correct diagnosis was significantly reduced (brucellosis--from 17.9 to 4.5 days, p = 0.0001, murine typhus--from 11.5 to 8.6 days, p = 0.001). This study demonstrates the potential value of knowledge-based patient screening for rare infectious and parasitic diseases.