The Escherichia coli TolC efflux pump protein is immunogenic and elicits protective antibodies.

Antimicrobial resistance is an increasing worldwide public health burden that threatens to make existent antimicrobials obsolete. An important mechanism of antimicrobial resistance is the overexpression of efflux pumps, which reduce the intracellular concentration of antimicrobials. TolC is the outer membrane protein of an efflux pump that has gained attention as a therapeutic target. Little is known about the immune response against TolC. Here we evaluated the immune response against TolC from Escherichia coli. TolC in silico epitope prediction showed several residues that could bind to human antibodies, and we showed that human plasma presented higher titers of anti-TolC IgG and IgA, than IgM. E. coli recombinant TolC protein stimulated macrophages in vitro to produce nitric oxide, as well as IL-6 and TNF-α, assessed by Griess assay and ELISA, respectively. Immunization of mice with TolC intraperitoneally and an in vitro re-stimulation led to increased T cell proliferation and IFNγ production, evaluated by flow cytometry and ELISA, respectively. TolC mouse immunization stimulated anti-TolC IgM and IgG production, with higher levels of IgG1 and IgG2, amongst the IgG subclasses. Anti-TolC murine antibodies could bind to live E. coli and increase bacterial uptake and elimination by macrophages in vitro. Intraperitoneal or intranasal, but not oral, immunizations with inactivated E. coli also led to anti-TolC antibody production. Finally, TolC immunization increased mouse survival rates to antimicrobial-sensitive or resistant E. coli infection. Our results showed that TolC is immunogenic, leading to the production of protective antibodies against E. coli, reinforcing its value as a therapeutic target.

Overview on Chikungunya Virus Infection: From Epidemiology to State-of-the-Art Experimental Models.

Chikungunya virus (CHIKV) is currently one of the most relevant arboviruses to public health. It is a member of the Togaviridae family and alphavirus genus and causes an arthritogenic disease known as chikungunya fever (CHIKF). It is characterized by a multifaceted disease, which is distinguished from other arbovirus infections by the intense and debilitating arthralgia that can last for months or years in some individuals. Despite the great social and economic burden caused by CHIKV infection, there is no vaccine or specific antiviral drugs currently available. Recent outbreaks have shown a change in the severity profile of the disease in which atypical and severe manifestation lead to hundreds of deaths, reinforcing the necessity to understand the replication and pathogenesis processes. CHIKF is a complex disease resultant from the infection of a plethora of cell types. Although there are several in vivo models for studying CHIKV infection, none of them reproduces integrally the disease signature observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the potentials and limitations of the state-of-the-art experimental models is imperative to advance in the field. In this context, the present review outlines the present knowledge on CHIKV epidemiology, replication, pathogenesis, and immunity and also brings a critical perspective on the current in vitro and in vivo state-of-the-art experimental models of CHIKF.

Zidovudine (AZT) for treatment of patients infected with human immunodeficiency virus type 1. An evaluation of effectiveness in clinical practice.

To learn about the patterns of use and the effectiveness of zidovudine therapy in clinical practice, we conducted an observational cohort study of 86 patients with human immunodeficiency virus type 1 infection. All patients were followed up for at least 6 months after starting zidovudine (AZT) therapy. Of the 86 patients, 78 (91%) initially received full-dosage zidovudine (1200 mg/d), and eight received a reduced dosage (600 mg/d). During follow-up, the number able to maintain full-dosage zidovudine therapy decreased to 54 (63%) at 3 months and 40 (47%) at 6 months. Thirty-five patients required dosage reductions that lasted at least 7 days and were not preceded by an adverse outcome (death or opportunistic infection). Overall, adverse outcomes occurred for nine (26%) of those with dosage reductions compared with 22 (43%) of 51 patients with no previous dosage change. Even after adjusting for baseline cytopenias and the time of the dosage reductions, adverse outcomes did not occur significantly more often in patients who received reductions in their zidovudine dosage. Our results indicate that full-dosage zidovudine therapy cannot be maintained for most patients infected with human immunodeficiency virus, but that clinicians need not be pessimistic about treatment outcomes when dosage reductions are needed.

Departments of medicine and international health.

There is an emerging role in international health for departments of medicine that care to accept the challenge. Supervised medical rotations in the developing world and the care of culturally distinct immigrant populations provide unique opportunities to expand the scope of medical education while emphasizing a sensitive and humanistic approach to health care. The restraints imposed by diminished laboratory support and limited availability of drugs can foster reliance on diagnostic skills and the essential elements of therapy. Medical schools may elect to become involved in international health, but they must do so without becoming exploitative. Rotations of students, residents, and faculty in both directions should lead to productive interaction at both the clinical and research levels, for all participants.

Thymic hypoplasia, splenomegaly and immune depression in guinea pigs with neonatal cytomegalovirus infection.

The effects of cytomegalovirus (CMV) infection on the spleen and thymus of neonatal guinea pigs were assessed. Guinea pigs with neonatally acquired CMV infection developed growth retardation, thymic hypoplasia and splenomegaly. Significant depletion of the T lymphocyte population occurred in the thymuses of these animals whereas inflammatory and immune proliferative responses were clearly evident in their spleens. Higher titers of infectious virus were recovered from the spleen than from the thymus. In addition, spleen cells from neonatally infected animals had significantly reduced proliferative responses to both the T-cell mitogen, concanavalin A, and the B-cell mitogen, lipopolysaccharide. Responses to concanavalin A were most severely impaired. These results point to the significant immunodepressive effect of acute CMV infection and to the dissimilar alterations induced by CMV in the spleen and thymus of acutely infected neonates.

Medical considerations for the pregnant traveler.

The care of pregnant travelers requires clinical information and skills that are derived from many disciplines. Issues to be considered include the safety of both mother and fetus during commercial air travel, vigorous exercise, scuba diving, and even high-altitude trekking. Immunizations require a balanced approach to the risk of disease versus the risks of vaccine complications. Safe or treated water sources are of paramount importance to prevent unnecessary exposure to antimicrobial and antiparasitic agents during pregnancy. Malaria prophylaxis is made even more difficult by an increasingly widespread resistance of Plasmodium species to chloroquine.

The compromised traveler.

Compromised travelers represent a diverse and challenging group of individuals. They include HIV-infected patients who are at risk for potentially adverse reactions to immunizations, and new exposures to enteric water-borne opportunistic pathogens associated with chronic infections. Such travelers may encounter unfamiliar opportunistic fungi and classical tropical infections, such as leishmaniasis, whose pathogenesis can be enhanced by the presence of prior HIV infection. Other immunocompromised groups include those who are functionally or anatomically asplenic, and patients who are iatrogenically immunosuppressed from medications utilized for solid organ transplantation, chemotherapy, or treatment of malignancies. This population of travelers also includes those with diabetes mellitus who may require adjustments in their dosing, administration, and possibly even the types of insulin used on their trips. These patients are also at greater risk for acquisition of tuberculosis, severe community-acquired pneumonia, urinary tract infections, and pyomyositis. Older travelers present both the infectious disease and travel medicine specialist with issues such events, malignancy-related infections, myocardial infarction, and other forms of cardiopulmonary compromise, which the authors address in this article.

Initial screening for antituberculous drug resistance at an inpatient facility in Leon, Nicaragua.

Antituberculous (anti-TB) drug resistance has become a major tuberculosis control issue in the United States, where this situation has closely paralleled the current acquired immunodeficiency syndrome epidemic associated with human immunodeficiency virus type-1 (HIV-1) infections. In less developed countries, especially those like Nicaragua with an apparently low prevalence of known HIV-1 infections, less is known about the epidemiology of antituberculous drug resistance. To understand the potential extent of this problem in Nicaragua, we conducted a cross-sectional prevalence study at Nicaragua's only inpatient tuberculosis treatment facility, located in Leon, Nicaragua. A radiometric method was used during recovery, purification, and drug susceptibility testing of clinical Mycobacterium tuberculosis isolates. Resistance to at least one of the major anti-TB medications was found in 15 (40.5%) of 37 sputum isolates, of which seven (19%) were resistant to either isoniazid alone, or to isoniazid plus another agent other than rifampin. Five were resistant to at least isoniazid and rifampin (i.e., 13.5% demonstrated multidrug resistance). Two isolates were resistant to pyrazinamide alone, and one was resistant to streptomycin alone. These initial results suggest that anti-TB drug resistance is a defined problem for tuberculosis control programs in Nicaragua, a problem that is largely related to individual noncompliance, lack of extensive drug susceptibility testing facilities, and a general unavailability of expensive anti-TB medications for re-treatment. Ongoing surveillance for drug resistance, using the methodology presented here, might assist Nicaraguan public health officials in their tuberculosis control programs.

The International Health Program: the fifteen-year experience with Yale University's Internal Medicine Residency Program.

The purpose of this study was to assess the impact of international health electives on physicians-in-training. A retrospective study was conducted using an anonymous, self-administered mailed survey to internal medicine residents who trained at Yale from 1982 to 1996 based on their experience with our International Health Program (IHP). The response rate was 61%, with 96 completed surveys in the participant group and 96 completed surveys in the nonparticipant group. Participants were more likely than nonparticipants to care for patients on public assistance (77 versus 49; P < 0.001) and immigrant patients (41 versus 23; P = 0.006). Among residents who changed their career plans, participants (22) were more likely than nonparticipants (14) to switch from subspecialty medicine to general medicine (P = 0.02). Participants were significantly more likely to have a positive view of health care delivery in developing countries. Compared with nonparticipants (64), IHP participants (74) believed that the physical examination is under-used by physicians from the United States as a diagnostic skill (P = 0.03). International health experiences appeared to have an important impact on the decisions and attitudes of residents.

Comparison of enzyme-linked immunosorbent and indirect immunofluorescence assays for the detection of human T-cell lymphotropic virus type-I antibodies in sera from rural Haiti.

Serum samples were obtained from 340 healthy individuals without evidence of neurologic disease living in rural Haiti. Sera were screened for antibodies to human T-cell lymphotropic virus type I (HTLV-I) using two commercially available enzyme immunoassays (EIA) and by an indirect immunofluorescence assay (IFA) using a mixture of uninfected H9 cells and HTLV-I-infected MT-2 cells. Repeatedly positive samples were confirmed by Western blot (WB). Results with the two EIA systems were concordant and detected 13 positive samples, each of which was confirmed by WB. Only 9 (69%) of 13 WB-positive sera were detected by IFA, and four additional samples, positive by IFA, could not be confirmed by WB. The prevalence of HTLV-I seropositivity in this selected rural Haitian population was 3.8% (13 of 340).

Special health considerations for travelers.

Special health considerations include many issues that affect travelers at both ends of the age spectrum. Pulmonary diseases may seriously alter the physiologic responses to both cabin pressures in commercial airliners and exposure to high altitudes, but many of these responses can be predicted by blood gas determinations and simple measurements of pulmonary function conducted at sea level. Cardiac events represent the most common and unpredictable health problems that threaten both serious morbidity and death for adult travelers. Diabetic travelers require insulin dosage adjustments during east-west travel and well-stocked travel kits with adequate supplies. Human immunodeficiency virus-infected travelers require consideration of their levels of immunosuppression at the time of immunizations and special precautions for preventing potentially chronic enteric infections. Young children pose similar questions, and there is the additional problem posed by a limited number of readily available antimalarial agents for pediatric use.

Propionibacterium acnes causes postoperative brain abscesses unassociated with foreign bodies: case reports.

Propionibacterium acnes was isolated in pure culture from brain abscesses that occurred in two patients after intracranial surgery. Although such infections are usually associated with cerebrospinal fluid shunts and other foreign bodies, these cases clearly demonstrate the pathogenicity of this anaerobic diphtheroid in the absence of such. Progression of P. acnes infection in the central nervous system can be insidious. To treat such infections adequately, therapy cannot rely upon some standard antimicrobial agents. Metronidazole, which is useful against most anaerobic organisms, is not effective against P. acnes.

Experimental Bacillus cereus post-traumatic endophthalmitis and treatment with ciprofloxacin.

BACKGROUND: Bacillus species remain an important cause of post-traumatic endophthalmitis, often causing permanent visual loss. METHODS: Twenty two rabbits were used to evaluate the clinical and histological findings of Bacillus cereus experimental post-traumatic endophthalmitis. Eyes that had received a scleral laceration and surgical repair were inoculated with Bacillus cereus. Thirty four other rabbits were used to evaluate the efficacy of intravitreal ciprofloxacin in treating experimental disease. RESULTS: Animals developed a post-traumatic endophthalmitis that closely mimicked human disease, characterised by a rapidly progressive and destructive endophthalmitis. Histological evaluation revealed retinal detachment, retinal necrosis, and the infiltration of inflammatory cells into the subretinal space. Intravitreal ciprofloxacin (100 micrograms) prevented the development of disease when given 1 hour and 6 hours after trauma and inoculation. CONCLUSIONS: Clinical and histological examination of experimental Bacillus cereus post-traumatic endophthalmitis suggests that retinal detachment and retinal necrosis play important roles in visual loss. Ciprofloxacin may be of benefit in the management of certain intraocular infections following penetrating injury.

Fulminant postsurgical Bacillus cereus meningitis: case report.

A 25-year-old woman presented with decreased level of consciousness, bilateral papilledema, and bitemporal hemianopsia. While receiving oxacillin prophylaxis, she underwent ventriculostomy and a transsphenoidal approach for the removal of a growth hormone- and prolactin-secreting adenoma of the pituitary. Within 4 days, fewer, symptoms of meningitis, and marked cerebrospinal fluid (CSF) pleocytosis developed, associated with many large Gram-positive rods in the CSF, subsequently identified as Bacillus cereus. This case emphasizes the potential for Bacillus species to cause serious disease following surgery, including meningitis after intracranial surgery. Meningitis may be severe, and organisms are often resistant to standard surgical prophylactic regimens, which might include penicillin or cephalosporin derivatives. Isolation of Bacillus species from the CSF requires evaluation; these organisms should not be dismissed as contaminants or "non-pathogens," particularly when isolated from CSF of patients who have recently undergone neurosurgical procedures.

Immunization coverage of children in a semi-urban village panchayat in Nepal, 1985.

This research project, funded by the Yale International Committee and in cooperation with UNICEF, Nepal, used a questionnaire to survey and assess the immunization status of children 3 years or younger in a semi-urban panchayat. Mothers of children ranging in age from less than 1 month to 3 years were questioned both about immunization status of their children and their own use of health care and specific sources of information. 54% (124/228) of the children had received at least one vaccine and only 4% (10/228) had full coverage with the recommended vaccines (3 doses of DPT and TOPV, one dose of measles and BCG). The mean number of vaccinations for males was significantly greater than that for females (2.12 vs 1.39, P = 0.007, t = 2.80). Male children were twice as likely to have received vaccines as females (76/122, 62% vs 48/106, 45%; Odds Ratio = 2.00). Children born at a hospital were more likely than those born at home to have been vaccinated (23/34, 68% vs 101/194, 52%; P = 0.05, chi 2 = 12.52, d.f. = 2). Most mothers obtained health information from neighbors (38%), radio (22%), or health workers (18%), and 85% of the children were born at home; the majority (164/228, 72%) of the women received assistance during childbirth, 28% of the total reported self delivery. More than 70% of the women felt that vaccinations were good preventive measures. The study results suggest that health education about immunization efforts should be focused on women and these efforts should be intensified.

Parasitic infections of the central nervous system.

The authors give a comprehensive review of the epidemiology, clinical presentations, diagnosis and current therapy of parasitic infections with CNS manifestations in both the normal and immunocompromised host. These include toxoplasmosis, malaria, amebiasis, neurocystcersosis, hydatid disease, and trichinosis. Additional sections cover disseminated strongyloidiasis, eosinophilic meningitis, visceral and ocular larva migrans, schistosomiasis, and cerebral paragonimiasis. Emphasis is on the neurologic complications of these diseases and their presentations in populations at increased risk for acquiring or reactivating these infections.

Assuring safe travel for today's elderly.

The increased availability of time and resources has made travel attractive to many elderly patients. Both healthy and chronically ill geriatric patients can travel safely and without medical complications in many circumstances. Many of these patients, however, have special health needs that call for specific advice from practitioners. Patients with medical problems, such as chronic obstructive pulmonary disease, cardiovascular disease, thrombotic disease, sinus conditions, or diabetes, should be aware of possible complications involved in travel. In addition, medical advice regarding vaccinations, traveler's diarrhea, jet lag, and malaria prophylaxis should be tailored to this population. Such a prescribed regimen may make travel safe and feasible for many geriatric patients.

Cryomyolysis in the management of uterine fibroids: technique and complications.

Uterine fibroids are common benign tumors of the uterus and a major public health problem. Between 20 and 25% of women over 35 years of age are estimated to have fibroids. Three subtypes of fibroids are recognized depending on their relationship to the myometrium, namely, submucosal, subserosal and intramural. Fibroids are frequently asymptomatic, but may be associated with menorrhagia, dysmenorrhea, pregnancy loss or infertility. They are composed predominantly of smooth muscle, with a variable amount of connective tissue, and they have a characteristic smooth white whorled appearance on cross sectional examination.

Malaria prophylaxis: taking aim at constantly moving targets.

The prevention of malaria infections is one of the most important functions that any clinician can perform for those traveling to tropical geographic regions where malaria risks are present. The prophylaxis question has become complicated by continued emergence of chloroquine-resistant strains of Plasmodium falciparum, the recent appearance of Plasmodium vivax resistance, and the availability of a wide choice of antimalarial pharmaceuticals. Chemoprophylaxis may produce different toxicities among various patient populations. With increasing numbers of women who travel during their professional lives, there are potential implications for using chemoprophylaxis during pregnancy. Children are unable to tolerate certain antimalarials because of toxicities unique for them. In some instances, the safest and most palatable formulations for children are not even available in the United States and must be purchased in Canada or elsewhere. Reliance upon chemoprophylaxis alone has proven to be increasingly futile. With the introduction of new repellent formulations and nontoxic insecticides for use on clothing or bed netting, there are non-pharmacologic adjunctive measures which can now be considered first-line for the prevention of malaria infections.