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Brucellosis remains one of the main zoonoses worldwide. Epidemiological data on human brucellosis in Spain are scarce. The objective of this study was to assess the epidemiological characteristics of inpatient brucellosis in Spain between 1997 and 2015. A retrospective longitudinal descriptive study was performed. Data were requested from the Health Information Institute of the Ministry of Health and Equality, which provided us with the Minimum Basic Data Set of patients admitted to the National Health System. We also obtained data published in the System of Obligatory Notifiable Diseases. A total of 5598 cases were registered. The period incidence rate was 0.67 (95% CI 0.65-0.68) cases per 100 000 person-years. We observed a progressive decrease in the number of cases and annual incidence rates. A total of 3187 cases (56.9%) came from urban areas. The group most at risk comprised men around the fifth decade of life. The average (±s.d.) hospital stay was 12.6 days (±13.1). The overall lethality rate of the cohort was 1.5%. The number of inpatients diagnosed with brucellosis decreased exponentially. The group of patients with the highest risk of brucellosis in our study was males under 45 years of age and of urban origin. The lethality rate has reduced to minimum values. It is probable that hospital discharge records could be a good database for the epidemiological analysis of the hospital management of brucellosis and offer a better information collection system than the notifiable diseases system (EDO in Spanish).

Introduction: Brucellosis is a zoonotic disease caused by Brucella spp. affecting multiple body systems and may lead to complications. Saudi Arabia is a country where brucellosis is endemic. This study aimed to describe the epidemiological characteristics of uncomplicated brucellosis and to assess outcomes of different antibiotic regimens., Methodology: A retrospective cohort study in a Saudi tertiary academic medical center. Adults with confirmed uncomplicated brucellosis between January 2008 and December 2018 who received antibiotics were included. The primary endpoint was clinical cure. Secondary endpoints included all-cause mortality and length of stay., Results: Fifty-four patients met the inclusion criteria and were included in the study. Twenty five patients received a combination of doxycycline, rifampin, and aminoglycoside (group 1), whereas 29 patients received doxycycline and rifampin (group 2). There was no significant difference between the two groups in clinical cure, all-cause mortality, length of stay, and end of therapy parameters, including temperature, white blood cells count, C-reactive protein levels, and erythrocyte sedimentation rates., Conclusions: Due to lack of differences in clinical outcomes, mortality, length of stay, and end of therapy parameters between the two groups, a regimen comprising two, rather than three, agents can be sufficient for uncomplicated brucellosis. This finding conforms to previous studies. Therefore, replacing rifampin with an aminoglycoside for its presumed superior efficacy as per the World Health Organization's guidelines is not substantiated by our study. Further studies with a larger sample size are required to confirm these findings., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Rawan O Al-Madfaa, Mai A Alalawi, Lana O Basudan, Shahad F Alhejaili, Khalid Eljaaly, Tariq A Madani, Abrar K Thabit.)

The aim of our study was to examine and compare the clinical presentations, complications, laboratory findings, treatment and outcome of patients with acute, subacute and chronic forms of brucellosis in a tertiary care setting. This hospital-based observational study was undertaken between April 2015 and March 2017. Patients diagnosed with brucellosis, either by blood culture and/or serology, were recruited. A total of 94 cases of brucellosis of acute, subacute and chronic forms were observed in 78.7%, 15.9% and 5.3%, respectively. Blood culture grew Brucella spp. in 70.2% cases. Serological tests showed positivity in 96.8% of the patients. Using multivariate logistic regression analysis, fever and upper back pain were significant predictors for both acute and chronic forms of the disease, respectively. There is a need to increase awareness and understand the local sero-epidemiological pattern of brucellosis as it is still little known.

Background: Knowledge of the spectrum of presentations and the outcome of congenital brucellosis should expedite diagnosis and improve prognostication., Methods: A systematic review of literature of cases of congenital brucellosis was performed on October 10, 2017 (registered as PROSPERO CRD42017072061)., Results: A case seen by the authors was added to the review, yielding 44 reported cases of which 22 (50%) were from Turkey, Saudi Arabia, or Kuwait. For cases with the gestational age reported, 23 of 37 (62%) were preterm. The species was Brucella melitensis in 35 cases, Brucella abortus in 3 cases and not documented in 6 cases. The diagnosis was based on a positive blood culture from the first day of life in 20 cases (45%). Presentation was usually typical for a bacteremic infant of that GA, but two infants were asymptomatic at diagnosis. There were two recurrences and seven deaths (six in preterm infants), but the role of Brucella infection in the deaths was not clear., Conclusion: Brucellosis remains a concern in endemic countries, adversely affecting pregnancy and very rarely causing neonatal infection. Prematurity appeared to be the prime cause of death in neonates with congenital brucellosis.

An anti-Brucella vaccine candidate comprising rough Salmonella vector delivering Brucella antigens was developed. This system provides a platform for live Brucella-free vaccine development as it can mimic active-intracellular infection of Brucella organism. Exploiting this phenomenon thus provides significant protection at a single dose and also re-assured the safety. To date, no human anti-Brucella vaccines are available, owing to the lack of safe and effective formulation. This study investigated the safety of the vaccine formulation in mice model and in vitro human cell cultures. The experiment was designed to determine the LD50 of the vaccine formulation. The vaccine formulation did not induce any mortality even when mice were administered at 8 × 10 9 CFU per oral or per subcutaneous (SC), which was 100-times more than the actual vaccine dose intended for mice model. In contrast, wild-type (WT) Salmonella positive control strain induced 100% mortality at 8 × 10 7 CFU per mice via oral or SC routes. Interaction of the vaccine with phagocytic (THP-1 derived macrophage) and non-phagocytic (Caco-2) human cell lines as well as human PBMC was investigated. In in vitro experiments, inflammatory and pyretic cytokines TNF-α, and IL-1β inductions were significantly lower in vaccine group as compared to WT group. Further, apoptosis, nitric oxide synthase and cytotoxicity inductions were comparable and not exacerbated, given that the strain is based on a rough bacterial vector that may have endotoxic lipid-A more readily exposed. These findings corroborated that the vaccine formulation is highly safe in mice model and is relatively mild in the induction of inflammatory cytokines and cellular changes in human cell lines., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Brucella spp infections of marine mammals are often asymptomatic but have been associated with reproductive losses and deaths. Zoonotic infections originating from marine isolates have also been described. Hector's dolphins (Cephalorhynchus hectori) are an endangered species with a declining population, and the role of infectious disease in population dynamics is not fully understood. In this study, 27 Hector's dolphins found dead around the New Zealand coastline between November 2006 and October 2010 were evaluated for lesions previously associated with cetacean brucellosis. Tissues were examined using histological, immunohistochemical, and molecular (polymerase chain reaction [PCR]) techniques. Seven of 27 dolphins (26%) had at least 1 tissue that was positive on PCR for Brucella spp. Lesions consistent with brucellosis were present in 10 of 27 (37%) dolphins, but in 8 of these dolphins Brucella infection could not be demonstrated in lesional tissues. Two dolphins (7%) were diagnosed with active brucellosis: 1 female with placentitis and metritis, and 1 stillborn male fetus. Brucella identified in these 2 dolphins had genetic similarity (99%) to Brucella pinnipedialis. The omp2a gene amplicon from the uterus of the female had 100% homology with ST27 genotype isolates from a human in New Zealand and a bottlenose dolphin of Pacific origin. The remaining 5 PCR-positive dolphins were assessed as having asymptomatic or latent infection. While most Brucella infections identified in this study appeared to be subclinical, the finding of 2 dolphins with reproductive disease due to Brucella infection suggests that this disease has the potential to affect reproductive success in this species.

Brucella are highly infectious bacterial pathogens responsible for brucellosis, a frequent worldwide zoonosis. The Brucella genus has recently expanded from 6 to 11 species, all of which were associated with mammals; The natural host range recently expanded to amphibians after some reports of atypical strains from frogs. Here we describe the first in depth phenotypic and genetic characterization of a Brucella strains isolated from a frog. Strain B13-0095 was isolated from a Pac-Man frog ( Ceratophyrus ornate ) at a veterinary hospital in Texas and was initially misidentified as Ochrobactrum anthropi . We found that B13-0095 belongs to a group of early-diverging brucellae that includes Brucella inopinata strain BO1 and the B. inopinata -like strain BO2, with traits that depart significantly from those of the "classical" Brucella spp. Analysis of B13-0095 genome sequence revealed several specific features that suggest that this isolate represents an intermediate between a soil associated ancestor and the host adapted "classical" species. Like strain BO2, B13-0095 does not possess the genes required to produce the perosamine based LPS found in classical Brucella , but has a set of genes that could encode a rhamnose based O-antigen. Despite this, B13-0095 has a very fast intracellular replication rate in both epithelial cells and macrophages. Finally, another major finding in this study is the bacterial motility observed for strains B13-0095, BO1, and BO2, which is remarkable for this bacterial genus. This study thus highlights several novel characteristics in strains belonging to an emerging group within the Brucella genus. Accurate identification tools for such atypical Brucella isolates and careful evaluation of their zoonotic potential, are urgently required.

A northern Gulf of Mexico (GoM) cetacean unusual mortality event (UME) involving primarily bottlenose dolphins (Tursiops truncatus) in Louisiana, Mississippi, and Alabama began in February 2010 and continued into 2014. Overlapping in time and space with this UME was the Deepwater Horizon (DWH) oil spill, which was proposed as a contributing cause of adrenal disease, lung disease, and poor health in live dolphins examined during 2011 in Barataria Bay, Louisiana. To assess potential contributing factors and causes of deaths for stranded UME dolphins from June 2010 through December 2012, lung and adrenal gland tissues were histologically evaluated from 46 fresh dead non-perinatal carcasses that stranded in Louisiana (including 22 from Barataria Bay), Mississippi, and Alabama. UME dolphins were tested for evidence of biotoxicosis, morbillivirus infection, and brucellosis. Results were compared to up to 106 fresh dead stranded dolphins from outside the UME area or prior to the DWH spill. UME dolphins were more likely to have primary bacterial pneumonia (22% compared to 2% in non-UME dolphins, P = .003) and thin adrenal cortices (33% compared to 7% in non-UME dolphins, P = .003). In 70% of UME dolphins with primary bacterial pneumonia, the condition either caused or contributed significantly to death. Brucellosis and morbillivirus infections were detected in 7% and 11% of UME dolphins, respectively, and biotoxin levels were low or below the detection limit, indicating that these were not primary causes of the current UME. The rare, life-threatening, and chronic adrenal gland and lung diseases identified in stranded UME dolphins are consistent with exposure to petroleum compounds as seen in other mammals. Exposure of dolphins to elevated petroleum compounds present in coastal GoM waters during and after the DWH oil spill is proposed as a cause of adrenal and lung disease and as a contributor to increased dolphin deaths.

Background: Recently, novel atypical Brucella strains isolated from humans and wild rodents have been reported. They are phenotypically close to Ochrobactrum species but belong to the genus Brucella, based on genetic relatedness, although genetic diversity is higher among the atypical Brucella strains than between the classic species. They were classified within or close to the novel species Brucella inopinata. However, with the exception of Brucella microti, the virulence of these novel strains has not been investigated in experimental models of infection., Methods: The type species B. inopinata strain BO1 (isolated from a human) and Brucella species strain 83-210 (isolated from a wild Australian rodent) were investigated. A classic infectious Brucella reference strain, B. suis 1330, was also used. BALB/c, C57BL/6, and CD1 mice models and C57BL/6 mouse bone-marrow-derived macrophages (BMDMs) were used as infection models., Results: Strains BO1 and 83-210 behaved similarly to reference strain 1330 in all mouse infection models: there were similar growth curves in spleens and livers of mice and similar intracellular replication rates in BMDMs. However, unlike strain 1330, strains BO1 and 83-210 showed lethality in the 3 mouse models., Conclusions: The novel atypical Brucella strains of this study behave like classic intracellular Brucella pathogens. In addition, they cause death in murine models of infection, as previously published for B. microti, another recently described environmental and wildlife species., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Brucella endocarditis (BE) is a rare but life-threatening complication of human brucellosis. The aim of this study was to investigate the course of BE along with the therapeutic interrelations. A total of 53 patients with BE hospitalised in 19 health institutions between 2006 and 2011 were included in the Gulhane study. Diagnosis of brucellosis was established by either isolation of Brucella sp. or the presence of antibodies, and the definition of endocarditis was made according to Duke's criteria. There were four treatment groups: ceftriaxone combined with oral antibiotics (Group 1); aminoglycosides combined with oral antibiotics (Group 2); oral antibiotic combinations (Group 3); and aminoglycoside plus ceftriaxone combined with an oral antibiotic (Group 4). Involvement rates of the aortic, mitral and tricuspid valves were 49.1%, 43.4% and 5.7%, respectively. Thirty-two patients (60.4%) had an underlying cardiac valvular problem, including previous prosthetic valve replacement (n=18). Medical treatment was provided to 32 patients (60.4%), whilst concordant medical and surgical approaches were provided to 21 patients (39.6%). Mortality in Group 1 was 15% (3/20), whilst in Group 2 it was 5.3% (1/19). In Group 3, 25.0% (3/12) of the cases died, whereas none of the cases in Group 4 died. In conclusion, mortality increased 47-fold with pericardial effusion and 25-fold due to congestive heart failure that developed after BE. Although mortality was lower in the aminoglycoside-containing arm (Groups 2 and 4), statistical analysis could not be performed owing to the small number of patients., (Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

In murine infections, Brucella microti exhibits an atypical and highly pathogenic behavior resulting in a mortality of 82%. In this study, the possible involvement of the virB type IV secretion system, a key virulence factor of Brucella sp., in this lethal phenotype was investigated. As previously described for B. suis, expression of the virB operon of B. microti was induced in acid minimal medium, partially mimicking intracellular environment. Early neutralization of cellular compartments abolished intracellular replication of B. microti, showing that acidity of the Brucella-containing vacuole is an essential trigger. A ΔvirB mutant of B. microti exhibited strong attenuation in murine and human macrophages in vitro. Interestingly, infection with this mutant was not lethal in Balb/c mice and lacked the typical intrasplenic peak at 3 days post-infection, hence demonstrating that lethality of B. microti in murine infection absolutely requires a functional virB operon., (© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.)

Background: The recent isolation of Brucella microti from the common vole, the red fox, and the soil raises the possibility of an eventual reemergence of brucellosis in Europe. In this work, the pathogenic potential of this new Brucella species in both in vitro and in vivo models of infection was analyzed., Methods: The ability of B. microti (as compared to that of the closely related species Brucella suis) to replicate in human macrophages and in human and murine macrophage-like cells was determined. The behavior of B. microti and B. suis was evaluated in vivo in murine models of infection with Balb/c, CD1, and C57BL/6 mice., Results: B. microti showed an enhanced capacity for intramacrophagic replication compared with that of B. suis. Surprisingly, and in contrast to other species of Brucella, 10(5) colony-forming units of B. microti killed 82% of Balb/c mice within 7 days. Infection of spleen and liver with B. microti peaked at day 3, compared with B. suis infection, which peaked at day 7. Sublethal doses of B. microti induced good protection against a subsequent challenge with lethal doses., Conclusions: In experimental cellular and murine infections, B. microti exhibited a high pathogenic potential, compared with other Brucella species.

Background: Brucella endocarditis is a life-threatening complication of human brucellosis. In this study, our aim was to evaluate the effects of combined medical and surgical treatment in the midterm to long term., Methods: We retrospectively analyzed 13 patients (mean age 44 +/- 18 years; 8 males) who were operated on from January 1993 to June 2009. Duke criteria were used for the diagnosis of endocarditis. The primary endpoint was defined as the overall mortality and readmission to the hospital during early and late follow-up periods. The other collected data included baseline and follow-up clinical findings, along with echocardiographic and laboratory measurements., Results: No patients died in the early period (up to 1 month) and 2 patients (15.3%) died during the late follow-up period. Aortic valve disease was observed in 11 of 13 patients (85%). The most commonly performed procedure was aortic valve replacement (10 of 13 patients; 77%) during a mean follow-up period of 95 +/- 60 months (range, 10 to 184; median, 74)., Conclusions: For Brucella endocarditis, perioperative antibiotic therapy combined with surgical treatment (prosthetic valve replacement) has satisfactory results and increases the quality of life in the long-term follow-up., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Brucellosis is frequently seen in Mediterranean and Middle East countries, including Turkey. We report the medical and surgical management of 31 cases of native endocarditis., Material and Method: Thirty-one patients were admitted to our clinic with suspected Brucella Endocarditis. The diagnosis was established by either isolation of Brucella species, or the presence of antibodies. Following preoperative antibiotic therapy patients underwent valve replacement with excessive tissue debridement. Patients were followed up with Brucella titers, blood cultures, and echocardiography., Results: On admission all patients were febrile and mostly dyspneic (NYHA Class 3 or 4). The blood tests were normal except for elevated ESR, CRP and serological tests. The aortic valve was involved in 19 patients, mitral valve in 7 patients, and both valves in 5. After serological confirmation of BE, antibiotic therapy was maintained. Twenty-five of the patients received rifampicine, doxycycline, and cotrimaxozole; 2 of them received a combination of rifampicine, streptomycin, and doxycycline; and 4 of them received rifampicine, tetracycline, and cotrimaxozole. Tissue loss in most of the affected leaflets and vegetations were presenting all patients. Valve replacements were performed with mechanical and biologic prostheses. All the patients were afebrile at discharge but received the antibiotics for 101, 2+/-16, 9 days. The follow-up was 37, 1+/-9, 2 months., Discussion: In our retrospective study, combination of adequate medical and surgical therapy resulted in declined morbidity and mortality rate. The valve replacement with aggressive debridement is the most important part of the treatment, which should be supported with efficient preoperative and long term postoperative medical treatment., (Copyright 2010 Wiley Periodicals, Inc.)

Brucella species are important zoonotic pathogens affecting a wide variety of mammals. Therefore, the identification of new Brucella virulence factors is of great interest in understanding bacterial pathogenesis and immune evasion. In this study, we have identified Brucella abortus vacB gene that presents 2343 nucleotides and 781 amino acids and it shows 39% identity with Shigella flexneri vacB gene that encodes an exoribonuclease RNase R involved in bacterial virulence. Further, we have inactivated Brucella vacB by gene replacement strategy generating a deletion mutant strain. In order to test the role of Brucella vacB in pathogenesis, BALB/c and interferon regulatory factor-1 (IRF-1) knockout (KO) mice received Brucella vacB mutant, the virulent parental strain 2308 or the vaccine strain RB51 and the bacterial CFU numbers in spleens and mous survival were monitored. Our results demonstrated that the B. abortus DeltavacB mutant and the wild type strain 2308 showed similar CFU numbers in BALB/c mice. Additionally, IRF-1 KO mice that received either the vacB mutant or S2308 strain died in 12-14 days postinfection; in contrast, all animals that received the RB51 vaccine strain survived for 30 days postinoculation. In summary, this study reports that the vacB gene in B. abortus has no impact on bacterial pathogenesis.

Two-dimensional gel electrophoretic analysis of cell lysates from Brucella abortus 2308 and the isogenic hfq mutant Hfq3 revealed that the RNA binding protein Hfq (also known as host factor I or HF-I) is required for the optimal stationary phase production of the periplasmic Cu,Zn superoxide dismutase SodC. An isogenic sodC mutant, designated MEK2, was constructed from B. abortus 2308 by gene replacement, and the sodC mutant exhibited much greater susceptibility to killing by O(2)(-) generated by pyrogallol and the xanthine oxidase reaction than the parental 2308 strain supporting a role for SodC in protecting this bacterium from O(2)(-) of exogenous origin. The B. abortus sodC mutant was also found to be much more sensitive to killing by cultured resident peritoneal macrophages from C57BL6J mice than 2308, and the attenuation displayed by MEK2 in cultured murine macrophages was enhanced when these phagocytes were treated with gamma interferon (IFN-gamma). The attenuation displayed by the B. abortus sodC mutant in both resting and IFN-gamma-activated macrophages was alleviated, however, when these host cells were treated with the NADPH oxidase inhibitor apocynin. Consistent with its increased susceptibility to killing by cultured murine macrophages, the B. abortus sodC mutant also displayed significant attenuation in experimentally infected C57BL6J mice compared to the parental strain. These experimental findings indicate that SodC protects B. abortus 2308 from the respiratory burst of host macrophages. They also suggest that reduced SodC levels may contribute to the attenuation displayed by the B. abortus hfq mutant Hfq3 in the mouse model.

The aims of this prospective study were to: (1) determine the rate of blood culture contamination; (2) describe and compare the epidemiologic, clinical and microbiological characteristics of hospital- and community-acquired bloodstream infections; and (3) determine the mortality resulting from bloodstream infections. The rate of true bacteremia was 12.1%, and 10.7% of cultures were contaminated. Of the 567 episodes of bloodstream infection, 73.4% were hospital-acquired, and 26.6% were community-acquired. The most commonly isolated microorganisms were staphylococci (44%, methicillin resistant 69.4%), enterococci (15%) and Escherichia coli (12.5%) in hospital-acquired episodes, and Brucella spp. (21.9%), E. coli (19.2%) and Staphylococcus aureus (14.6%, methicillin resistant 9.1%) in community-acquired episodes. While the overall mortality rate was 25.4%, death attributable to bloodstream infections was 16.6% in hospital-acquired episodes and 13.9% in community-acquired episodes. The highest mortality occurred in patients with bacteremia due to Pseudomonas aeruginosa (37.5%) in hospital-acquired episodes, and in patients with bacteremia due to Streptococcus pneumoniae (50%) in community-acquired episodes. Underlying diseases, severity of illness, presence of bladder catheter, previous use of antibiotics, tracheal intubation and adequacy of treatment were found to be significantly associated with death.

Interferon regulatory factor 1-deficient (IRF-1(-/-)) mice infected with virulent Brucella abortus 2308 at 5 x 10(5) CFU developed acute hepatitis similar to many natural hosts but, unlike natural hosts, IRF-1(-/-) mice were unable to resolve infection and died. In contrast, IRF-1(-/-) mice survived when infected at 5 x 10(5) CFU with several attenuated Brucella strains (S19, RB51, cbp, and cyd). The survival of infected IRF-1(-/-) mice is likely a function of the level of virulence of each Brucella strain and the extent of retained immunity. Further, these findings suggest that adaptive immunity may be important to the survival of IRF-1(-/-) mice since attenuated Brucella strains can protect IRF-1(-/-) mice against lethal challenge with virulent Brucella: Using the IRF-1(-/-) mouse model, the following set of criteria were identified to define Brucella virulence: (i) the day of death for 50% of mice infected with 5 x 10(5)CFU of Brucella, (ii) the extent of liver toxicity, and (iii) the minimum immunizing dose of Brucella to protect against challenge with virulent S2308. Thus, IRF-1(-/-) mice are important to determining the level of Brucella virulence, to evaluating Brucella mutants for attenuation, and to investigating adaptive immunity in brucellosis.

Hispanic immigrants are an increasing portion of the United States (US) population. In addition to being at risk for diseases common in the US-born population, Hispanic immigrants also are at risk for infections that do not usually occur in the US-born population. Thus, such diseases as tuberculosis, neurocysticercosis, brucellosis, typhoid fever, malaria, amebiasis, viral exanthems, and hepatitis need to be considered in Hispanics who present with fever or focal lesions. When included in the differential diagnosis, most of these infections can be readily diagnosed and treated with currently available methods.

The susceptibility of nine species of rodents and one species of lagomorph to Brucella suis type 4 was studied experimentally. The rodent species included: guinea pig (Cavia porcellus), Scandinavian lemming (Lemmus lemmus), brown lemming (L. sibiricus), northern red-backed vole (Clethrionomys rutilis), varying lemmings (Dicrostonyx stevensoni and D. rubricatus), yellow-cheeked vole (Microtus xanthognathus), flying squirrel (Glaucomys sabrinus) and ground squirrel (Citellus parryii). The lagomorph, Lepus americanus (varying hare), was also studied. All of these species were readily infected by intraperitoneal inoculations of brucellae. Pathologic responses were not marked in most of these species. However, both species of varying lemmings responded dramatically to infections initiated by about as few as two cfu. All individuals of both species that were not killed eventually died from the infection.

Six cases of well-documented Brucella endocarditis are reported. All the patients gave a history of ingestion of raw milk and/or being in contact with sheep and/or camels during herding. The diagnosis was based in each case on a history of ingestion of raw milk, high titres of Brucella antibodies, a positive blood culture and echocardiography. A combination of tetracycline, rifampicin and streptomycin was found to be effective in eradicating the Brucella organism. Two cases required aortic valve replacement, and another two required replacement of both aortic and mitral valves. One case died before any surgical intervention could be performed and one patient did not require surgery. Although it was noted that the Brucella organism attacks mainly valves which are already damaged, it may also attack and infect normal valves.

Different procedures have been used in attempts to increase the production of interferon by polyriboinosinic acid-polyribocytidylic acid (poly [rI].poly [rC]) in mice: simultaneous injection of lead acetate, cycloheximide, or actinomycin D and prior injection of Freund's adjuvant, chlorite-oxidized oxyamylose (COAM), endotoxin, or Brucella abortus. In the experimental conditions tested, lead acetate, cycloheximide, Freund's adjuvant, and COAM brought about a parallel increase in interferon production and toxicity (lethality) of poly (rI).poly (rC); actinomycin D, endotoxin, and B. abortus increased the lethality of poly (rI).poly (rC) without a concomitant raise of its interferon-inducing capacity. Our results indicate that no significant increase in interferon production (or antiviral activity, as far as the antiviral activity is accounted for by interferon production) without an accompanying increase in toxicity can be achieved with poly (rI).poly (rC) and that it might be impossible to increase its therapeutic ratio (ratio of maximum tolerated dose to minimum effective dose).