John B. Zabriskie

Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer's type.

Previous studies have suggested that estrogen may have an effect on cognitive and emotional function in women. Studies in rodents and non-human primates have demonstrated the presence of estrogen receptors in brain, and that estrogen can affect behavior in animals. Estrogen administration to ovariectomized rats increases choline acetyltransferase activity in certain regions of brain. Choline acetyltransferase activity is known to be significantly decreased in senile dementia-Alzheimers type (SDAT). Based on these observations, we treated seven women with SDAT with low dosages of estradiol over a six week period. A battery of assessments was performed throughout the study period. Significant improvements in three women were noted on measures of attention, orientation, mood and social interaction. These estrogen-responsive women were characterized by dementia associated with an affective disorder, older age at onset, and evidence of osteoporosis. Side effects of estradiol therapy included withdrawal bleeding in one woman and transient breast tenderness in another. Estradiol therapy thus may benefit some postmenopausal women with SDAT. The occurrence of osteoporosis in the estrogen-responsive group suggests that SDAT in some women may be associated with or related to a systemic estrogen deficiency state. However, considering the potential for serious side effects as a result of estrogen therapy, the current risk to benefit ratio precludes the routine clinical use of estrogen for dementia until careful clinical research trials have been performed.

Association of a B-cell alloantigen with susceptibility to rheumatic fever

THE possibility that genetic factors determine susceptibility to rheumatic fever following infection with Group A streptococci was suggested by epidemiological and family studies1. However, with the exception of a slightly increased frequency of Lewis group secretors2, the identification of a genetic marker in the patient group has been unsuccessful. In particular, the distribution of HLA-A and B allotypes did not reveal any consistent difference from controls3–5. We report here that a novel B-cell alloantigen has been found at a significantly increased frequency among patients with rheumatic fever, providing further evidence for the value of B-cell alloantisera as reagents for the demonstration of disease associations with genetic determinants relevant to the immune system. This alloantigen was of particular interest because it was not found to be associated with any recognised HLA-D locus determinant.

Mimetic relationships between group A streptococci and mammalian tissues.

Publisher Summary This chapter discusses the role of structural similarities between parasite and host in initiating pathological events, primarily through immunological reactions to the parasite affecting the host. It is a particularly promising approach to the study of rheumatic fever and the various connective tissue disorders and is summarized well by a pioneer in this field. In this connection, special emphasis is placed on the nature of the role this biological mimicry play in streptococcal infections and their nonsuppurative sequelae. Evidence for cross-reactions between host and parasite in other biological organisms is discussed primarily as they relate to similar observations in the Group A streptococcus and its host. Orientation to specific details of biological mimicry among bacteria or helminthes and the blood group substances, heterophile antigens, and tissue-specific antigens is obtained. The long association of this organism to the pathogenic infections of man and its relationship to the nonsuppurative sequelae following a streptococcal infection makes it an ideal model for the study of biological mimicry between host and parasite.

Why have group A streptococci remained susceptible to penicillin? Report on a symposium

In spite of 50 years of extensive use of penicillin, group A streptococci remain exquisitely susceptible to this antibiotic. This observation that continuing susceptibility has occurred despite the development of resistance to other antimicrobial agents prompted a day-long meeting at Rockefeller University (New York) in October 1996. Among the most likely explanations for this remarkable state of continued susceptibility to penicillin are that beta-lactamase may not be expressed or may be toxic to the organism and/or that low-affinity penicillin-binding proteins either are not expressed or render organisms nonviable. Other potential explanations are that circumstances favorable for the development of resistance have not yet occurred and/or that there are inefficient mechanisms for or barriers to genetic transfer. Recommended future actions include (1) additional laboratory investigations of gene transfer, penicillin-binding proteins, virulence factors, and homeologous recombination and mismatch repair; (2) increased surveillance for the development of penicillin resistance; (3) application of bioinformatics to analyze streptococcal genome sequences; and (4) development of vaccines and novel antimicrobial agents. Thus far the susceptibility of group A streptococci to penicillin has not been a major clinical or epidemiological problem. A similar observation, however, could have been made decades ago about Streptococcus pneumoniae. It is therefore vital for the scientific community to closely examine why penicillin has remained uniformly highly active against group A streptococci in order to maintain this desirable state.

The association of the human herpesvirus-6 and MS

Given the clinical and pathological nature of multiple sclerosis (MS), a viral infection has long been hypothesized as part of the etiology. In this study we investigated the possibility that the human herpesvirus-6 (HHV-6) is present in a dormant or active phase in the tissue of MS patients, specifically oligodendrocytes. Using PCR assays of MS and non-MS brain sections with primers prepared against the HHV-6 structural protein 101, the results demonstrated that 36% of MS brains were positive for the virus, while 13.5% of non-MS brains were positive. Antibody to the HHV-6 structural protein was also used in immunohistochemical experiments in brain tissue. 47% (7/15) of MS brains were positive for HHV-6, whereas 0/16 controls were positive. In addition, MS patients demonstrated high immune reactivity to this virus, even when compared to auto-immune diseases, which might cause polyclonal activation. Sera obtained from MS and control patients revealed that the IgM response to the HHV-6 virus was significantly elevated in 80% patients compared to 16% non-MS controls, P5.001. The above experiments strongly suggest that a significant number of MS brain samples contain HHV-6 antigens and genomic fragments in a dormant or active phase compared to control specimens and that MS patients mount a brisk, early IgM response.

Identification of mononuclear cells and T cell subsets in rheumatic valvulitis.

The composition of the mononuclear cellular filtrates was investigated in 13 valve specimens from nine patients with rheumatic carditis, some of whom had clinical and laboratory evidence of acute disease at the time of surgery. In acute valvulitis (AV) as well as in chronic active valvulitis (CAV), the cellular infiltrates were primarily composed of T cells and macrophages. In AV the majority of these T cells were of the helper phenotype (Leu 3a). The T cells subsets were more heterogeneous in CAV. In five valves, the helper T cells exceeded the number of suppressor T cells, whereas in three others, helper and cytotoxic/suppressor T cells were present in equal numbers. The HLA-DR antigen was expressed by the majority of the mononuclear cells and by the vascular endothelium. These findings indicate that the valvular injury may at least in part be mediated by delayed-type hypersensitivity mechanisms. Those cells comprising the Aschoff body were primarily positive for the HLA-DR and a novel monoclonal antibody called D8/17 which identifies an antigen known to be present on the B cells of rheumatic fever patients.

The Postpericardiotomy Syndrome and Antiheart Antibodies

In a prospective, double-blind study, heart-reactive antibody in high titer was detected, using an indirect immunofluorescent technique, in the serum of patients in whom the postpericardiotomy syndrome developed after intrapericardial surgery. The syndrome occurred in 26 of 86 consecutive longterm survivors of such surgery, an incidence of 30%. Presence of antibody correlated closely with the clinical syndrome. Demonstration of this antiheart antibody in high titer appears to offer laboratory confirmation of the syndrome.

Studies of the continuing susceptibility of group A streptococcal strains to penicillin during eight decades.

BACKGROUND In view of the widespread use of penicillin for >50 years for the treatment of group A streptococcal infections, we examined the question of whether there has been a change in susceptibility to penicillin in group A streptococcal strains collected during a span of 80 years (1917 to 1997). METHODS One hundred thirty-three group A streptococcal strains collected during 80 years were tested for changes in penicillin susceptibility. Three tests were used: (1) the microtiter broth minimal inhibitory concentration (MIC); (2) the minimal bactericidal concentration (MBC); and (3) the penicillin E strip MIC. RESULTS The results indicate there has been no change in the susceptibility to penicillin in these group A streptococci during the past 80 years. The microtiter broth MIC90 for the oldest strains (0.032 microg/ml) was not significantly different from those collected most recently (0.032 microg/ml); there is no statistical difference between the raw MIC data for the four collection periods (P=0.468, analysis of variance on ranks). CONCLUSIONS There has been no change in the susceptibility of group A streptococci during this time in spite of well-documented cases of penicillin resistance in other Gram-positive organisms and despite recognized resistance of group A streptococci to other antibiotics.

Inhibition of Bacterial Superantigens by Peptides and Antibodies

ABSTRACT The pyrogenic exotoxins of group A streptococci and staphylococcal enterotoxins are a family of structurally related superantigens with similar biological activity. Two distinct areas have been identified which have a highly conserved amino acid homology in all of the toxin families. A number of peptides were constructed from these regions, some of which were concatenated and polymerized to enhance their immunogenicity in animals. Antibodies prepared against these polymerized peptides were used to serologically identify the majority of the superantigen toxins, block the biological activities of the superantigens, and protect an experimental animal model against shock. In addition certain peptides were able per se to block up to 90% of the proliferative responses induced by the toxins. The peptide also proved protective in a septic shock model in mice. Binding experiments indicate that the peptide binds tightly to the major histocompatibility complex class II molecule, thus preventing binding and hence activation of the superantigen. The selective and rapid binding of the peptide to the major histocompatibility complex class II molecule may lead to a novel therapeutic modality in treatment of superantigen-mediated diseases.

Viral illness and the postpericardiotomy syndrome. A prospective study in children.

long-term survivors of intrapericardial surgery in the pediatric age group. We evaluated clinical evidence of syndrome and concurrent appearance of antiheart antibody (AHA) by indirect immunofluorescence and antiviral antibody (AVA) by complement fixation in sera preoperatively and serially postoperatively. Incidence of PPS was 27% overall in 400 subjects, but only 3.5% in infants younger than 2 years of age. AHA in high titer appeared in all patients with PPS. A fourfold or greater rise in titer to AVA was found in 70% of these but in only 5% of those with negative AHA and no PPS. AVA rise, tested in 280 consecutive patients, was to no single one of the eight viruses studied (adenovirus, cytomegalovirus, and coxsackievirus B 1-6). Instead, the rise and fall, consistent with antiviral response to a recent infection, was exhibited usually to one but occasionally to two or more viruses, and the viral prevalence changed from year to year, as did that in the community. The study suggests that concurrent fresh or reactivated viral illness plays a role in triggering the immunologic response that characterizes the PPS.