Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo.

Inhibition of p38 kinase blocks the production of tumor-promoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38alpha, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-X(L) and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in MM cells, suggesting great potential for co-therapy.

A combinatorial approach to the identification of dipeptide aldehyde inhibitors of beta-amyloid production.

In an effort to rapidly identify potent inhibitors of Abeta production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Abeta in CHO cells stably transfected with the cDNA encoding betaAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3, 5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC(50) of 9.6 microM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Abeta1-40 or Abeta1-42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1-40 form of Abeta, whereas the longer 1-42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Abeta through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Abeta production.

Evaluation of vancomycin use in a pediatric teaching hospital based on CDC criteria.

This study was performed to determine whether vancomycin use at our pediatric hospital was consistent with modified Centers for Disease Control and Prevention guidelines. Vancomycin use was inappropriate in 54% of patients. Inappropriate use briefly decreased by 14% after educational efforts. Further education regarding vancomycin use was deemed necessary and is continuing.

Repeated invasive pneumococcal infections in young children without apparent underlying immunodeficiency.

During a 30-month interval at LeBonheur Children's Medical Center, 394 patients had a blood or cerebrospinal fluid culture positive for Streptococcus pneumoniae. Sixteen of these episodes (4%) were repeated infections; 6 of these 16 patients had sickle cell disease. Six of the remaining 10 patients had immunologic evaluations of varying completeness; no immunodeficiency was identified by these tests or on follow-up. Nine of the ten previously healthy patients with repeated pneumococcal disease were less than 2 years of age. In our experience, repeated invasive pneumococcal infections in otherwise healthy young children were relatively common (10/394, or 2.5% of patients with invasive pneumococcal infections) and did not indicate the presence of an unsuspected immunodeficiency.

Invasive group B streptococcal disease in children beyond early infancy.

There is little information available on invasive group B Streptococcus (GBS) infection in pediatric patients older than 3 months of age. Review of infection control records at LeBonheur Children's Medical Center from January 1, 1986, to June 30, 1993, identified 143 patients with a positive GBS culture from normally sterile body fluid. Medical records of 18 (13%) patients > 3 months old with their first GBS infection were reviewed. Age range was 15 weeks to 18 years (median age, 13 months). Ten were black and 11 were girls. Five infants had a history of premature birth and 2 infants were infected with human immunodeficiency virus. The serotype distribution of 12 available GBS isolates was 4 type III, 2 each type V and Ia and 1 each type Ia/c, Ib/c, II and II/c. Bacteremia without a focus (9 patients) was the most common clinical manifestation. All 4 type III isolates were associated with bacteremia. One infant with human immunodeficiency virus infection had sepsis and bullous desquamation; a toxin-producing type V strain was isolated from her blood. Two adolescents with ventriculoperitoneal shunts had meningitis, including one whose cerebrospinal fluid also grew a type V strain. Other clinical manifestations were septic arthritis, endocarditis (Ia, II/c), central venous catheter (Ia/c) and ventriculostomy infections.

Group A streptococcal bacteremia in a mid-south children's hospital.

We reviewed microbiology and infection control records at a Memphis children's hospital from 1982 to 1990 to obtain epidemiologic, clinical, and microbiologic data on group A streptococcal (GAS) bacteremia. Varicella was the underlying condition in 8 of 37 (22%) patients identified and was often associated with severe GAS disease, including toxic shock-like syndrome. Twenty-one of 31 (68%) available blood isolates made GAS pyrogenic exotoxin (SPE) B by Ouchterlony immunodiffusion; gene probes identified speC and speA in 18 (58%) and 8 (26%) isolates, respectively. The B/C toxin profile, identified in 11 (35%) isolates, was the most common profile in this population, and the overall rate for speC was higher than rates recently reported from other areas. Although the clinical significance of the toxin profiles in our population is unclear, these data emphasize the geographic and temporal variability in the microbiologic properties of GAS disease.

Prevalence of histoplasmosis in a midsouthern population.

We found a histoplasmin reactivity rate of 69% in a selected population of normal midsouthern adults. This prevalence is similar to that previously reported and has major clinical implications for area residents who are infected with human immunodeficiency virus and are at risk for disseminated disease with Histoplasma capsulatum.