Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome.

BACKGROUND: There are limited studies of large cohorts of patients with specific polysaccharide antibody deficiency (SPAD) syndrome. OBJECTIVE: To study the clinical and laboratory characteristics of patients with specific polysaccharide antibody deficiency syndrome. METHODS: We retrospectively studied 75 patients with total IgG levels of at least 500 mg/dL and fewer than 9 of 12 responses to vaccination with pneumococcal vaccine polyvalent. Exclusion criteria included an IgG level less than 500 mg/dL, established immunodeficiency syndrome, and secondary immunodeficiency. RESULTS: The most common clinical presentation was frequent infections (n = 69; 92%), including sinusitis (n = 53; 77%), pneumonia (n = 29; 42%), ear infections (n = 18; 26%), and bronchitis (n = 19; 28%). Other presentations were systemic infections (n = 5; 7%), autoimmune or rheumatic diseases (n = 6; 8%), and chronic diarrhea (n = 4; 5%). The median IgG2 level of patients with no response to pneumococcal vaccine polyvalent tended to be lower than that of patients with at least 1 response (150 vs 193 mg/dL, respectively; P = .06). There was no association between total IgG level (categorized as 500-600 or > or = 600 mg/dL) and frequency of infection (P = .43). Patients with fewer responses to pneumococcal vaccine polyvalent and a higher frequency of infections were more likely to receive intravenous immunoglobulin (IVIG) therapy (P = .01 and .003, respectively). Treatment with IVIG significantly reduced the number of infections (P < .001). CONCLUSION: Patients with no response to pneumococcal vaccine polyvalent tended to have lower IgG2 levels; those with fewer responses were more likely to receive IVIG therapy.     

Phospho-akt expression is associated with a favorable outcome in non-small cell lung cancer.

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.     

Effects of indomethacin,triamcinolone, and dexamethasone on recombinant human interleukin-1-induced substance P and prostaglandin E2 levels in rabbit knee joints

Intra-articular (i.a.) injection of recombinant human interleukin-1 alpha (rHuIL-1) in rabbit knees induced both an inflammation, as determined by increases in leukocytes in the joint fluid, and cartilage degradation, as measured by loss of proteoglycan. Substance P (SP) and prostaglandin E₂ (PGE₂) levels in the joint lavage are also elevated. Treatment with 5 mg indomethacin/kg, p.o., b.i.d., 2 mg triamcinolone i.a., and 10 mg dexamethasone/kg, p.o., reduced synovial lavage leukocyte counts, as well as PGE₂ and SP lavage concentrations induced with IL-1 injection. However, none of the treatments inhibited rHuIL-1-induced proteoglycan loss.     

Lack of costimulation by both sphingomyelinase and C2 ceramide in resting human T cells

Resting T cells require a signal transduced through their antigen-specific T-cell receptor (TCR) and an antigen-independent costimulatory signal in order to proliferate and become activated. Ligation of the CD28 receptor costimulates T-cell proliferation and is critical to correct T-cell function. A putative effector of CD28-mediated costimulation is the sphingomyelinase enzyme, which generates the potent second messenger ceramide. We have examined the role of sphingomyelinase and C2 ceramide for their ability to costimulate resting human T cells. We observed that neither sphingomyelinase nor C2 ceramide could costimulate human T-cell proliferation in combination with anti-CD3 antibody, whereas CD80, a natural CD28 ligand, was strongly costimulatory. Surprisingly, both sphingomyelinase and C2 ceramide strongly inhibited the proliferation of resting T cells stimulated through TCR and CD28 receptors. Despite these inhibitory effects, neither sphingomyelinase nor C2 ceramide induced apoptosis and we found that upregulation of activation markers CD25 and CD69 could still occur in the presence of sphingomyelinase/C2 ceramide. These data indicate that neither sphingomyelinase nor C2 ceramide can substitute for CD28 costimulation and that these molecules may be involved in negatively regulating T-cell proliferation.     

Pathogenesis ofLactobacillus casei-induced polyarthritis in Lewis rats: 2. Time related changes in organ weights and liver enzymes

Hepatic enzymes and organ weights were measured in LEW/N female rats during the acute and the chronic phases ofL. casei-induced arthritis on day 3 and days 30 and 59, respectively. In the acute phase, day 3, adrenal and spleen weights were increased and thymus weights were decreased inL. casei arthritic rats as compared to normal control rats. Adrenal, liver, kidney, spleen and thymus weights of arthritic rats were in the normal range on days 30 and 59. Liver cytochrome P450, aminopyrineN-demethylase and analine hydroxylase were reduced in livers ofL. casei-treated rats on day 3 as compared to normal controls. On days 30 and 59 hepatic enzymes inL. casei-arthritic rats were in the normal range. Unlike adjuvant arthritis in which changes in liver enzymes alter drug metabolism; after the acute onset ofL. casei-induced arthritis, hepatic enzymes return to the normal range.     

Omalizumab and the immune system: an overview of preclinical and clinical data.

OBJECTIVE: This review discusses the role of immunoglobulin (Ig)E in allergic disease, inhibition of IgE with omalizumab, and the consequences of IgE inhibition (both clinically and in terms of the effect on the immune system). DATA SOURCES: Relevant publications obtained from a literature review. STUDY SELECTION: Relevant publications on IgE, allergic disease, and anti-IgE were critically evaluated. RESULTS: IgE plays a key role in allergic diseases such as allergic asthma and allergic rhinitis. Its role in healthy individuals is less well defined. Treatment of allergic asthma and rhinitis with omalizumab, a humanized monoclonal anti-IgE antibody, causes a marked reduction in circulating free IgE levels. This has been shown to reduce symptoms and decrease the need for other medication in patients with these allergic diseases. Anti-IgE treatment with omalizumab did not cause any of the complications that might, in theory, be expected to result from reduction in circulating free IgE, such as adverse effects upon the immune system or other body systems. CONCLUSIONS: The limited clinical data currently available suggest that this novel method of treatment for allergic asthma and rhinitis seems to be both effective and well tolerated in clinical use.     

Progenitor egress from the bone marrow after allergen challenge: role of stromal cell-derived factor 1alpha and eotaxin

BACKGROUND: CCR3 expression on CD34+ cells mediates migration to eotaxin in vitro. CXCR4 and stromal cell-derived factor (SDF)-1alpha are important for stem cell homing to hemopoietic compartments. OBJECTIVE: To study chemokine-mediated progenitor cell traffic in allergic inflammation. METHODS: Bone marrow (BM) aspirates were obtained at baseline from normal subjects; atopic subjects without asthma; and subjects with asthma before, 5 hours after, and 24 hours after allergen inhalation (dual and early responders). Changes in chemokine receptor expression and migration were assessed. RESULTS: Expression of CXCR4, but not CCR3, on BM CD34+ cells was greater in normal subjects compared with atopic subjects with asthma. Likewise, SDF-1alpha, but not eotaxin, stimulated a greater migrational response by BM CD34+ cells from normal subjects compared with subjects with asthma. For all subjects, a positive correlation was found between intensity of CXCR4 expression and magnitude of CD34+ cell response to SDF-1alpha. Allergen inhalation attenuated both intensity of CXCR4 expression and SDF-1alpha levels in marrow from dual compared with early responders 24 hours postallergen. In contrast, the intensity of CCR3 expression on BM CD34+ cells increased in dual compared with early responders at 24 hours postallergen. In addition, an increase in migrational responsiveness of BM CD34+ cells to eotaxin and a decrease to SDF-1alpha 24 hours postallergen was found in dual responder subjects with asthma. CONCLUSION: After allergen inhalation in subjects with asthma, a downregulation in CXCR4 intensity on BM CD34+ cells and a reduction in BM SDF-1alpha levels may reduce progenitor retention to marrow stroma promoting peripheral egress, possibly mediated by the CCR3/eotaxin axis.