Phenotypic and functional characterization of ex vivo T cell responses to the live attenuated herpes zoster vaccine

To define the phenotypic characteristics and kinetics of T cell responses to a shingles vaccine in elderly individuals, 20 subjects > or =60 years of age received two doses of vaccine or placebo 6 weeks apart. VZV-specific T cell phenotypes and intracellular cytokines were determined by flow cytometry on blood mononuclear cells obtained pre-vaccination and up to 6 months after the second immunization. Results were compared with responses of five unvaccinated young adults. Pre-vaccination, elderly individuals had significantly lower VZV-specific effectors and cytokine-producing T cells compared with young adults. The vaccine significantly increased VZV-specific Th1, memory, early effector, and cutaneous homing receptor-bearing T cells.     

Low-literacy interventions to promote discussion of prostate cancer: a randomized controlled trial

BACKGROUND: Professional organizations recommend that physicians discuss prostate cancer with patients to make individual screening decisions. However, few studies have tested strategies to encourage such discussions, particularly among high-risk populations. We examined the effects of two low-literacy interventions on the frequency of prostate cancer discussion and screening. DESIGN: Randomized, blinded, controlled trial with concealed allocation. SETTING/PARTICIPANTS: Inner-city primary care clinic, serving a predominately African-American population. Participants were men aged 45-70 with no history of prostate cancer, presenting for a regular appointment. INTERVENTIONS: While waiting to see their physician, patients received a patient education handout on prostate cancer screening (PtEd), a handout simply encouraging patients to talk to their doctor about prostate cancer (Cue), or a control handout. The interventions did not advocate for or against screening. MEASURES: Patient-reported discussion of prostate cancer with the physician and chart reviews determine prostate-specific antigen (PSA) test orders and performance of digital rectal examination (DRE). Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were computed. Data were collected in 2003, and analyses were completed in 2006. RESULTS: Most of the 250 subjects (90.4%) were African American and 78.8% read below the ninth grade level. Overall, 48.4% reported discussing prostate cancer during the appointment. Compared to the control group (37.3%), discussions were significantly more common in the Cue group (58.0%, aOR=2.39 [1.26-4.52]), as well as in the PtEd group (50.0%, aOR=1.92 [1.01-3.65]). When prostate cancer was discussed, patients in the intervention groups more commonly initiated the conversation (47.6% PtEd and 40.0% Cue, vs 9.7% control, p<0.01 for each comparison to control). Compared to the control group (2.4%), PSA test orders increased in the PtEd group (14.1%, aOR=7.62 [1.62-35.83]) and in the Cue group (12.3%, aOR=5.86 [1.24-27.81]). Documentation of DRE did not change significantly (4.7% PtEd, 6.2% Cue, and 6.0% control). CONCLUSIONS: Two simple low-literacy interventions significantly increased discussion of prostate cancer and PSA test orders but not performance of DRE. Both interventions were effective in empowering low-literacy patients to initiate conversations about prostate cancer with their physician.     

Receptor-mediated monocytoid differentiation of human promyelocytic cells by tumor necrosis factor: synergistic actions with interferon-gamma and 1,25-dihydroxyvitamin D3

Human myeloid leukemia cells respond to various signals by differentiating to more mature cells. This study was designed to evaluate the effects of a mononuclear phagocyte-derived factor, tumor necrosis factor/cachectin (TNF), on the proliferation and differentiation of the human cell lines HL-60 (promyelocytic) and U937 (monoblastic), and to characterize TNF receptors on these cells. TNF had no effect on HL-60 cell growth or thymidine incorporation, but it markedly inhibited that of U937 cells. HL-60 cells treated with TNF formed osteoclast-like polykaryons and developed nonspecific esterase positivity. In a dose-dependent fashion, TNF enhanced HL-60 cell nonspecific esterase activity, H2O2 production, NBT reduction, and acid phosphatase content. Together, TNF and interferon-gamma (IFN-gamma) additively and synergistically caused increases in these activities as well as the expression of HLA-DR and the monocyte antigens LeuM3 (CDw14) and OKM1 (CD11). TNF also synergistically enhanced the differentiating effects of 1,25-dihydroxyvitamin D3. The potentiating actions of D3 of IFN-gamma on the TNF effect were maximal when the two agents were present together throughout the incubation, and pretreatment with TNF augmented the subsequent response to D3, but not IFN-gamma. HL-60 and U937 cells bound 125I-labeled TNF specifically, rapidly, and reversibly with binding constants of 227 and 333 pmol/L and receptors per cell of 4,435 and 6,806 for HL-60 and U937, respectively. Scatchard plots were linear, which suggested single classes of receptors. HL-60 TNF receptors were not changed by a three-day treatment with IFN-gamma or D3. U937 and HL-60 cells internalized and degraded 125I-labeled TNF to comparable degrees. TNF has differing effects on HL-60 and U937 cells that are apparently mediated through comparable high-affinity TNF receptors. The unique responses of different cell types to TNF may be due to postreceptor factors.     

Impaired systemic production of prostaglandin E2 in children with cerebral malaria

Prostaglandins (PGs) are important mediators of macrophage activity, vascular permeability, fever, erythropoiesis, and proinflammatory responses to infection. Our recent studies have shown that plasma levels of bicyclo-PGE2 (a stable end product of PGE2 metabolism) and leukocyte cyclooxygenase (COX)-2 gene expression are suppressed in children with malarial anemia. Since the role of PGs as immunomodulators of human cerebral malaria (CM) has not been examined, we investigated urinary levels of bicyclo-PGE2/creatinine in children with varying clinical outcomes of CM. Among parasitemic children, those with asymptomatic parasitemia had the highest levels of bicyclo-PGE2/creatinine, whereas those with CM had significantly lower levels of bicyclo-PGE2. Systemic levels of bicyclo-PGE2/creatinine were not significantly associated with parasitemia, hemoglobin levels, or levels of the PG-regulatory cytokine tumor necrosis factor- alpha but were positively correlated with levels of interleukin-10. The results presented here show that impaired systemic production of PGE2 is associated with adverse outcomes of CM, whereas elevated levels of PGE2 in asymptomatic parasitemia suggest a potential role for PGs in protective immunity.     

Retrospective study of the renal effects of amphotericin B lipid complex when used at higher-than-recommended dosages and longer durations compared with lower dosages and shorter durations in patients with systemic fungal infections

BACKGROUND: Patients with fungal infections who are treated with amphotericin B lipid complex (ABLC) often receive dosages less than that recommended in the product information (5 mg/kg.d). This occurs despite the described safety and increased efficacy in select patients treated with higher ABLC dosages. OBJECTIVE: The purpose of this study was to compare the renal effects of high-dosage/long-duration (HDos/LDur) ABLC therapy (>5 mg/kg.d for >12 days) with those of low-dosage/short-duration (LDos/SDur) ABLC therapy (or=4 ABLC doses according to a large, multicenter patient database, the Collaborative Exchange of Antifungal Research (CLEAR) registry. The safety profile of each dosage was evaluated using serum creatinine concentration (S-Cr) and calculated creatinine clearance (CCcr). RESULTS: A total of 1726 patients were studied. The HDos/LDur group included 309 patients and theLDos/SDur group included 1417 patients. The median ages of the HDos/LDur and LDos/SDur groups were 42 and 48 years, respectively (ranges, <1 to 83 and <1 to 95 years; P < 0.001); females comprised 51% and 42% of the 2 populations (P = 0.004); and 6% and 12% had solid tumors (P = 0.002). The HDos/LDur group was more likely than the LDos/SDur group to have been treated for multiple systemic fungal pathogen infections (16% and 9%, respectively) and for mold infections (28% and 12%, respectively) (both, P < 0.001). The median change in S-Cr from baseline was 0.1 mg/dL in both groups (range, -4.9 to 5 mg/dL in the HDos/LDur group and -3.96 to 4.7 mg/dL in the LDos/SDur group). No increased risk for renal dysfunction, as reflected in the median change from baseline in CCcr, was observed in either cohort (-3 mL/min [range, -118.65 to 69.03 mL/min] in the HDos/LDur group; -2.17 mL/min [range, -107.48 to 104.45 mL/min] in the LDos/SDur group). CONCLUSION: These data suggest that higher ABLC dosages appear to be as well tolerated as lower dosages, warranting further study of ABLC dosages >5 mg/kg.d for >12 days in the treatment of systemic fungal infections.     

The increase in body temperature of elderly patients in the first twenty-four hours following admission to hospital

In 76 unselected patients aged 70 years or over, the mean increase in rectal temperature in the 24 hours following admission to hospital was 0.4 degrees C. In those who did not receive antibiotics on admission, the mean increase in rectal temperature was 0.6 degrees C, with increases of up to 2.3 degrees C recorded. There were no significant changes in C-reactive protein, white cell count or erythrocyte sedimentation rate over that period, suggesting that the changes were due to passive warming rather than to progression of the underlying disease. Infected patients may have low or normal body temperatures on admission. Within 24 hours, nearly all infected patients (excluding a few with low or normal temperatures on admission, who receive antibiotics) have a raised body temperature. The most sensitive test for a raised body temperature is the rectal temperature measured at least 24 hours after admission. A patient who has a low or normal body temperature on admission has a 61% chance of having a raised body temperature the next day. At least 55% of patients admitted with a febrile illness have low or normal body temperatures on admission.     

Ecology and epidemiology of zoonotic pathogens

The possibility that a perplexing febrile illness may represent a zoonotic infection should be explored. The history should include where the person has been, what he or she has done, what has been eaten and drunk, what contacts have occurred with vertebrates or arthropods in wild or domestic venues, and whether there has been exposure to unusual animal products. The preceding discussion emphasized, via some examples, mechanisms of spread as well as the physical and biologic conditions that enhance the probability of an encounter with a pathogen. From clues in the history and physical examination the appropriate diagnostic and therapeutic decisions can be made. These decisions may be life saving for the patient, and perhaps protect care providers and family from acquiring the same disease. Many of the infections mentioned in this article will be amplified in subsequent articles, which will deal with diseases encountered primarily in the United States.     

Pro-oxidant effect of vitamin E in cigarette smokers consuming a high polyunsaturated fat diet

Dietary polyunsaturated fats and vitamin E are associated with reduced risk for atherosclerosis, but in smokers, they could promote lipid oxidation. Therefore, we examined the effects of a high polyunsaturated fat diet and vitamin E supplementation on measures of lipid oxidation in cigarette smokers. Ten subjects who smoked >1 pack of cigarettes per day were sequentially fed the following: a baseline diet in which the major fat source was olive oil, a diet in which the major fat source was high-linoleic safflower oil, and finally, the safflower oil diet plus 800 IU vitamin E per day. LDL oxidation lag time and rate and plasma total F(2)-isoprostanes and prostaglandin F(2alpha) (PGF(2alpha)) were determined after 3 weeks on each diet. The safflower oil diet increased total F(2)-isoprostanes from 53.0+/-7.2 to 116.2+/-11.2 nmol/L and PGF(2alpha) from 3.5+/-0.2 to 5.5+/-0.5 nmol/L, without changing LDL oxidation parameters. Addition of vitamin E prolonged mean LDL oxidation lag time but, paradoxically, further increased F(2)-isoprostanes to 188.2+/-10.9 nmol/L and PGF(2alpha) to 7.8+/-0.4 nmol/L. These data suggest that vitamin E may function as a pro-oxidant in cigarette smokers consuming a high polyunsaturated fat diet.     

Circulating malignant cells in non-Hodgkin's lymphoma: correlation with binding by peanut agglutinin

A significant number of patients with non-Hodgkin's lymphoma have peripheral blood involvement during the course of their disease. Because the expression of receptor for the lectin peanut agglutinin PNA by normal lymphocytes is associated with noncirculating (stationary phase) cells, we studied the relationship between PNA binding by lymphoma cells and the presence of clonal B cells in the blood of 38 patients with B-cell lymphoma. The binding of PNA by cells in tissues was determined by the immunoperoxidase method and by two-color flow cytometry. Circulating lymphoma cells (clonal B cells) were identified by a sensitive flow-cytometric technique (kappa-lambda analysis) and were also studied for PNA binding in some cases. In all, 16 of 38 (42%) of lymphomas were PNA+, including a spectrum of histologic types. Circulating lymphoma cells were demonstrated in 17 of 22 PNA-lymphomas, whereas only 3 of 16 of PNA+ lymphomas had such circulating cells. Thus, there is a significant association between PNA binding and peripheral blood involvement by lymphoma (P less than .005 by chi- square analysis). In 12 cases, the circulating and tissue lymphoma cells had similar expression of PNA receptor (2 PNA+ and 10 PNA- cases), indicating that modulation of the PNA binding sites did not occur. In three patients who presented with lymphosarcoma cell leukemia, the circulating malignant cells were PNA-. These findings suggest that for both normal and malignant lymphocytes the absence of binding sites for PNA is associated with the capacity of these cells to circulate freely.