Differential T-cell responses of semi-immune and susceptible malaria subjects to in silico predicted and synthetic peptides of Plasmodium falciparum

Malaria remains a public health hazard in tropical countries as a consequence of the rise and spread of drug and insecticide resistances; hence the need for a vaccine with widespread application. Protective immunity to malaria is known to be mediated by both antibody and cellular immune responses, though characterization of the latter has been less extensive. The aim of the present investigation was to identify novel T-cell epitopes that may contribute to naturally acquired immune responses against malaria. Using the Microsoft software, Epitome™ T-cell peptide epitopes on 19 Plasmodium falciparum proteins in the Plasmodium Database (www.plasmodb.org.PlasmoDB 9.0) were predicted in-silico. The peptides were synthesized and used to stimulate peripheral blood mononuclear cells (PBMCs) in 14 semi-immune and 21 malaria susceptible subjects for interferon-gamma (IFN-γ) production ex-vivo. The level of IFN-γ production, a marker of T-cell responses, was measured by ELISPOT assay in semi-immune subjects (SIS) and frequently sick subjects (FSS) from an endemic zone with perennial malaria transmission. Of the 19 proteins studied, 17 yielded 27 pools (189 peptides), which were reactive with the subjects’ PBMCs when tested for IFN-γ production, taking a stimulation index (SI) of ≥2 as a cutoff point for a positive response. There were 10 reactive peptide pools (constituting eight protein loci) with an SI of 10 or greater. Of the 19 proteins studied, two were known vaccine candidates (MSP-8 and SSP2/TRAP), which reacted both with SIS and FSS. Similarly the hypothetical proteins (PFF1030w, PFE0795c, PFD0880w, PFC0065c and PF10_0052) also reacted strongly with both SIS and FSS making them attractive for further characterization as mediators of protective immunity and/or pathogenesis.     

Three blistering diseases

The three blistering conditions described in this article—dermatitis herpetiformis, pemphigus vulgaris, and bullous pemphigoid—are unusual but not rare. Proper management is critical and should include supervision by a physician thoroughly familiar with treatment and potential complications. Dr Wooldridge discusses the primary care physician's role in diagnosis, treatment, and follow-up of these diseases.     

Combining the antigen processing components TAP and Tapasin elicits enhanced tumor-free survival.

PURPOSE: Tpn is a member of the MHC class I loading complex and functions to bridge the TAP peptide transporter to MHC class I molecules. Metastatic human carcinomas often express low levels of the antigen-processing components Tapasin and TAP and display few functional surface MHC class I molecules. As a result, carcinomas are unrecognizable by effector CTLs. The aim of this study is to examine if Tapasin (Tpn) plays a critical role in the escape of tumors from immunologic recognition. EXPERIMENTAL DESIGN: To test our hypothesis, a nonreplicating adenovirus vector encoding human Tpn (AdhTpn) was constructed to restore Tpn expression in vitro and in vivo in a murine lung carcinoma cell line (CMT.64) that is characterized by down-regulation of surface MHC class I due to deficiency in antigen-processing components. RESULTS: Ex vivo, Tpn expression increased surface MHC class I and restored susceptibility of tumor cells to antigen-specific CTL killing, and AdhTpn infection of dendritic cells also significantly increased cross-presentation and cross-priming. Furthermore, tumor-bearing animals inoculated with AdhTpn demonstrated a significant increase in CD8(+) and CD4(+) T cells and CD11c(+) dendritic cells infiltrating the tumors. Provocatively, whereas syngeneic mice bearing tumors that were inoculated with AdhTpn a significant reduction in tumor growth and increased survival compared with vector controls, combining AdhTpn inoculation with AdhTAP1 resulted in a significant augmentation of protection from tumor-induced death than either component alone. CONCLUSIONS: This is the first demonstration that Tpn alone can enhance survival and immunity against tumors but additionally suggests that Tpn and TAP should be used together as components of immunotherapeutic vaccine protocols to eradicate tumors.     

SU5416 delays wound healing through inhibition of TGF-beta 1 activation

Angiogenesis, development of new blood vessels, is essential for wound healing and tumor growth. A potentially important side effect of anti-angiogenic therapy can be delayed wound healing. In this study we address this issue by using a novel in vivo method utilizing fibrin containing dual porous plexiglass chambers (Fibrin Z-Chambers; F-ZC) to investigate wound healing in rats administered with SU5416 (inhibitor of Flk-1 and Flt-1, at 20 mg/kg i.p.). SU5416 treated F-ZCs developed 45% less granulation tissue (p = 0.0076) and showed a 10% reduction in microvessel density (p = 0.0009) than controls treated with drug carrier alone. The granulation tissue showed distinctly decreased collagen deposition (p = 0.0006) in SU5416 treated animals that was associated with 90% reduction in active TGF-beta 1 level. We found that tissue transglutaminase (TG), a cross-linking enzyme involved in TGF-beta 1 activation and matrix stabilization, was inhibited by SU5416. These results suggest that SU5416 delays wound healing by reducing matrix synthesis and stabilization through inhibition of TGF-beta 1 activation. This study was made feasible via the development of a unique method to study anti-angiogenic compounds that provides highly reproducible and quantitative results. Further studies are needed to evaluate in vivo whether anti-angiogenic agents alter wound healing.     

Executive dysfunction in geriatric depression

OBJECTIVE: The purpose of this study was to characterize the neuropsychological presentation of geriatric depression and to determine whether depression-related executive dysfunction is more pronounced during advanced age. METHOD: The attention and executive functioning of 40 adults with major depression were compared with those of 40 healthy comparison subjects; 20 subjects were 20-60 years old, and 20 were > or =61 years. It was hypothesized that depressed subjects, regardless of age, would perform more poorly than comparison subjects on both attention and executive tasks but that the older depressed adults would evidence significantly greater impairment on executive measures. RESULTS: A significant interaction between age and depressive status was noted for tasks of executive functioning, while no age-depression interaction was found for tasks of selective or sustained attention. Older depressed adults demonstrated the slowest psychomotor speed and the poorest performance on tasks requiring set shifting, problem solving, and initiation of novel responses. CONCLUSIONS: Patients with late-life depression have significant impairment in executive functioning. These findings can guide the development of stimulated functional neuroimaging paradigms that may clarify the pathophysiology of geriatric depression. Timely identification of attentional and executive processes fundamental to the daily functioning of depressed older adults may lead to compensatory strategies that will improve the outcomes of late-life depression.     

Percutaneous vertebroplasty for severe osteoporotic vertebral body compression fractures

PURPOSE: To determine the efficacy of percutaneous vertebroplasty in treating severe vertebral body compression fractures, or vertebra plana, in patients with osteoporosis. MATERIALS AND METHODS: In 155 patients, 310 percutaneous vertebroplasties were performed during 25 months and 15 days. Of these, 37 patients (27 women, 10 men; mean age, 73.6 years) underwent 48 vertebroplasties for severe osteoporotic vertebral body compression fractures. The fractures were defined as vertebrae that have collapsed to less than one-third of their original height. Imaging and clinical features were analyzed, including the extent of vertebral collapse, location of the involved vertebra, pattern of vertebral compression, volume of polymethylmethacrylate injected, vertebroplasty complications, and clinical outcome. RESULTS: Vertebral body collapse averaged 23% (range, 4.5%-33.0%) of the original height. Involved vertebrae were located from levels T5 to L5, with one-half affected at the thoracolumbar junction. Patterns of vertebral compression were divided into gibbus (31 of 48 or 65%), plana (13 of 48 or 27%), and H shape (four of 48 or 8%). The mean volume of the cement injected was 6.0 mL (range, 1.5-12.5 mL). Complications observed on radiographs included cement leakage to the adjacent disc (17 of 48 or 35%) and the paravertebral soft tissues (four of 48 or 8%). There were no major complications. At clinical follow-up (mean duration, 11 months and 3 days; range, 3-24 months), pain relief was complete in 14 (47%) of 30 patients, partial in 15 (50%), and unchanged in one (3%). No patient required surgery. CONCLUSION: Percutaneous vertebroplasty for severe osteoporotic vertebral body compression fractures is safe and effective and should not be withheld in this group of patients.