Finding the evidence: resources and skills for locating information on clinical effectiveness.

Limited time and lack of knowledge about where and how to search for information often present barriers to practitioners who want to locate current best evidence for treating their patients. There is as yet no single place they can go to get an answer to all their questions. High quality clinical studies are difficult to filter out from the mass of information on large databases, and secondary resources of evaluated information are dispersed over hundreds of Internet sites worldwide. This overview presents a practical guide for the busy practitioner who searches only occasionally and needs to maximise the time spent. Major collections of secondary resources are identified and their individual features described briefly. Following this, several services using PubMed are outlined that automatically apply filters for studies with high quality research design. Further sources of information and assistance are listed for those who wish to learn more.

Anti-CD3 epsilon F(ab')2 prevents graft-versus-host disease by selectively depleting donor T cells activated by recipient alloantigens.

Transplantation tolerance is facilitated by activation-induced apoptosis of peripheral T cells triggered by specific AG: Abs specific for the nonpolymorphic CD3 component of the TCR complex bind to APCs through Fc-FcR interactions, mimic MHC-peptide, and activate polyclonal T cells. In contrast, F(ab')(2) of anti-CD3epsilon Abs do not activate naive T cells but induce apoptosis of Ag-activated, cycling T cells. Here, we report that treatment with anti-CD3epsilon F(ab')(2) can selectively induce apoptosis of donor T cells that recognize a recipient alloantigen, thereby preventing graft-vs-host disease initiated by a TCR-transgenic T cell population. The selective elimination of Ag-activated T cells by non-FcR-binding anti-CD3epsilon Abs could serve as an ideal strategy to prevent graft-vs-host disease and allograft rejection or to treat autoimmune disorders.

Therapeutic day programs in the treatment of adolescents with mental illness.

OBJECTIVES: This study aims to assess the effectiveness of day programs against other treatment modalities in adolescents with mental illnesses (including substance abuse). It also aims to identify patient and program factors associated with favourable outcomes for adolescents with mental illness treated in therapeutic day programs. METHOD: An extensive database search of published literature was conducted, supplemented by hand-searching of references of retrieved articles, and a search by author. There was no restriction by study design. Relevant studies were identified and appraised using standardised criteria. RESULTS: Of the 231 studies identified in the search, 26 were relevant to this review. The majority of studies identified day programs as effective. There was a lack of adequate comparisons between day programs and other organisational arrangements. CONCLUSIONS: The quality of the studies identified was low. Twenty-two of the 26 studies did not have an adequate control group. Higher-quality research is required in the evaluation of the effectiveness of day programs, and the identification of other factors promoting successful outcome in the treatment of adolescent mental illness.

CD28-specific antibody prevents graft-versus-host disease in mice.

The costimulatory molecules B7-1 and B7-2 regulate T cell activation by delivering activation signals through CD28 and inhibitory signals through CTLA4. Graft-vs-host disease (GVHD) is caused by activated donor T cells. Previously, we showed that CD28-deficient donor T cells induced less-severe GVHD than wild-type donor T cells, suggesting that CD28 signals exacerbate GVHD. In this paper we demonstrate that CTLA4 signals attenuate the severity of GVHD. Targeting the CD28 receptor with a specific mAb modulates the receptor in vivo, inhibits donor T cell expansion, and prevents GVHD. CTLA4 signaling was necessary for this effect because treatment with a soluble ligand that blocks binding of B7 to both CD28 and CTLA4 did not prevent GVHD as effectively as anti-CD28 mAb. These results support the current model of T cell costimulation in which CD28 signals amplify GVHD while CTLA4 signals inhibit GVHD, providing evidence that selective targeting of CD28 might be a better therapeutic strategy for inducing immunological tolerance than blocking the ligands for both CD28 and CTLA4.

Visualization, fate, and pathogenicity of antigen-specific CD8+ T cells in the graft-versus-host reaction.

To follow the fate of alloreactive T cell effectors in graft-vs-host disease, Ld-specific CD8+ T cells from C57BL/6 2C TCR-transgenic donors were transplanted into sublethally irradiated (750 cGy) Ld+ or Ld- recipients. In Ld- C57BL/6 or (BALB/c-dm2 x C57BL/6)F1 recipients, naive 2C T cells engrafted and survived long term, but did not acquire effector function. In Ld+ (BALB/c x C57BL/6)F1 recipients, 2C T cells engrafted, expanded, became cytolytic, destroyed host B cells and double-positive thymocytes, and later disappeared. Despite marked damage to lymphoid and hemopoietic cells by 2C T cells, no significant pathology was detected in other organs, and recipients survived. Ld+ (BALB/c x C57BL/6)F1 recipients died when LPS/endotoxin was administered on day 7 after cell transfer, while Ld- (BALB/c-dm2 x C57BL/6)F1 recipients survived. Our findings show that under certain conditions, a CD8+ T cell population recognizing an extremely limited repertoire of Ags can initiate graft-vs-host disease.