Postincident conferring by law enforcement officers: determining the impact of team discussions on statement content, accuracy, and officer beliefs.

In many jurisdictions, law enforcement officers are permitted to discuss their recall of an incident when preparing their official statement. This practice has been criticized on the grounds that it lacks transparency and may produce inaccurate corroborative accounts. In the current study, 300 armed officers took part in an interactive staged crime scenario and were permitted to confer (or not) while writing statements. Alternative procedures for statement production by teams were also evaluated. Some officers also provided an independent statement prior to conferring while others were provided with retrieval support instructions. Although errors were transmitted during discussions, conferring had no overall impact on the accuracy or content of final statements. However, officers who wrote an initial independent statement did not incorporate any errors obtained from colleagues into their final accounts. Conferring officers expressed greater confidence in the accuracy of their accounts than nonconferring officers despite no differences in accuracy.

Evaluation of a nonsteroidal topical cream in a guinea pig model of Malassezia furfur infection.

Malassezia furfur is an important causal factor for seborrheic dermatitis, and topical antifungal therapy is an effective treatment approach. This study assessed the antifungal activity of Promiseb Topical Cream (Promius Pharma, LLC, Bridgewater, NJ), a novel nonsteroidal prescription medical device cream, in the M furfur-infected skin model for guinea pigs. Guinea pigs (N = 28) were divided into 4 groups and infected with M furfur for 7 days. On day 8, the first group of animals was sacrificed. The scrapings of inoculation site on each animal were tested for the presence of the organism, and the skin was excised for quantitation of M furfur. The second group was left untreated. The remaining 2 groups were treated with one of the test agents (Promiseb) and the positive control product (ciclopirox olamine cream, 0.77%; Loprox, Medicis, Scottsdale, AZ) each once daily for 3 days. At the end of treatment, animals were sacrificed and analyzed similarly to the first group. M furfur was recovered from all animals in the first group. Visual signs of infection, such as erythema and edema, were not observed in the infected animals at the end of the study. In the animals treated for 3 days with the test agents, the M furfur counts were reduced to below the limit of quantitation. Both test agents were equally effective in substantially reducing the density of M furfur compared with the untreated control.

IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding.

A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.

IRAK-4 inhibitors. Part 1: a series of amides.

The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.

IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines.

Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.

Regulatory CD4+CD25+Foxp3+ T cells selectively inhibit the spontaneous form of lymphopenia-induced proliferation of naive T cells.

Regulatory CD4(+)CD25(+)Foxp3(+) T cells play a critical role in controlling autoimmunity and T cell homeostasis. However, their role in regulation of lymphopenia-induced proliferation (LIP), a potential mechanism for generation of autoaggressive T cells, has been poorly defined. Currently, two forms of LIP are recognized: spontaneous and homeostatic. Spontaneous LIP is characterized by fast, burst-like cell-cycle activity, and may allow effector T cell differentiation. Homeostatic LIP is characterized by slow and steady cell cycle activity and is not associated with the acquisition of an effector phenotype. In this study, we demonstrate that CD4(+)CD25(+)Foxp3(+) T cells suppress the spontaneous, but not homeostatic, LIP of naive CD8 and CD4 T cells. However, selective inhibition of spontaneous LIP does not fully explain the tolerogenic role of Tregs in lymphopenia-associated autoimmunity. We show here that suppression of LIP in the lymphoid tissues is independent of Treg-derived IL-10. However, IL-10-deficient Tregs are partially defective in their ability to prevent colitis caused by adoptive transfer of CD4 T cells into RAG(-/-) mice. We propose that Tregs may inhibit emergence of effector T cells during the inductive phase of the immune response in the secondary lymphoid tissues by IL-10-independent mechanisms. In contrast, Treg-mediated inhibition of established effector T cells does require IL-10. Both Treg functions appear to be important in control of lymphopenia-associated autoimmunity.

De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR.

Although regulatory CD4+CD25+ forkhead box p3+ (Foxp3+) T cells (Tregs) are generally thought to arise in the thymus as a separate lineage of CD4 T cells, they can also be induced de novo in the periphery. Peripheral development of Tregs from naïve T cells is favored by low-intensity activation and absence of inflammation. We show here that absence of CD28 costimulation results in a modest decrease in activation of naïve, antigen-specific CD4 T cells under noninflammatory conditions and benefits their initial Foxp3 induction. However, expression of Foxp3 following T cell activation without CD28 costimulation remains sensitive to the antigen dose. Furthermore, basal CD28 costimulation is critical for survival of the induced Foxp3+ CD4 T cells, and their accumulation is abrogated in the absence of CD28. In contrast, pharmacologic blockade of mammalian target of rapamycin enhances lasting induction of Tregs, irrespective of the initial antigen dose used to activate the antigen-specific T cells. This finding may have important practical, clinical implication in development of tolerance protocols.

Abortive activation precedes functional deletion of CD8+ T cells following encounter with self-antigens expressed by resting B cells in vivo.

InsHA mice express the haemagglutinin (HA) protein from influenza virus A/PR/8 H1N1 (PR8) as a self antigen on pancreatic islet beta cells. We have utilized these mice to investigate the ability of resting B cells expressing Kd to induce self-tolerance among naive KdHA-specific clone 4 CD8+ T cells. Adoptive transfer of KdHA-peptide-pulsed resting B cells into clone 4-->InsHA recipients resulted in the activation and proliferation of clone 4 CD8+ T cells throughout the peripheral lymphoid tissues. Significantly, proliferation was not associated with the acquisition of T cell effector function; as evidenced by a lack of interferon-gamma production and the complete absence of any autoimmune pathology even after immunization of recipient mice with PR8. These data demonstrate that resting B cells pulsed with self-epitopes can induce abortive activation of potentially self-reactive naive CD8+ T cells resulting in their functional deletion from the peripheral T-cell repertoire in the absence of any associated autoimmunity.

Low molecular weight indole fragments as IMPDH inhibitors.

The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.

Novel indole inhibitors of IMPDH from fragments: synthesis and initial structure-activity relationships.

The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.

A causal link between lymphopenia and autoimmunity.

It is well recognized that the composition of the mature T cell population is subject to strict homeostatic control. The TCR repertoire and relative proportions of various T cell subsets are established in the thymus, and continue to be shaped and regulated in the periphery. As the thymic function declines, peripheral homeostatic mechanisms assume increasing importance. Indeed, loss of thymic function does not lead to progressive decline of T cell numbers because peripheral mechanisms ensure that the size of the T cell population is maintained due to proliferation of residual cells. However, our current understanding of the basic mechanisms of 'homeostatic' or lymphopenia-induced proliferation suggests that this drive to maintain population size may be accompanied by loss of TCR diversity and emergence of auto-reactive effector T cells. This prediction is supported by experimental and clinical evidence. This consideration is important because lymphopenia is seen commonly in clinical practice as a consequence of viral infections, or medical treatment of cancer, autoimmunity, and graft rejection. Lymphopenia may be a simple link between viral infections and autoimmunity, and may be one reason for common failure of very potent, but non-specific, immunosuppressive drugs in current clinical use.

New therapy update--A unique combination formulation in the treatment of inflammatory acne.

Duac Topical Gel (clindamycin 1%-benzoyl peroxide 5%) is a uniform, aqueous gel manufactured under the US Food and Drug Administration (FDA) Current Good Manufacturing Practice (cGMP) regulations and controls, which ensure that consistent product is delivered to the patient every time. Since the product is premixed, the patient does not have to wait for mixing or compounding by the pharmacist. The active ingredients have been shown to be stable for 60 days at room temperature, so that neither the patient nor the physician needs to store the product in the refrigerator. When kept at temperatures of 2 degrees C to 8 degrees C, the product is stable for 2 years. In a clinical study of 358 subjects with moderate to moderately severe acne vulgaris, once-daily treatment with clindamycin 1%-benzoyl peroxide 5% for 11 weeks reduced inflammatory lesions by 53% and noninflammatory lesions by 25%. Good or excellent global response was experienced in 50% of subjects. Overall tolerance ratings were good to excellent in 99% of subjects, and, except for mild to moderate expected local reactions, there were no adverse events related to treatment.