Photoaggravated hand and foot psoriasis

The majority of patients with psoriasis benefit from ultraviolet radiation exposure, but psoriasis can deteriorate on exposure to sunlight in some people. We report a patient with longstanding palmoplantar psoriasis that showed an unusual evolution into photoaggravated psoriasis, with change of distribution from the palmar to the dorsal aspect of the hands, and confirmation by photoprovocation with solar-simulated radiation. The onset of photosensitivity should be suspected in patients with hand and foot psoriasis showing a similar change in distribution.     

Laugier-Hunziker syndrome: A case report and review of the literature

Laugier-Hunziker syndrome (LHS) is a rare acquired disorder characterized by diffuse macular hyperpigmentation of the oral mucosa and, at times, longitudinal melanonychia. Although LHS is considered a benign disease with no systemic manifestations or malignant potential, it is important to rule out other mucocutaneous pigmentary disorders that do require medical management. Prompt clinical recognition also averts the need for excessive and invasive procedures and treatments. To date, only four cases have been reported in the United States. We present a 77-year-old man who had clinical features typical of LHS and we then provide a review of the literature on LHS and its mimickers.     

Novel 2-Aminobenzamides as Potential Orally Active Antithrombotic Agents

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Shp1 regulates T cell homeostasis by limiting IL-4 signals

The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell–intrinsic role of Shp1, we characterized mice with a T cell–specific Shp1 deletion (Shp1^fl/fl CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1^fl/fl CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4⁺ T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1-deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44^hi population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes.T cells are characterized by their ability to expand dramatically in an antigen-specific manner during an immune challenge. After an initial immune response, a small proportion of responding T cells survive and give rise to memory cells (Bruno et al., 1996). Memory T cells express elevated levels of CD44 and can be divided further into central-memory (CD62L^hi CCR7^hi) and effector-memory (CD62L^lo CCR7^lo) compartments. However, not all T cells that display the phenotype of memory cells are the product of a classical antigen-specific immune response (Sprent and Surh, 2011). For example, such cells are found in unimmunized mice, including those raised in germ-free and antigen-free conditions (Dobber et al., 1992; Vos et al., 1992). The precise ontogeny of such cells remains elusive, although several mechanisms by which naive cells can adopt a memory phenotype have been characterized. Naive T cells introduced into lymphopenic environments adopt a memory phenotype through a process of homeostatic proliferation in response to IL-7 and MHC (Goldrath et al., 2000; Murali-Krishna and Ahmed, 2000). Additionally, increased production of IL-4 has been linked to the development of memory phenotype–innate T cell populations in studies of several knockout mouse models (Lee et al., 2011).The T cell response is tightly regulated by the balance of phosphorylation and dephosphorylation of intracellular signaling molecules. Shp1 (encoded by Ptpn6) is a protein tyrosine phosphatase expressed ubiquitously in hematopoietic cells and has been broadly characterized as a negative regulator of immune cell activation (Pao et al., 2007a; Lorenz, 2009). The physiological relevance of Shp1 as a key negative regulator of the immune response is illustrated by the motheaten (me) and motheaten viable (me^v) mutations, which ablate Shp1 expression or greatly reduce Shp1 activity, respectively (Shultz et al., 1993; Tsui et al., 1993). Homozygous me/me or me^v/me^v mice (hereafter, referred to collectively as me mice) suffer from severe systemic inflammation and autoimmunity, which result in retarded growth, myeloid hyperplasia, hypergammaglobulinemia, skin lesions, interstitial pneumonia, and premature death. More recently, a study has identified a third allele of Ptpn6, named spin, which encodes a hypomorphic form of Shp1 (Croker et al., 2008). Mice homozygous for spin develop a milder autoimmune/inflammatory disease that is ablated in germ-free conditions.Shp1 has been implicated in signaling from many immune cell surface receptors (Zhang et al., 2000; Neel et al., 2003), including the TCR (Plas et al., 1996; Lorenz, 2009), BCR (Cyster and Goodnow, 1995; Pani et al., 1995), NK cell receptors (Burshtyn et al., 1996; Nakamura et al., 1997), chemokine receptors (Kim et al., 1999), FAS (Su et al., 1995; Takayama et al., 1996; Koncz et al., 2008), and integrins (Roach et al., 1998; Burshtyn et al., 2000). Shp1 also has been demonstrated to regulate signaling from multiple cytokine receptors by dephosphorylating various Jak (Klingmüller et al., 1995; Jiao et al., 1996; Minoo et al., 2004) and/or Stat (Kashiwada et al., 2001; Xiao et al., 2009) molecules. Several of these cytokines are pertinent to T cell biology. For example, Stat 5 is an essential mediator of signals from IL-2 and IL-7 (Rochman et al., 2009). IL-4 signaling results in Stat 6 phosphorylation and has potent Th2 skewing effects. Additionally, IL-4 has mitogenic effects on CD8⁺ T cells (Rochman et al., 2009). Notably, mutation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) in IL-4Rα results in ablation of Shp1 binding and hypersensitivity to IL-4 stimulation (Kashiwada et al., 2001), implicating Shp1 as a regulator of this cytokine receptor.Although development of the me phenotype does not require T cells (Shultz, 1988; Yu et al., 1996), several aspects of T cell biology reportedly are controlled by Shp1 (Lorenz, 2009). Most previous studies that examined the role of Shp1 in T cells used cells derived from me/me or me^v/me^v mice (Carter et al., 1999; Johnson et al., 1999; Zhang et al., 1999; Su et al., 2001) or cells expressing a dominant-negative allele of Shp1 (Plas et al., 1996, 1999; Zhang et al., 1999). Several such reports have concluded that Shp1 negatively regulates the strength of TCR signaling during thymocyte development and/or peripheral activation (Carter et al., 1999; Johnson et al., 1999; Plas et al., 1999; Zhang et al., 1999; Su et al., 2001). Despite the large number of studies that implicate Shp1 in control of TCR signaling, there is no consensus on which component of the TCR signaling cascade is targeted by the catalytic activity of Shp1. Suggested Shp1 targets downstream of T cell activation include TCR-ζ (Chen et al., 2008), Lck (Lorenz et al., 1996; Stefanová et al., 2003), Fyn (Lorenz et al., 1996), ZAP-70 (Plas et al., 1996; Chen et al., 2008), and SLP-76 (Mizuno et al., 2005). Shp1 also is implicated in signal transduction downstream of several immune inhibitory receptors that negatively regulate T cell activity, such as PD-1 (Chemnitz et al., 2004), IL-10R (Taylor et al., 2007), CEACAM1 (Lee et al., 2008), and CD5 (Perez-Villar et al., 1999).The severe inflammation characteristic of the me phenotype might have confounded studies examining the cell-intrinsic role of Shp1 in various hematopoietic cell types. We previously generated a floxed Shp1 allele that facilitates analysis of the role of Shp1 in various lineages (Pao et al., 2007b). Previous studies have used this approach to study the role of Shp1 in T cells during antiviral and antitumor immune responses, respectively (Fowler et al., 2010; Stromnes et al., 2012). However, a more fundamental analysis of the cell-intrinsic role of Shp1 during T cell development, homeostasis, and activation has not been reported. Here, we provide evidence that a major role for Shp1 in T cells is to maintain normal T cell homeostasis through negative regulation of IL-4 signaling.     

Child sexual abuse in Tanzania: much noise,little justice

Every day in Tanzania, newspapers report horrible stories of the sexual abuse of children. This serious situation has aroused calls for stricter punishment of perpetrators, but little is being done to help the abused children. A 1997 analysis of these reports by the Tanzania Legal Human Rights Center has revealed that the majority of the perpetrators are adult males who are close to their victims and who hold positions of respect in society. The sexual abuse of children is fundamentally an expression of power over a child's life, and Tanzanian children have little control over their lives and are usually disciplined with corporeal punishment. Tanzanian children are accustomed to seeing men hurt weaker people without censure, and the children do not have the status to defend themselves against physical, psychological, or sexual abuse. Thus, child sexual abuse is an inevitable consequence in a society where children have no voice. It is impossible to condone physical and verbal abuse while condemning sexual abuse, and punishing the abusers will not solve the problem. Instead, perpetrators must be held accountable and made to understand the seriousness of their actions. In order to make amends to their victims, they should be required to pay for the child's health care and education and to perform mandatory community service to make children safer. Children must be given the opportunity to learn that they can say no to adults and refuse to accept abuse.     

Country watch. Tanzania

The Kuleana Center for Children's Rights in Mwanza, Tanzania, is using peer education, focus group discussions, and individual counseling to decrease high-risk sexual behavior on the part of street children. These program activities seek to raise the children's self-esteem, engage them in trusting and respectful relationships, and teach sex-related negotiation skills. The Center is also involved in advocacy work to build compassion and respect for these children within the community, thereby decreasing their harassment on the streets and isolation. Incidents of street children being held in police custody or prison, where they are frequently sexually assaulted, have significantly decreased as a result. To promote the health of these children at high risk of sexually transmitted diseases, the Center operates a small clinic to address basic health problems and runs training sessions for health workers on the special needs of this population. The Center's future goals include formation of a street children's mobile theater group, activities designed to promote group identity and solidarity, and research on the physical and sexual abuse of young girls working as domestic laborers.     

The perspective of employers/families and care recipients of migrant live‐in caregivers: a scoping review

In high‐income countries, migrant live‐in caregivers are increasingly in demand to provide health and social care in the home. While there is a wide range of research on the perspectives of live‐in caregivers (including domestic workers) in destination countries, few studies address the perspective of families who hire them. The aim of this study was to explore the extent, range and nature of international literature on the needs and experiences of employers/families and care recipients of live‐in caregivers. We undertook a scoping review of the literature on this topic using Arksey and O'Malley's five stages. With the assistance of a health science librarian, a comprehensive search of nine databases was undertaken from April to July 2014. Two research assistants independently reviewed 2493 articles. The data were analysed through data charting, numerical summary and thematic analysis. Thirteen articles met the inclusion criteria for the scoping review. Many of these studies (n = 7) were conducted in Israel, and the majority (n = 8) focus on elderly care recipients. The findings reveal the diverse roles live‐in caregivers perform, including emotional and physical care; changes in family dynamics and roles upon hiring a live‐in caregiver; the negative experiences, including abuse, of live‐in caregivers and elderly care recipients; the positive outcomes for families with a live‐in caregiver; and families’ common perception that live‐in caregivers are like kin, a part of the family. Furthermore, evidence points to some degree of bi‐directional emotional support between caregivers and employers/families, which adds complexity to their relations and the negotiation of power.