Hyperkeratotic Plaques on the Palms and Soles. Palmoplantar Lichen Planus, Hyperkeratotic Variant

Archives of Dermatology. Oct, 2004  |  Pubmed ID: 15492196

Unilateral Darier's Disease Associated with Migraine Headache Responsive to Isotretinoin

Journal of the American Academy of Dermatology. Jan, 2005  |  Pubmed ID: 15627112

Palisaded Encapsulated Neuroma--a Classic Presentation of a Commonly Misdiagnosed Neural Tumor

Journal of Drugs in Dermatology : JDD. Jan-Feb, 2005  |  Pubmed ID: 15696992

We present a case report of a classical presentation of palisaded encapsulated neuroma (PEN) of the skin occurring on the nasolabial crease and a review of the literature. A young woman presented with a smooth lobulated papule on the cheek enlarging over 2 years. Histologic examination revealed a well-circumscribed dermal nodule of small spindle cells with wavy nuclei arranged in fascicles, consistent with the diagnosis of PEN. PEN is a previously described, benign cutaneous neural tumour, with a histological appearance between that of a neurofibroma and a schwannoma. Though not uncommon, PEN remains under-diagnosed by many pathologists. Clinically, PEN is most commonly misdiagnosed as a basal cell carcinoma, a nevus, or as a neurofibroma.

Redefining the Dermatologist-academy-industry Relationship: an Open Letter

Journal of the American Academy of Dermatology. Mar, 2005  |  Pubmed ID: 15761445

Scrotal Ulceration As a Consequence of All-trans-retinoic Acid (ATRA) for the Treatment of Acute Promyelocytic Leukemia

Journal of Drugs in Dermatology : JDD. Mar-Apr, 2005  |  Pubmed ID: 15776785

Induction therapy with all-trans-retinoic acid (ATRA), an oral vitamin A derivative, has been shown to improve the short and long-term outcome of patients with acute promyelocytic leukemia (APML). Common side effects include headache, fever, dry skin, and bone pain, and approximately 25% of treated patients experience ATRA syndrome, which includes fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions. Scrotal ulcerations due to ATRA are rare with 16 previously documented cases, most of whom were Asian. We report a Caucasian male with APML who developed scrotal ulceration during ATRA induction therapy and review the previously reported cases. Physicians and patients should be aware of this disturbing, but self-limited, dermatologic complication of ATRA.

Characterization of Anti-self CD8 T-cell Responses Stimulated by Recombinant Listeria Monocytogenes Expressing the Melanoma Antigen TRP-2

Vaccine. Jul, 2005  |  Pubmed ID: 15913853

A potential approach to activate tumor-specific T cells is to use live bacterial vectors to deliver appropriate antigens in a highly immunostimulatory context. We constructed a recombinant strain of Listeria monocytogenes (rLM) expressing murine tyrosinase-related protein-2 (TRP-2), a nonmutated melanocyte-derived differentiation antigen highly expressed in melanomas. Immunization of C57Bl/6 mice with this rLM strain efficiently primed CD8 T cells to recognize the MHC class I-restricted TRP-2180-188 epitope and express IFN-gamma upon in vitro peptide stimulation. Peptide-loaded target cells were lysed in vitro by TRP-2-specific T cells in cytotoxicity assays, and mice immunized and boosted with rLM expressing TRP-2 were functionally protected from subcutaneous challenge with B16 melanoma cells. These results identify and characterize the anti-"self" T-cell responses induced by recombinant L. monocytogenes expressing an endogenous, nonmutated tumor antigen.

Bioluminescent Imaging of Melanoma in Live Mice

The Journal of Investigative Dermatology. Jul, 2005  |  Pubmed ID: 15982316

Melanoma is highly resistant to conventional chemotherapeutic agents and novel therapeutic approaches are needed. Current animal models of melanoma in animals are sub-optimal. The most commonly used homograft model is the B16 mouse melanoma. Evaluation of potential melanoma therapies with this model is limited by the inaccuracy of caliper measurement of subcutaneous tumors, of counting lung nodules in metastasis models, and the indirect nature of "survival" curves when studying brain metastases. We have developed and characterized an accurate, sensitive, and reproducible bioluminescent B16 melanoma model that allows for serial, real-time analyses of tumor burden in live mice. We demonstrate that this model is applicable to subcutaneous tumors, lung metastases, and intracranial tumors and offers a solution to many of the limitations of previous models. As proof of principle, we use this model to show the efficacy of a live, Listeria monocytogenes vaccine expressing the melanoma antigen tyrosinase-related protein-2 to protect mice against intravenous B16 melanoma challenge. Additionally, we extend our approach to include the human A375 melanoma model and are able to show in vivo differences between sub-lines with varying metastatic potential. These models represent an accurate and reproducible means for in vivo melanoma monitoring in preclinical studies.

The TLR7 Agonist Imiquimod Enhances the Anti-melanoma Effects of a Recombinant Listeria Monocytogenes Vaccine

Journal of Immunology (Baltimore, Md. : 1950). Aug, 2005  |  Pubmed ID: 16034143

Activation of innate immune cells through TLR triggers immunomodulating events that enhance cell-mediated immunity, raising the possibility that ligands to these receptors might act as adjuvants in conjunction with T cell activating vaccines. In this report, topical imiquimod, a synthetic TLR7 agonist, significantly enhanced the protective antitumor effects of a live, recombinant listeria vaccine against murine melanoma. This tumor protective effect was not dependent on direct application to the tumor and was associated with an increase in tumor-associated and splenic dendritic cells. Additionally, the combination of imiquimod treatment with prior vaccination led to development of localized vitiligo. These findings indicate that activation of the innate immune system with TLR ligands stimulates dendritic cell activity resulting in a bypass of peripheral tolerance and enhanced antitumor activity. The results of these studies have broad implications for future designs of immunotherapeutic vaccines against tumors and the treatment of metastatic melanoma.

The TLR-7 Agonist, Imiquimod, Enhances Dendritic Cell Survival and Promotes Tumor Antigen-specific T Cell Priming: Relation to Central Nervous System Antitumor Immunity

Journal of Immunology (Baltimore, Md. : 1950). Jan, 2006  |  Pubmed ID: 16365406

Immunotherapy represents an appealing option to specifically target CNS tumors using the immune system. In this report, we tested whether adjunctive treatment with the TLR-7 agonist imiquimod could augment antitumor immune responsiveness in CNS tumor-bearing mice treated with human gp100 + tyrosine-related protein-2 melanoma-associated Ag peptide-pulsed dendritic cell (DC) vaccination. Treatment of mice with 5% imiquimod resulted in synergistic reduction in CNS tumor growth compared with melanoma-associated Ag-pulsed DC vaccination alone. Continuous imiquimod administration in CNS tumor-bearing mice, however, was associated with the appearance of robust innate immune cell infiltration and hemorrhage into the brain and the tumor. To understand the immunological mechanisms by which imiquimod augmented antitumor immunity, we tested whether imiquimod treatment enhanced DC function or the priming of tumor-specific CD8+ T cells in vivo. With bioluminescent, in vivo imaging, we determined that imiquimod dramatically enhanced both the persistence and trafficking of DCs into the draining lymph nodes after vaccination. We additionally demonstrated that imiquimod administration significantly increased the accumulation of tumor-specific CD8+ T cells in the spleen and draining lymph nodes after DC vaccination. The results suggest that imiquimod positively influences DC trafficking and the priming of tumor-specific CD8+ T cells. However, inflammatory responses induced in the brain by TLR signaling must also take into account the local microenvironment in the context of antitumor immunity to induce clinical benefit. Nevertheless, immunotherapeutic targeting of malignant CNS tumors may be enhanced by the administration of the innate immune response modifier imiquimod.

Central Nervous System Tumor Immunity Generated by a Recombinant Listeria Monocytogenes Vaccine Targeting Tyrosinase Related Protein-2 and Real-time Imaging of Intracranial Tumor Burden

Neurosurgery. Jan, 2006  |  Pubmed ID: 16385341

Previously, we demonstrated that a recombinant Listeria monocytogenes (rLM) vector encoding the melanoma-associated antigen, tyrosinase related protein (TRP)-2, could successfully treat subcutaneous B16 melanomas. The purpose of the present study was twofold: 1) to test whether this rLM-nucleoprotein (NP)/TRP-2 could generate antitumor immunity to a B16 tumor challenge in the immunologically privileged central nervous system (CNS) and 2) to develop a noninvasive imaging modality to monitor tumor progression in the brain after immunotherapy.

Adult-onset Tufted Angioma: a Case Report and Review of the Literature

Cutis; Cutaneous Medicine for the Practitioner. Nov, 2006  |  Pubmed ID: 17186794

Tufted angiomas (TAs) are benign vascular tumors, primarily occurring on the trunk and extremities of children younger than 5 years. Few cases occurring on the oral mucosa and in adults have been reported. Although they are typically isolated lesions, TA has been associated with port-wine stains. We describe a case of adult-onset TA on the lower lip mucosa.

Cutaneous Signs of Child Abuse

Journal of the American Academy of Dermatology. Sep, 2007  |  Pubmed ID: 17707148

Maltreatment of children is a major public health crisis, and it is estimated that each year more than 3 million children are victims of abuse. Safeguarding the welfare of children is a priority, and it is the moral and ethical responsibility of healthcare professionals to detect cases of abuse and intervene appropriately to prevent further harm. Clinicians are often challenged to differentiate signs of child abuse from skin conditions that mimic maltreatment. Because cutaneous injury represents the most recognizable and common form of abuse, dermatologists are often called upon to help distinguish signs of intentional injury from skin conditions that mimic maltreatment. However, few resources specific to dermatologic signs of abuse exist to aid in diagnosis. A review of the literature will provide an educational resource to assist dermatologists and other clinicians in differentiating cutaneous signs of child abuse, including physical and sexual abuse, from mimickers of inflicted injury. LEARNING OBJECTIVE: After completing this learning activity, participants should be able to distinguish signs of intentional injury from skin conditions that mimic maltreatment and understand the clinician's role in the diagnosis and reporting of cases of suspected child abuse.

Listeria As a Vaccine Vector

Microbes and Infection / Institut Pasteur. Aug, 2007  |  Pubmed ID: 17719258

The immunostimulatory characteristics and intracellular niche of Listeria monocytogenes make it uniquely suitable for use as a live bacterial vaccine vector. Preclinical results supporting this idea, and current strategies to induce beneficial cell-mediated immunity to both infectious diseases and cancer with this vector, are discussed in this review.

Immunosensitization with a Bcl-2 Small Molecule Inhibitor

Cancer Immunology, Immunotherapy : CII. May, 2009  |  Pubmed ID: 18807035

Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x(L), was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models. The addition of systemic therapy with ABT-737 to the immunization of BALB/c mice with tumor antigen peptide-pulsed dendritic cells (DC) resulted in a significant delay in CT26 murine colon carcinoma tumor growth and improvement in survival. However, the addition of ABT-737 to either a vaccine strategy involving priming with TRP-2 melanoma antigen peptide-pulsed DC and boosting with recombinant Listeria monocytogenes expressing the same melanoma antigen, or the adoptive transfer of TCR transgenic cells, did not result in superior antitumor activity against B16 murine melanoma. In vitro studies failed to demonstrate increased cytotoxic lytic activity when testing the combination of ABT-737 with lymphokine activated killer (LAK) cells, or the death receptor agonists Fas, TRAIL-ligand or TNF-alpha against the CT26 and B16 cell lines. In conclusion, the Bcl-2 inhibitor ABT-737 sensitized cancer cells to the antitumor effect of antigen-specific immunotherapy in a vaccine model for the CT26 colon carcinoma in vivo but not in two immunotherapy strategies against B16 melanoma.

Enhanced Antitumor Activity Induced by Adoptive T-cell Transfer and Adjunctive Use of the Histone Deacetylase Inhibitor LAQ824

Cancer Research. Nov, 2009  |  Pubmed ID: 19861533

Tumors grow in the presence of antigen-specific T cells, suggesting the existence of intrinsic cancer cell escape mechanisms. We hypothesized that a histone deacetylase (HDAC) inhibitor could sensitize tumor cells to immunotherapy because this class of agents has been reported to increase tumor antigen expression and shift gene expression to a proapoptotic milieu in cancer cells. To test this question, we treated B16 murine melanoma with the combination of the HDAC inhibitor LAQ824 and the adoptive transfer of gp100 melanoma antigen-specific pmel-1 T cells. The combined therapy significantly improved antitumor activity through several mechanisms: (a) increase in MHC and tumor-associated antigen expression by tumor cells; (b) decrease in competing endogenous lymphocytes in recipient mice, resulting in a proliferative advantage for the adoptively transferred cells; and (c) improvement in the functional activity of the adoptively transferred lymphocytes. We confirmed the beneficial effects of this HDAC inhibitor as a sensitizer to immunotherapy in a different model of prophylactic prime-boost vaccination with the melanoma antigen tyrosinase-related protein 2, which also showed a significant improvement in antitumor activity against B16 melanoma. In conclusion, the HDAC inhibitor LAQ824 significantly enhances tumor immunotherapy through effects on target tumor cells as well as improving the antitumor activity of tumor antigen-specific lymphocytes.

Cutaneous and Mucocutaneous Leishmaniasis

Dermatologic Therapy. Nov-Dec, 2009  |  Pubmed ID: 19889134

Leishmaniasis is a cluster of diseases caused by protozoa in the genus Leishmania. There are three basic clinical forms: cutaneous, mucocutaneous, and visceral leishmaniasis. The present review focuses on the diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Characteristics of both the human host and the parasite species influence the clinical disease manifestations that range from asymptomatic exposure, to self-healing skin ulcers, to life-threatening widespread destructive ulcerations. Whether through medical treatment or through spontaneous resolution, skin ulcerations generally result in disfiguring scars with significant social and economic impact. Tests to confirm the diagnosis should be performed on patients who have recently visited endemic areas and have skin or mucosal manifestations consistent with leishmaniasis. Treatment depends on the species of Leishmania and the risk of widespread or disfiguring disease. Because of increasing trends in global travel, educating health care providers to recognize and treat leishmaniasis in both endemic and non-endemic countries is imperative.

Disseminated Strongyloides Stercoralis: Hyperinfection During Medical Immunosuppression

Journal of the American Academy of Dermatology. Nov, 2010  |  Pubmed ID: 20172622

Hyperinfection caused by Strongyloides stercoralis in iatrogenically immunosuppressed patients is becoming more frequently observed. Here, we review the relevant literature and present a recent case of hyperinfection syndrome of S stercoralis in a patient chronically treated with systemic corticosteroids and methotrexate for dermatomyositis. The patient was born in Guatemala but no history of Strongyloides infection was documented. Disseminated Strongyloides is often associated with the immunocompromised state and is commonly seen with cutaneous lesions, respiratory failure, and sepsis. In this patient, a protracted course of progressive muscle weakness and multiple hospital stays for respiratory distress led to acute respiratory failure, septic shock, and rapid physical decline. A few days preceding his death, the patient developed petechiae and multiple purpuric macules and patches over the abdomen and thighs. Histologic review of skin biopsy specimens demonstrated multiple intravascular and interstitial filariform larvae. Dermatologists should be aware of patient populations at risk for infection with S stercoralis and be able to make this diagnosis to initiate earlier treatment of hyperinfection and dissemination.

Mucocutaneous Leishmaniasis Masquerading As Wegener Granulomatosis

Journal of Clinical Rheumatology : Practical Reports on Rheumatic & Musculoskeletal Diseases. Apr, 2010  |  Pubmed ID: 20375822

A 43-year-old Brazilian female presented in 2001 with nasal stuffiness and sinusitis. A biopsy was consistent with limited Wegener's granulomatosis although antineutrophil cytoplasmic antibodies were negative. Her nasal inflammation progressed despite trials of prednisone, methotrexate, and azathioprine. A septal perforation developed and a repeat biopsy showed granulomatous inflammation. In 2006 the patient was referred to Division of Rheumatology, University of California, Los Angeles. The nose was grossly erythematous and a magnetic resonance imaging revealed nasal destruction and sinusitis. Palatine biopsies showed chronic inflammation. Cyclophosphamide at 150 mg/d resulted in markedly improved mucocutaneous lesions. The patient developed a leg and arm rash in 2007. A skin biopsy was positive for Leishmania braziliensis. The cyclophosphamide was discontinued and amphotericin B was initiated with transient benefit. Remission was achieved with pentavalent antimony. Despite multiple nasopharyngeal biopsies, for a 6-year span, mucocutaneous leishmaniasis masqueraded as Wegener's granulomatosis. Cyclophosphamide not only resulted in clinical improvement, due to reduced inflammatory response, but also allowed widespread cutaneous dissemination.

Human Immunodeficiency Virus and Leishmaniasis

Journal of Global Infectious Diseases. Sep, 2010  |  Pubmed ID: 20927287

The Leishmaniases are a group of diseases transmitted to humans by the bite of a sandfly, caused by protozoan parasites of the genus Leishmania. Various Leishmania species infect humans, producing a spectrum of clinical manifestations. It is estimated that 350 million people are at risk, with a global yearly incidence of 1-1.5 million for cutaneous and 500,000 for visceral Leishmaniasis (VL). VL is a major cause of morbidity and mortality in East Africa, Brazil and the Indian subcontinent. Co-infection with human immunodeficiency virus (HIV) alters the immune response to the disease. Here we review the immune response to Leishmania in the setting of HIV co-infection. Improved understanding of the immunology involved in co-infections may help in designing prophylactic and therapeutic strategies against Leishmaniasis.

LXR Deficiency Confers Increased Protection Against Visceral Leishmania Infection in Mice

PLoS Neglected Tropical Diseases. 2010  |  Pubmed ID: 21103366

The liver X receptors (LXRs) are a family of nuclear receptor transcription factors that are activated by oxysterols and have defined roles in both lipid metabolism and cholesterol regulation. LXRs also affect antimicrobial responses and have anti-inflammatory effects in macrophages. As mice lacking LXRs are more susceptible to infection by intracellular bacteria Listeria monocytogenes and Mycobacterium tuberculosis, we hypothesized that LXR might also influence macrophage responses to the intracellular protozoan parasite Leishmania chagasi/infantum, a causative agent of visceral leishmaniasis.

CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-expressing Mice

PloS One. 2011  |  Pubmed ID: 21359208

Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF₂ receptor antagonist, astressin₂-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.

Diagnostic Accuracy in Patients Admitted to Hospitals with Cellulitis

Dermatology Online Journal. 2011  |  Pubmed ID: 21426867

Misdiagnosis of non-infectious conditions such as cellulitis is a common error and can result in unnecessary hospitalization and antibiotic use. We sought to prospectively determine the misdiagnosis rate of cellulitis among hospitalized patients and to determine if a visually-based computerized diagnostic decision support system (VCDDSS, also named VisualDx) could generate an improved differential diagnosis (DDx) for misdiagnosed patients. In two separate institutions, attending dermatologists or infectious disease specialists evaluated all consecutive patients hospitalized for "cellulitis" by the emergency department. Among 145 subjects enrolled, misdiagnosis occurred in 41 (28%) patients. The diagnosis most commonly mistaken as cellulitis was stasis dermatitis (37%). At one center, in cases that were misdiagnosed by the emergency department, the VCDDSS included the correct diagnosis in the DDx more frequently than the admitting team (18/28 cases (64%) compared to 4/28 cases (14%), p=0.0003). These results demonstrate the capability of this VCDDSS to assist primary care physicians with generating a more accurate DDx when confronted with patients presenting with possible skin infections. Misdiagnoses may result in a significant source of healthcare costs and misdiagnosis-related patient harm. Inclusion of decision support tools early in the diagnostic workflow may reduce misdiagnosis and result in more efficient healthcare management.

A Critical Role for GRP78/BiP in the Tumor Microenvironment for Neovascularization During Tumor Growth and Metastasis

Cancer Research. Apr, 2011  |  Pubmed ID: 21467168

Glucose-regulated protein 78 (GRP78)/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis, and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we showed that Grp78 heterozygosity impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis and the Grp78(+/-) mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors, while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this article, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models in which wild-type (WT), syngeneic mammary tumor cells were injected into the host, we showed that Grp78(+/-) mice suppressed tumor growth and angiogenesis during the early phase but not during the late phase of tumor growth. Growth of metastatic lesions of WT, syngeneic melanoma cells in the Grp78(+/-) mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and showed severe reduction of tumor angiogenesis and metastatic growth, with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells showed that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression, and metastasis.

Characteristic Purpura of the Ears, Vasculitis, and Neutropenia--a Potential Public Health Epidemic Associated with Levamisole-adulterated Cocaine

Journal of the American Academy of Dermatology. Oct, 2011  |  Pubmed ID: 21658797

Dermatologists at the University of California, San Francisco recently reported two patients in the online Journal of the American Academy of Dermatology with purpura presumably induced by levamisole in contaminated cocaine. Levamisole-induced vasculitis and neutropenia has been reported elsewhere in the United States and Canada. Up to 70% of cocaine in the United States could be contaminated.

MMP-9 Activity is Induced by Leishmania Braziliensis Infection and Correlates with Mucosal Leishmaniasis

Acta Tropica. Aug, 2011  |  Pubmed ID: 21663729

Infection of humans with Leishmania braziliensis typically results in localized cutaneous leishmaniasis (LCL). Rarely, after months or years of apparent clinical cure, some patients develop the destructive mucosal leishmaniasis (ML). ML results from L. braziliensis dissemination, probably via phagocytic cells. As the preferred cells for Leishmania spp. colonization, macrophages are critical to infection control, and may contribute to parasite dissemination. However, the host factors that determine this outcome are unknown. Matrix metalloproteinase 9 (MMP-9) is known to be important for immune cell migration, macrophage recruitment, and effective granuloma formation. Moreover, MMP-9 has been involved in Mycobacterium tuberculosis dissemination. Here, we demonstrate that in vitro infection of human macrophages with L. braziliensis increased the secretion and activation of MMP-9. We also demonstrate that macrophages from healthy cured individuals with previous history of ML had increased MMP-9 activity compared to LCL cured individuals. These findings may represent a fundamental difference in host innate immunity that could contribute to the clinical leishmaniasis presentation.

Innate Immunity and Leishmania Vaccination Strategies

Dermatologic Clinics. Jan, 2011  |  Pubmed ID: 21095533

Despite the ubiquity and severity of parasitic diseases and our desire to prevent them, there are no effective antiparasitic vaccines in widespread clinical use. This review focuses on strategies for development of a vaccine against cutaneous leishmaniasis as a representative parasitic disease of paramount interest to dermatologists and all who care for patients who live in or travel to the developing world. Any effective strategy will require attention to the central role that host innate immunity plays during induction of durable resistance to these virulent protozoa. The cell types, receptors, and molecules of the innate immune system that will likely play a role in any effective vaccine against cutaneous leishmaniasis are reviewed.

Dermatology and HIV/AIDS in Africa

Journal of Global Infectious Diseases. Jul, 2011  |  Pubmed ID: 21887061

Human immunodeficiency virus and the acquired immunodeficiency syndrome (HIV/AIDS) have greatly complicated dermatologic disease and the required care in most regions of Africa. Opportunistic infections, ectoparasites, Kaposi sarcoma, and skin manifestations of systemic infections are exceedingly common in patients with HIV/AIDS. Dermatologists have contributed significantly to our knowledge base about HIV/AIDS and have played an important educational role regarding the clinical manifestations historically. Because of the increased burden of skin disease in Africa due to the HIV/AIDS epidemic we must redouble our efforts to provide dermatology education to care providers in Africa. We review the burden of skin disease in Africa, how it relates to HIV/AIDS and global infectious disease, current educational strategies in Africa to address this need, and suggest potential solutions to move these efforts forward.

Mobile Teledermatology: As Doctors and Patients Are Increasingly Mobile, Technology Keeps Us Connected

Skinmed. Jul-Aug, 2011  |  Pubmed ID: 21980708

With advancements in electronics and health informatics, telemedicine has emerged as a cost-effective tool capable of increasing care to remote regions, facilitating specialist consults, supporting self-management by patients, and sharing knowledge over great distances. In this review, the authors discuss existing telemedicine modalities, highlight examples of mobile systems documented in the literature to date, and emphasize the data supporting the feasibility of telecommunication technologies to deliver dermatology services and education remotely. While many studies have suggested the potential for teledermatology to increase access to care in developing countries with few dermatologists, the authors share some of the most recent developments, including the use of diagnostic decision support software. The authors encourage a thriving and open network that will enhance the ongoing research and development of innovative and useful products. This network will also connect dermatologists willing to volunteer their consultation to health care workers in remote areas lacking specialists.

Efficacy of Synthetic Peptides RP-1 and AA-RP-1 Against Leishmania Species In Vitro and In Vivo

Antimicrobial Agents and Chemotherapy. Feb, 2012  |  Pubmed ID: 22123683

Host defense peptides are naturally occurring molecules that play essential roles in innate immunity to infection. Based on prior structure-function knowledge, we tested two synthetic peptides (RP-1 and AA-RP-1) modeled on the conserved, microbicidal α-helical domain of mammalian CXCL4 platelet kinocidins. These peptides were evaluated for efficacy against Leishmania species, the causative agents of the group of diseases known as leishmaniasis. In vitro antileishmanial activity was assessed against three distinct Leishmania strains by measuring proliferation, metabolic activity and parasite viability after exposure to various concentrations of peptides. We demonstrate that micromolar concentrations of RP-1 and AA-RP-1 caused dose-dependent growth inhibition of Leishmania promastigotes. This antileishmanial activity correlated with rapid membrane disruption, as well as with a loss of mitochondrial transmembrane potential. In addition, RP-1 and AA-RP-1 demonstrated distinct and significant in vivo antileishmanial activities in a mouse model of experimental visceral leishmaniasis after intravenous administration. These results establish efficacy of RP-1 lineage synthetic peptides against Leishmania species in vitro and after intravenous administration in vivo and provide further validation of proof of concept for the development of these and related systemic anti-infective peptides targeting pathogens that are resistant to conventional antibiotics.

Delineation of Antigen-specific and Antigen-nonspecific CD8+ Memory T-cell Responses After Cytokine-based Cancer Immunotherapy

Blood. Jan, 2012  |  Pubmed ID: 22251483

Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naïve, CD8(+) T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through TCR or CD3 in both mouse and human memory CD8(+) T cells markedly upregulated programmed death-1 (PD-1) and CD25 (IL-2 receptor alpha chain) and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8(+) T cells expressing NKG2D, granzyme B and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished anti-tumor effects after immunotherapy. Treatment of TCR-transgenic mice bearing non-antigen expressing tumors with immunotherapy still resulted in significant anti-tumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted increased numbers of these CD8(+) CD25(-) cells within the tumor site. These findings demonstrate that memory CD8(+) T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species.

Killed but Metabolically Active Leishmania As a Novel Whole-cell Vaccine for Visceral Leishmaniasis

Clinical and Vaccine Immunology : CVI. Feb, 2012  |  Pubmed ID: 22323556

There are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here we describe a novel whole-cell vaccine approach using Leishmania infantum chagasi promastigotes treated with the psoralen compound amotosalen (S-59) and low doses of ultraviolet A radiation. This treatment generates permanent, covalent DNA crosslinks within parasites, and results in Leishmania organisms termed killed but metabolically active (KBMA). In this report, we characterize the in vitro growth characteristics of both KBMA-L. major and KBMA-L. infantum chagasi (KBMA-Lic). Concentrations of S-59 that generate optimally attenuated parasites were identified. Like live L. infantum chagasi, KBMA-Lic parasites were able to initially enter liver cells in vivo after intravenous infection. However, whereas live L. infantum chagasi infection leads to hepatosplenomegaly in mice after six months, KBMA-Lic were undetectable in the organs of mice at this time point. In vitro, KBMA-Lic retained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMA-Lic correlated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either live L. infantum chagasi or KBMA-Lic displayed similar cytokine patterns in vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoan L. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens.

Immunomodulation by Imiquimod in Patients with High-risk Primary Melanoma

The Journal of Investigative Dermatology. Jan, 2012  |  Pubmed ID: 21850019

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.