GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.

Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study.

A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA.

Objective: This was an open-label, phase 1/2 dose-escalation, safety trial of intrathecal recombinant human heparan-N-sulfatase (rhHNS) administered via intrathecal drug delivery device (IDDD) for treating mucopolysaccharidosis IIIA (NCT01155778).

Study Design: Twelve patients received 10, 45, or 90mg of rhHNS via IDDD once monthly for a total of 6 doses. Primary endpoints included adverse events (AEs) and anti-rhHNS antibodies.

Quantifying behaviors of children with Sanfilippo syndrome: the Sanfilippo Behavior Rating Scale.

The Sanfilippo Behavior Rating Scale (SBRS), a 68 item questionnaire, has been developed to assess the behavioral phenotype of children with Sanfilippo syndrome and its progression over time. Fifteen scales rate orality, movement/activity, attention/self-control, emotional function including anger and fear, and social interaction. Items within scales intercorrelate; measures of internal consistency are adequate.

Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome.

Objectives: (1) Develop a methodology for obtaining reliable cognitive and developmental data in children with neurodegenerative disease and cognitive impairment and in turn monitor disease state and treatment outcomes. (2) Demonstrate validity of age-equivalent scores.

Methods: We present guidelines for obtaining accurate test scores in low-functioning and behaviorally disruptive pediatric patients, followed by a method validation study: (1) using disease-specific protocols to assess salient aspects of the known phenotype, (2) selecting appropriate tests, (3) managing behavior, and (4) using age-equivalent scores on standardized tools.

A potential role for complement in immune evasion by Mycobacterium leprae.

Lepromatous leprosy is a model of immune evasion wherein pathogen-specific IL-10-secreting T cells and concomitant failure of Th-1 immunity permit uncontrolled proliferation of the intracellular pathogen, Mycobacterium leprae (M. leprae). The mechanism of this immune escape is unknown.

Immune cellular parameters of leprosy and human immunodeficiency virus-1 co-infected subjects.

Leprosy and human immunodeficiency virus-1 (HIV-1) are examples of human infections where interactions between the pathogen and the host cellular immunity determine the clinical manifestations of disease. Hence, a significant immunopathological interaction between HIV-1 and leprosy might be expected. In the present study we explored several aspects of cellular immunity in patients co-infected with HIV-1 and Mycobacterium leprae.

Selective defect in plasmacyoid dendritic cell function in a patient with AIDS-associated atypical genital herpes simplex vegetans treated with imiquimod.

We report a case of acquired immunodeficiency syndrome (AIDS)-associated, acyclovir-refractory genital herpes infection treated with topical imidazoquinoline therapy. The patient's plasmacytoid dendritic cells made a robust interferon- alpha response following in vitro stimulation with imidazoquinoline but not with herpes simplex virus. We hypothesize that disease resulting from defective herpes simplex virus-stimulated interferon- alpha may be overcome by stimulating intact alternative pathways.

Regulation of acquired immunity by gamma delta T-cell/dendritic-cell interactions.

In humans, innate immune recognition of mycobacteria, including Mycobacterium tuberculosis and Mycobacterium leprae, involves toll-like receptor-2 (TLR-2), expressed on immature dendritic cells (DCs), and the T-cell gammadelta receptor expressed by a subpopulation of T cells that utilize Vdelta2 (Vdelta2 T cells). To investigate modulatory relationships between these host-cell populations in a microbial context, in vitro experiments were performed with human DCs and Vdelta2 T cells stimulated with model TLR-2 ligands and phosphoantigens, respectively. We observed that TLR-2-stimulated DCs enhanced interferon-gamma (IFN-gamma) production by Vdelta2 T cells; conversely, activated Vdelta2 T cells enhanced TLR-2-induced DC maturation via soluble factors including IFN-gamma, which costimulated interleukin-12 (IL-12) p70 secretion by DCs.

A whole blood assay to assess peripheral blood dendritic cell function in response to Toll-like receptor stimulation.

We report a practical technique to assess peripheral blood dendritic cell (DC) maturation and function in whole blood (WB), which requires minimal blood volumes and minimizes ex vivo manipulations of clinical specimens. We determined optimal conditions for flow cytometric analysis of markers of DC maturation, including CCR7, CD25, CD80 and CD83, and of the intracellular cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha), in both myeloid (mDC) and plasmacytoid (pDC) lineages. We demonstrate concentration-dependent production of these cytokines by DC following short-term stimulation with ligands to Toll-like receptors (TLRs) 2/1, 3, 4, 7, 8 and 9.

Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.

The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days.

Presenilin-1 detection in brain neurons and FOXp3 in peripheral blood mononuclear cells: normalizer gene selection for real time reverse transcriptase pcr using the DeltaDeltaCt method.

Quantification of gene expression is important to confirm changes in levels of gene expression in disease. Prior quantification methods include standard curves, absolute quantification, and relative quantification. This paper describes an analytic method for the relative quantification of Presenilin-1 (PS-1) in neurons and Forkhead-box (FOX) p3 in PBMNCs using real-time PCR analytic techniques.

Novel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studies.

We optimized a whole blood intracellular cytokine assay to quantitate the frequency of specific CD4+ and CD8+ T cells in small volumes of whole blood from infants from developing countries. The assay is performed in two steps. First, whole blood is stimulated in the presence of specific antigens for 6-18 h, ending with cryopreservation of fixed white cells.

Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study.

Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor alpha inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study.

Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro.

To induce effector immunity, dendritic cells (DCs) must differentiate into fully mature cells. We show that, after human monocyte-derived DCs were infected with virulent Mycobacterium tuberculosis, up-regulation of cellular-surface maturation markers was minimal and reversible. In the presence of a potent stimulus for maturation (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and prostaglandin E2 [PGE2]), M.

Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro.

CD8(+) T cell immunity is critical for protection from viral disease, such as that caused by the human immunodeficiency virus (HIV) or cytomegalovirus (CMV). It is therefore important to identify therapies that can boost antiviral immunity. The recent finding that thalidomide acts as a T cell costimulator suggested that this drug may boost antiviral CD8(+) T cell responses.

Local nerve damage in leprosy does not lead to an impaired cellular immune response or decreased wound healing in the skin.

This study investigated whether peripheral nerve damage in patients with leprosy impairs local cellular immune responses, thereby reducing wound healing and leading to chronic skin ulceration. Anesthetic and contralateral sensitive skin sites in 42 patients with leprosy were compared for delayed-type hypersensitivity responses to purified protein derivative (PPD) of tuberculin. Leukocyte recruitment, epidermal activation, keratinocyte proliferation, and rates of wound healing after skin biopsy were compared.

Amplification of low-frequency antiviral CD8 T cell responses using autologous dendritic cells.

Objective: To utilize the potent antigen-presenting capacity of mature dendritic cells (MDC) in order to develop a rapid, sensitive method for quantifying antigen-specific CD8 T cells present at low frequency in peripheral blood.

Design: Peripheral blood mononuclear cells (PBMC) were obtained from seven HIV-1-positive individuals with low to moderate CD8 T cell responses, including five on highly active antiretroviral therapy (HAART). IFN-gamma ELISPOT assays were performed using either monocytes or MDC to present antigens expressed by recombinant vaccinia viruses (r-VV).