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Biomedical subjects

Michael David

Publications and source records attributed to Michael David.

At least 19 recordsLinked to original sources
PubMed2007

Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.

The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 microg once daily was well tolerated.

Administration, Oral↗
PubMed2006

The association between psoriasis, diabetes mellitus, and atherosclerosis in Israel: a case-control study.

BACKGROUND: Previous reports demonstrated an association between psoriasis and other diseases including heart failure and diabetes mellitus. OBJECTIVES: Our aim was to describe the association between psoriasis, diabetes mellitus, and atherosclerosis in Israel. METHODS: A cross-sectional study was performed utilizing the database of Maccabi Healthcare Services (MHS), a large health provider organization in Israel. Case patients were defined as subjects who were diagnosed with psoriasis. Patients with diabetes and atherosclerosis were identified by using the MHS diabetes and cardiovascular registries, respectively. The control group included MHS enrollees without psoriasis. The proportion of diabetes and atherosclerosis among case and control groups was compared. Chi-square tests were used to compare categorical parameters. Logistic regression models were used for multivariate analyses. RESULTS: The study included 46,095 patients with psoriasis (case patients) and 1,579,037 subjects without psoriasis (control patients). The age-adjusted proportion of diabetes was significantly higher in psoriasis patients as compared with the control group (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.1-1.48). The age-adjusted proportion of atherosclerosis was significantly higher in psoriasis patients as compared with the control group (OR 1.28, 95% CI 1.04-1.59). In patients with psoriasis, a multivariate logistic regression model demonstrated an association between diabetes and the multiple use of very potent topical steroids (P < .05) or use of systemic medication for psoriasis (methotrexate, cyclosporine or acitretin) (P < .001). A similar model demonstrated an association between atherosclerosis and the use of phototherapy (P < .001). LIMITATIONS: Our study was based on a computerized database. The diagnosis of psoriasis was based on digitally transmitted data. Therefore overestimation (false-positive cases) and underestimation (false-negative cases) of psoriasis patients may exist, thereby being a source for information bias. A second limitation is selection bias that may occur due to the possibility that reporting of both psoriasis and associated illnesses is higher in individuals who are seeking medical care. A third limitation concerns the causal effect between occurrence of psoriasis and atherosclerosis or diabetes. The dataset of MHS records diagnoses only from 1997 and does not record the date of disease onset. CONCLUSIONS: Our study supports previous reports for an association between psoriasis and atherosclerosis and psoriasis and diabetes. Further study is needed to support this observation.

Adolescent↗
PubMed2006

Cutting edge: inherent and acquired resistance to radiation-induced apoptosis in B cells: a pivotal role for STAT3.

Radiation-induced apoptosis (RiA) is used therapeutically for tumor cell ablation as well as a tool to characterize hemopoietic cell lineages. We report that the peritoneal B-1 B cell subset is selectively resistant to RiA. Inherent radioresistance is not shared by splenic B-2 or B-1 cells. However, it is conferred upon B-2 cells by BCR crosslinking in the presence of IL-6 or IL-10. In vivo experiments with gene-targeted mice confirm that IL-6 and, to a lesser extent, IL-10 are the relevant stimuli that combine with BCR ligands to promote B-1 cell radioresistance. STAT3 promotes cell survival in response to selected growth factors, and is activated by combined BCR crosslinking and IL-6 (IL-10). Importantly, STAT3(-/-) B-1 cells become susceptible to irradiation, indicating that STAT3 activation by the BCR in the presence of IL costimuli account for the inherent radioresistance of peritoneal B-1 B cells.

Animals↗
PubMed2006

Cutting edge: apoptosis-regulating signal kinase 1 is required for reactive oxygen species-mediated activation of IFN regulatory factor 3 by lipopolysaccharide.

IFN regulatory factor (IRF) 3 participates in the transcriptional induction of IFN-alpha, IFN-beta, and a subset of IFN-stimulated genes (ISGs) as a result of viral infection. In addition, bacterial cell wall components such as LPS activate IRF3 in a p38-dependent manner. In this study we show that IRF3-mediated ISG induction by LPS requires the production of reactive oxygen species (ROS) by the NADPH-dependent oxidase NOX4. Furthermore, we present evidence that LPS-mediated ROS production leads to activation of apoptosis-regulating-signal kinase (ASK) 1, a MAPK kinase kinase family member capable of activating the MAP kinase 6/p38 axis. ASK1 kinase activity proved essential for IRF3-mediated ISG induction by LPS. Thus, our results presented here suggest a novel role for ROS and ASK1 in the innate immune response as signaling intermediates in the IRF3 activation pathway.

Animals↗
PubMed2006

CD4/CD8 double-negative epidermotropic cutaneous T-cell lymphoma: an immunohistochemical variant of mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) is an epidermotropic cutaneous T-cell lymphoma in which the tumor cells express a mature T-helper memory phenotype, ie, CD3(+), CD4(+), CD8(-), CD45RO(+), with a T-cell receptor (TCR) of the alpha/beta heterodimer. A minority of patients have an unusual immunohistochemical profile consisting of a CD4(-), CD8(+) mature T-cell phenotype. An aberrant CD4/CD8 double-negative (DN) immunophenotype in patients with early MF has rarely been reported. OBJECTIVES: We sought to evaluate the frequency of CD4/CD8 DN immunophenotype in patients with early MF, and to study their clinical, histopathologic, and immunohistochemical features, and the course of their disease. METHODS: Our departmental archives were searched for patients with early-stage MF and CD4/CD8 DN immunophenotpye. RESULTS: Of the 140 patients with early MF immunophenotyped in our laboratory, 18 (12%) showed CD4 and CD8 expression in less than 10% of their intraepidermal T cells on fresh-frozen and paraffin-embedded samples. The group included 13 male and 5 female patients; 14 adults and 4 children; and 15 Jews and 3 Arabs. In all, 8 had classic MF and 10 had unusual clinical variants (5 hypopigmented, 3 localized, 1 ichthyosiform, 1 purpuric). All received skin-targeted therapies and all had an indolent course (mean follow-up 3.5 years). Histopathology revealed early MF. Results of immunohistochemical analysis of the intraepidermal lymphocytes were as follows: CD3(+), CD4(-), CD8(-) in all patients; CD7(-) in all of 17; CD45RO(+) in 15 of 16; T-cell-restricted intracellular antigen-1(+) in 11 of 15; CD30(+) in 2 of 16; and CD56(+) in 2 of 16. A betaF1(+)/delta(-) phenotype, indicating a TCR of the alpha/beta heterodimer, was found in 8 of 16; betaF1(-)/delta(+) phenotype, indicating a TCR of the gamma/delta heterodimer, in 1 of 16; betaF1(-)/ delta(-) in 5 of 16; and no determinable phenotype in 2 of 16. The TCR gamma gene was clonally rearranged in 10 of 16 patients. LIMITATION: This was a single-center case series. CONCLUSIONS: There is a subgroup of patients with early MF that exhibit a CD4/CD8 DN immunophenotype. In our region, this aberrant immunophenotype is not as rare as reflected in the literature, is overrepresented in the unusual clinical variants of MF, and does not seem to have prognostic significance. Like CD4(+) MF, the tumor cells represent memory T cells and in many cases express alpha/beta TCR, but unlike CD4(+) MF, they have a mostly cytotoxic phenotype. We suggest that CD4/CD8 DN MF should be recognized as another immunohistochemical variant of this lymphoma.

Adolescent↗
PubMed2006

Apoptotic mechanism in pemphigus autoimmunoglobulins-induced acantholysis--possible involvement of the EGF receptor.

Pemphigus is an autoimmune cutaneous disease characterized by circulating autoantibodies that cause blistering and erosions on skin and mucous membranes. Circulating autoantibodies bind to epidermal cell membrane and cause cell-cell detachment (acantholysis), leading to epidermal tissue damage and cell death. The principal target of pemphigus vulgaris autoantibodies (PV-IgG) is desmosomal cadherin desmoglein 3 (Dsg3), a constituent of desmosomes, mediating cell-cell adhesion. Several hypotheses for the mechanisms of acantholysis induction by PV-IgG exist, but the actual mechanism is not clear as yet. We have previously reported on apoptosis induction in PV-IgG-mediated epidermal tissue and cell damage as a possible mechanism of acantholysis and cell death (Wang et al. 2004, Apoptosis, 9:131-143). In this study we investigated the involvement of the EGFR and intracellular signal transduction pathways in the PV-IgG-induced apoptosis. We show here that PV-IgG induced activation/autophosphorylation of EGFR in cultured keratinocytes in vitro. The specific tyrosine kinase inhibitor AG1478 abrogated EGFR autophosphorylation, cell death, FasL appearance and acantholysis, all induced by PV-IgG, in parallel, confirming the involvement of EGFR in this Fas apoptotic cascade. Activation of EGFR was followed by phosphorylation of its downstream substrates, MAP kinase ERK and transcription factor c-Jun, and internalization of EGFR. Pharmacological inactivation of the EGFR and ERK kinase activities, by use of specific inhibitors AG1478 and PD98059 respectively, blocked PV-IgG-induced phosphorylation of EGFR, ERK and c-Jun and cellular apoptosis, measured by flow cytometry and caspase 3 activity. Prolonged activation of EGFR by PV-IgG led to dramatic internalization of this receptor, possibly reducing the ability of the cell to perform survival signals. This suggests that activation of EGFR, followed by its internalization, is pivotal for intracellular apoptotic signal transduction via ERK/c-Jun pathways, leading to acantholysis. Our experimental data indicate that the EGFR is instrumental in transducing apoptotic/acantholytic signals in keratinocytes cultures in response to PV-IgG treatment. The acantholytic effect caused by PV-IgG binding to cell surface receptors begins with and depends on cell surface receptor (EGFR) activation of intracellular signaling pathways (ERK pathway) and apoptosis induction (FasR pathway), which later lead to major cell-cell separation (acantholysis) and cell death.

Acantholysis↗
PubMed2006

Treatment of lymphangioma circumscriptum with combined radiofrequency current and 900 nm diode laser.

BACKGROUND: Laser treatment of lymphangioma circumscriptum is a major challenge because of the persistent nature of the disease and the large variations in lesion size, depth, and anatomic location. OBJECTIVE: To determine the safety and effectiveness of electro-optical synergy, a new technology that combines a 900 nm diode laser with radiofrequency current, for the treatment of lymphangioma circumscriptum. METHODS: Six patients with Fitzpatrick skin types II to IV were treated for lymphangioma circumscriptum with 1 to 3 sessions of simultaneous radiofrequency energy (60-80 J/cm3) and optical diode laser energy (fluence 90-100 J/cm2). Lesion clearance was evaluated by three specialists on the basis of digital photographs taken before the first treatment and 1 and 2 months after the last treatment. RESULTS: Results were rated as "excellent" in four patients and "good" in two patients. Transient swelling, erythema, and pain were present in all patients, and ulcers and scarring in two patients. CONCLUSION: The combination of laser light and radiofrequency energy is effective and relatively safe for the treatment of lymphangioma circumscriptum. It provides additional heating of the blood vesicles without increasing the laser intensity and allows the clinician to treat the clear lymphatic component, which lacks a specific optical chromophore. Side effects are tolerable.

Adolescent↗
PubMed2006

Treatment of angiokeratoma of Fordyce with pulsed dye laser.

BACKGROUND: Angiokeratomas of Fordyce are typically asymptomatic vascular lesions characterized by blue-to-red papules with a scale surface, most often located on the scrotum. Although considered benign, the lesions may bleed, either spontaneously or secondary to rupture, leading to patient anxiety and social embarrassment. OBJECTIVE: The objective was to determine the safety and effectiveness of 585-nm pulsed dye laser for the treatment of angiokeratomas of Fordyce. METHODS: Twelve patients with Fitzpatrick skin type II to IV were treated for angiokeratomas of Fordyce with pulsed dye laser (5.5-8.0 J/cm(2)) in two to six sessions. Lesion clearance was evaluated by two specialists on the basis of digital photographs taken before the first treatment and 2 months after the last treatment. RESULTS: Seven patients had an excellent response (clearance rating 75%-100%) and five patients had a good response (clearance rating 50%-75%). Transient purpura and pain were present in all patients. Bleeding during treatment occurred in five patients. There were no permanent side effects. CONCLUSION: Pulsed dye laser is effective and safe for the treatment of angiokeratoma of Fordyce, with minimum side effects, providing an additional nonablative therapeutic option.

Adult↗
PubMed2006

[Subacute cutaneous lupus erythematosus induced by terbinafine].

BACKGROUND: The onset of subacute cutaneous lupus erythematosus (SCLE) may be associated with the administration of a variety of drugs. Terbinafine, an oral antifungal agent, which rarely causes cutaneous eruptions, has been implicated as the cause or exacerbation of cutaneous lupus erythematosus in several patients. CASE: A 59-year-old man had received oral terbinafine for onychomycosis. The patient had a history of SCLE, which was in complete remission during the last 5 years. A month after initiating treatment with terbinafine the patient developed SCLE, which was diagnosed clinically and by histology. He had typical papulosquamous lesions. Immunological studies showed elevated titers of anti-nuclear antibodies. Following discontinuation of terbinafine therapy and under the treatment of systemic and topical steroids, a slow resolution of the eruption was noted over several weeks. CONCLUSIONS: This report, along with previous cases described, suggests the association between terbinafine therapy and the onset or exacerbation of SCLE often occurring in a patient with history of systemic lupus erythematosus or SCLE.

Antibodies, Antinuclear↗
PubMed2006

[Long-term effects of PUVA therapy on Israeli patients with vitiligo].

BACKGROUND: Long-term treatment of psoriasis patients with PUVA (psoralen and ultraviolet A) is associated with an increased risk of photoaging and non-melanomic skin cancer, and perhaps of melanoma as well. Very little information is available on the long-term effects of PUVA treatment on vitiligo patients in general, and specifically on the risk of developing skin tumors. Among vitiligo patients treated with PUVA or heliotherapy, only a few cases of squamous cell carcinoma (SCC) have been described. OBJECTIVE: The objective of this research is to examine the long-term effects of PUVA treatment among vitiligo patients and the incidence of long-term side effects, including various types of skin cancers. PATIENTS AND METHODS: The medical files of all patients treated with PUVA at the Rabin Medical Center and the Emek Medical Center between 1982 and 1996 were surveyed. Each patient was interviewed by telephone and then invited to come in for a medical examination. RESULTS: A total of 28 out of 31 patients completed the questionnaire, and 12 of them were also examined. The average age of the patients was 47 years (range 25-84). The average amount of radiation to which each patient was exposed was 546.8 J/cm2 (range 26.5-1561), with a median of 336.8 J/cm2. The average number of treatments per patient was 84.2 (median 77). The average time that elapsed since beginning the treatment was 11 years (range 7-20), and the average time since treatment ended was 9.4 years (range 2-23). Partial or total repigmentation was experienced by 60% of the patients. In 18% of the patients, total or almost total repigmentation was seen, which lasted an average of 46 months. No skin cancer of any kind was seen in any of the patients. CONCLUSION: A recurrence of the illness was seen in all the vitiligo patients who had responded to PUVA treatment. Long-term treatment with PUVA for vitiligo patients does not entail photoaging damages or increased risk of skin cancer.

Adult↗
PubMed2006

[Pemphigus vulgaris--an alternative for steroid treatment?].

Pemphigus vulgaris is an autoimmune disease with a well-established immunological basis. Treatment is based on high dose and maintenance systemic corticosteroids. We report on a patient with a recurrence of full-blown pemphigus vulgaris after a trial of alternative hypnosis therapy to replace the corticosteroids.

Adrenal Cortex Hormones↗
PubMed2005

Molecular determinants of crosstalk between nuclear receptors and toll-like receptors.

Nuclear receptors (NRs) repress transcriptional responses to diverse signaling pathways as an essential aspect of their biological activities, but mechanisms determining the specificity and functional consequences of transrepression remain poorly understood. Here, we report signal- and gene-specific repression of transcriptional responses initiated by engagement of toll-like receptors (TLR) 3, 4, and 9 in macrophages. The glucocorticoid receptor (GR) represses a large set of functionally related inflammatory response genes by disrupting p65/interferon regulatory factor (IRF) complexes required for TLR4- or TLR9-dependent, but not TLR3-dependent, transcriptional activation. This mechanism requires signaling through MyD88 and enables the GR to differentially regulate pathogen-specific programs of gene expression. PPARgamma and LXRs repress overlapping transcriptional targets by p65/IRF3-independent mechanisms and cooperate with the GR to synergistically transrepress distinct subsets of TLR-responsive genes. These findings reveal combinatorial control of homeostasis and immune responses by nuclear receptors and suggest new approaches for treatment of inflammatory diseases.

Animals↗
PubMed2005

Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-alpha beta responses in T lymphocytes.

Engagement of the IFN-alphabeta receptor initiates multiple signaling cascades, including activation of the STAT. In this study, we demonstrate that IFN-alphabeta, although antiproliferative in wild-type CD4(+) or CD8(+) T cells, act as strong mitogens on their STAT1(-/-) counterparts. Furthermore, IFN-alphabeta exert little effect on apoptosis in wild-type cells, but are potent survival factors in the absence of STAT1. The antiapoptotic response in the absence of STAT1 is predominantly mediated by STAT3, and to a lesser extent by STAT5A/B. In contrast, the mitogenic IFN-alphabeta response gained through the absence of STAT1 is only marginally affected when STAT5A/B expression is also abrogated, but is completely dependent on STAT3 activation. These findings provide the first evidence for a function of STAT3 and STAT5A/B in the IFN-alphabeta response, and support a model in which the IFN-alphabeta receptor initiates both pro- and antiapoptotic responses through STAT1, and STAT3 and STAT5A/B, respectively.

Animals↗
PubMed2005

Infection with Kaposi's sarcoma-associated herpesvirus among families of patients with classic Kaposi's sarcoma.

BACKGROUND: Classic Kaposi's sarcoma (CKS) primarily affects elderly Mediterranean or Eastern European men. Incidence rates of CKS in Israel are among the world's highest. In practically all cases, antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) can be detected. A relatively high seroprevalence rate of KSHV in Israel generally correlates with the incidence of CKS. A sexual mode of virus transmission is recognized among homosexual men, whereas the precise transmission routes in the heterosexual population and those with CKS are still unclear. OBJECTIVE: To better assess the transmission routes of KSHV in Israeli patients with CKS and their first-degree relatives as compared with a control group. DESIGN: Serum was collected from all study participants and tested for KSHV antibodies by means of latent and lytic immunofluorescence assays. An open reading frame 65 (ORF65) Western blot assay was applied as a confirmatory tool. SETTING: Three dermatological departments in Israel. PATIENTS: Sixty-four Jewish patients with CKS, 143 of their first-degree relatives, and 186 hospital-based control subjects. RESULTS: Seropositivity to KSHV was detected in 62 (96.9%) of the patients with CKS, in 56 (39.2%) of their first-degree relatives, and in only 21 (11.3%) of the hospital controls (P<.001). The specific relationship with the index patient (spouse, offspring, or sibling) had no significant effect on the prevalence of serpositivity in the family members. CONCLUSION: Our serologic evidence of familial clustering of KSHV infection suggests a predominantly nonsexual horizontal transmission route of the virus.

Adolescent↗
PubMed2005

Familial mycosis fungoides: report of 6 kindreds and a study of the HLA system.

BACKGROUND: The familial occurrence of mycosis fungoides (MF) has been reported only in 8 families. Recently, the HLA class II alleles DRB1* 11 and DQB1* 03 have been found to be significantly increased for patients with sporadic MF, suggesting a possible immunogenetic basis for the pathogenesis of this malignancy. OBJECTIVE: We sought to detect familial occurrences of MF, to describe familial features, and to investigate the possible association or linkage with the HLA system in such cases. METHODS: The files of 300 patients with MF were reviewed to search for familial occurrence in at least two first-degree relatives. A group of 252 healthy unrelated individuals served as control subjects. Tissue typing for HLA class I was performed using the microlymphocytotoxicity technique. DNA-based analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction amplification. RESULTS: Six families comprising 12 Jewish patients (9 male and 3 female) were detected: in 5, two first-degree relatives had MF; and in one, one member had MF and another had parapsoriasis en plaque. There were 5 families with two affected siblings and one family with a parent-child pair. In all but one family, the age of onset, clinical features, and response to therapy were similar to those in sporadic MF. One family, however, was exceptional: both affected siblings were children and both exhibited a similar but unusual morphology in the form of a hypopigmented variant of MF in conjunction with a psoriasiform variant. The allele frequency of HLA DQB1* 03 was found to be significantly greater among the patients than in the control group (66.7% vs 33%, respectively; P = .027), supporting an association of this allele with familial MF. Analysis of the HLA typing in the affected sibling pairs, when grouped together, did not support linkage to the HLA locus because no segregation distortion could be demonstrated ( P = .76). CONCLUSIONS: Familial aggregation of MF among Israeli Jews may not be as rare as is reflected in the literature. This familial clustering, together with the detection of certain HLA class II alleles with this malignancy (sporadic and familial), suggests that genetic factors may play a role in MF.

Adolescent↗
PubMed2005

Actinic damage among patients with psoriasis treated by climatotherapy at the Dead Sea.

BACKGROUND: Dead Sea climatotherapy is highly effective in the treatment of psoriasis. However, its potential side effects, especially the risk of skin cancer, are unclear. OBJECTIVE: We sought to determine the prevalence of solar damage and skin cancer among patients with psoriasis who underwent Dead Sea climatotherapy compared with control patients. METHODS: This multicenter controlled cross-sectional study was carried out at the Dead Sea Solarium Clinic and outpatient clinics of the participating centers. A total of 1198 participants (460 patients with psoriasis and 738 control patients) aged 20 to 70 years were included. A standard questionnaire including demographic parameters and sun exposure habits was administered to all participants. Patients were questioned about previous psoriatic treatments and climatotherapy at the Dead Sea. All participants underwent a structured physical examination of the skin. We compared the prevalence of solar damage for patients with psoriasis and control patients and assessed the extent of photodamage among patients with psoriasis according to exposure time at the Dead Sea in univariate and multivariate analyses. RESULTS: Elastosis ( P < .001), solar lentigines (P = .03), poikiloderma (P < .001), and facial wrinkles (P < .001) were significantly more common among patients with psoriasis compared with control patients and showed a dose response with increased Dead Sea exposure time. Self-reported previous skin cancers were more common in control patients compared with patients with psoriasis (8.2% vs 3.5%, P = .002), however, the prevalence of nonmelanoma skin cancer on examination did not differ between the two groups. No cases of malignant melanoma were detected in either group. CONCLUSIONS: Dead Sea climatotherapy is not associated with an increased risk of malignant melanoma or nonmelanoma skin cancer for patients with psoriasis in Israel. However, UV exposure at the Dead Sea may play a role in the development of solar damage.

Adult↗