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Biomedical subjects

Mark R Pittelkow

Publications and source records attributed to Mark R Pittelkow.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effectiveness of intravenous immunoglobulin therapy for skin disease other than toxic epidermal necrolysis: a retrospective review of Mayo Clinic experience.

OBJECTIVE: To examine retrospectively the use and effectiveness of intravenous immunoglobulin (IVIg) treatment of various skin diseases, primarily immunobullous disease. PATIENTS AND METHODS: We identified patients who had received IVIg therapy for skin disease between 1996 and 2003 at the Mayo Clinic in Rochester, Minn, Scottsdale, Ariz, and Jacksonville, Fla, and retrospectively reviewed their medical records. RESULTS: Eighteen patients were treated with IVIg for various skin diseases: immunobullous disease in 11 adults (pemphigus vulgaris [7 patients], bullous pemphigold [3], and cicatricial pemphigoid [1]); dermatomyositis (2); mixed connective tissue disease (1); chronic urticaria (1); scleromyxedema (1); leukocytoclastic vasculitis (1); and linear IgA bullous disease (1). Responses of patients by type of disease were as follows: pemphigus vulgaris, 1 partial response (PR) and 6 no response (NR); bullous pemphigoid, 1 complete response (CR) and 2 NR; cicatricial pemphigoid, 1 NR; dermatomyositis, 1 CR and 1 PR; mixed connective tissue disease, 1 CR; chronic urticaria, 1 CR; scleromyxedema, 1 CR; leukocytoclastic vasculitis, 1 PR; and linear IgA bullous disease, 1 CR. Six patients (33%) experienced CR, 3 (17%) had PR, and 9 (50%) had NR to IVIg therapy. All 9 nonresponders were adult patients with immunobullous disease. CONCLUSION: Although this was a retrospective study of a small cohort of a mixture of patients, the findings emphasize that our experience with IVIg treatment for skin disease, particularly immunobullous disease, is less favorable than that reported previously. Further studies are needed to verify the efficacy of IVIg for skin disease.

Adolescent↗
PubMed2005

Amphiregulin causes functional downregulation of adherens junctions in psoriasis.

Overexpression of amphiregulin (AR) has been linked to psoriasis in mouse and man. Since psoriasis is marked by hyperproliferation of keratinocytes and loss of epidermal barrier function with infiltration of inflammatory cells into the epidermis and dermis, we hypothesized that AR might contribute to the pathogenesis of psoriasis by affecting the integrity of cell-cell junctions. We find that there is a marked reduction of functional E-cadherin in psoriatic lesions from both INV-AR mice and individuals with psoriasis. Total E-cadherin levels are dramatically reduced in psoriatic lesions from INV-AR mice. Compared with normal skin, psoriatic lesions from individuals with psoriasis exhibit downregulation of the cytoskeletal-associated triton-insoluble pool of E-cadherin and the appearance of an 80 kDa ectodomain fragment in the cytoplasmic triton-soluble pool. There is reduced immunohistochemical staining for E-cadherin in the basal epidermis of human psoriatic lesions. Moreover, there is enhanced transmigration of human neutrophils through polarized epithelial cell monolayers of MDCK cells after administration of AR, but not transforming growth factor-alpha, further supporting a specific role for AR in the pathogenesis of psoriasis.

Adherens Junctions↗
PubMed2005

High recurrence rates of squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic leukemia.

BACKGROUND: Cutaneous cancers exhibit a much higher incidence in patients with chronic lymphocytic leukemia than in nonleukemic patients. Squamous and basal cell carcinomas also exhibit greater subclinical tumor extension in patients with chronic lymphocytic leukemia. OBJECTIVE: The purpose of this study was to estimate and compare the recurrence rates of squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic leukemia compared with those in controls and to evaluate differences among squamous cell carcinoma size and histologic grade. METHODS: We retrospectively assessed the clinical histories, postoperative notes, and surgical photographs of patients with chronic lymphocytic leukemia and controls matched (2:1) for age, sex, and surgical year. Both patients and controls underwent Mohs' surgery for squamous cell carcinoma of the head and neck at the Mayo Clinic between March 1988 and April 1999. RESULTS: Twenty-eight patients who underwent Mohs' surgery for 57 squamous cell carcinomas had 7 recurrences. The cumulative incidence of recurrence on a per-tumor basis was 4.3% at 1 year, 14.8% at 3 years, and 19.0% at 5 years. Squamous cell carcinoma was seven times more likely to recur in patients with chronic lymphocytic leukemia than in controls (p = .003). The distribution of tumor histologic grade was not significantly different between patients and controls (p = .39). Maximum preoperative tumor diameters were clinically similar between patients and controls (median 15 mm vs 14 mm; p = .04). CONCLUSION: The recurrence rates of squamous cell carcinoma were significantly higher in patients with chronic lymphocytic leukemia. Squamous cell carcinomas in patients with chronic lymphocytic leukemia did not exhibit a significant difference in histologic grade or clinical difference in preoperative tumor size. Close surveillance for squamous cell carcinoma recurrence is warranted in patients with chronic lymphocytic leukemia.

Aged↗
PubMed2004

Mitosis increases levels of secretory leukocyte protease inhibitor in keratinocytes.

Chronic wounds are a major health care burden. Multiple factors produced by healing wounds play important roles in efficient and orderly wound healing. Secretory leukocyte protease inhibitor (SLPI) is constitutively expressed in epithelial cells, and its expression is increased by inflammation. SLPI has antimicrobial activities and improves wound healing. We hypothesized that SLPI expression correlates with keratinocyte growth rate and is increased by epidermal growth factor (EGF). Keratinocytes were isolated from neonatal foreskin. Subconfluent and confluent culture conditions were used. SLPI-specific primers were designed for use in quantitative-competitive reverse-transcription polymerase chain reaction assays to detect and quantify SLPI mRNA expression levels. SLPI levels were increased 2-fold in subconfluent cultures and 1.6-fold in confluent cultures to which EGF had been added. Confluent cultures also demonstrated 7-fold (growth factor depleted) and 6-fold (EGF) increase in SLPI RNA copy number, compared to subconfluent cultures. The results indicate that EGF increases SLPI expression.

Cell Count↗
PubMed2004

Pemphigus vulgaris acantholysis ameliorated by cholinergic agonists.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune, IgG autoantibody-mediated disease of skin and mucosa leading to progressive blistering and nonhealing erosions. Patients develop autoantibodies to adhesion molecules mediating intercellular adhesion and to keratinocyte cholinergic receptors regulating cell adhesion. OBSERVATIONS: To determine whether a cholinergic agonist can abolish PV IgG-induced acantholysis, litter mates of neonatal athymic nude mice were injected with PV IgG together with carbachol (0.04 micro g/g body weight). None of these mice developed skin lesions. Through in vitro experiments, we measured the expression of adhesion molecules in monolayers of normal human keratinocytes incubated overnight in the presence of 0.25mM carbachol using semiquantitative Western blot and immunofluorescence. Carbachol caused an elevation of the relative amount of E-cadherin in keratinocytes (P<.05) without changing that of plakoglobin (P>.05). The phosphorylation level of E-cadherin and plakoglobin was increased by PV IgG, whereas this effect of PV IgG was attenuated in the presence of 0.5mM carbachol. Pyridostigmine bromide, an acetylcholinesterase inhibitor, produced effects similar to those of carbachol, which helps explain its clinical efficacy in a patient with active PV that was resistant to treatment with systemic glucocorticosteroids. Treatment with pyridostigmine bromide (360 mg/d) in a patient with PV allowed to keep his disease under control at a lower dose of prednisone than that used before starting pyridostigmine bromide treatment. Conclusion Elucidation of the cholinergic control of keratinocyte adhesion merits further consideration because of a potential for the development of novel antiacantholytic therapies using cholinergic drugs.

Acantholysis↗
PubMed2004

High recurrence rates of Basal cell carcinoma after mohs surgery in patients with chronic lymphocytic leukemia.

OBJECTIVES: To estimate and compare the recurrence rates of basal cell carcinoma (BCC) after Mohs surgery in patients with chronic lymphocytic leukemia (CLL) and controls and to evaluate differences among histologic subtypes of BCC. DESIGN: Retrospective assessment of clinical histories, postoperative notes, and surgical photographs. SETTING: Tertiary-care institution (Mayo Clinic, Rochester, Minn). PATIENTS: Twenty-four patients with CLL who underwent Mohs surgery for 33 BCCs and 66 controls matched for sex, age, and surgical year who underwent Mohs surgery for BCC of the head and neck from May 1988 through September 1998. RESULTS: Among the 24 patients with CLL who underwent Mohs surgery for 33 BCCs, there were 4 recurrences. The cumulative incidence of recurrence on a per-tumor basis was 3% at 1 year, 12% at 3 years, and 22% at 5 years. Basal cell carcinoma was 14 times more likely to recur in patients with CLL than in controls (P =.02). Overall, there were no significant differences between patients with CLL and controls in preoperative tumor size (median, 1.6 cm vs 1.4 cm; P =.18) and proportion of aggressive histologic subtypes of BCC (58% vs 41%; P =.12). CONCLUSIONS: Recurrence rates of BCC are significantly higher after Mohs surgery in patients with CLL. Overall, patients with CLL do not appear to have significantly larger BCCs or more aggressive histologic subtypes of BCC. In patients with CLL, close surveillance is warranted for recurrence of BCC and a decreased threshold is indicated for subsequent biopsies.

Aged↗
PubMed2004

Association of porphyria cutanea tarda with hereditary hemochromatosis.

BACKGROUND: An increased frequency of hereditary hemochromatosis gene mutations occurs in patients with porphyria cutanea tarda. Polymerase chain reaction analysis of peripheral blood for hemochromatosis gene (HFE) mutations is available for clinical use. Early detection and treatment of hereditary hemochromatosis limit disease progression and improve life expectancy. OBJECTIVE: We present 8 patients with porphyria cutanea tarda subsequently found to have hereditary hemochromatosis or mutations in the HFE gene. METHODS: Retrospective review of patients in whom both porphyria cutanea tarda and hereditary hemochromatosis or HFE gene mutations were diagnosed between 1976 and 2000. RESULTS: Eight patients with porphyria cutanea tarda (6 males, 2 females; age range, 4-60 years; mean age at diagnosis of porphyria cutanea tarda, 42 years) were subsequently found to have hepatic iron overload or HFE gene mutations. Two patients had liver biopsy findings compatible with homozygous hereditary hemochromatosis. In the other 6 patients, HFE gene analysis revealed 3 homozygous C282Y, 1 compound heterozygous C282Y/H63D, and 2 heterozygous C282Y mutations. Seven patients (88%) had no specific signs or symptoms of hereditary hemochromatosis at diagnosis. In 5 patients (63%), the diagnosis of hereditary hemochromatosis or HFE gene mutation was initially suspected by the dermatologist. CONCLUSION: Porphyria cutanea tarda can be an important cutaneous marker for patients with mutations of the HFE gene. HFE gene analysis should be done in patients who present with porphyria cutanea tarda. The dermatologist may play a key role in the early diagnosis of subclinical hereditary hemochromatosis in patients who present with porphyria cutanea tarda.

Adolescent↗
PubMed2004

Malignant basomelanocytic tumor manifesting as metastatic melanoma.

We report a case of an unusual basomelanocytic tumor from the scalp of a 56-year-old man. A 56-year-old white man presented with a scalp lesion that was biopsied and interpreted as a basal cell carcinoma. Fourteen months later, metastatic melanoma was discovered in a cervical lymph node and the liver. A subsequent biopsy from the area of the previously biopsied basal cell carcinoma of the scalp showed an invasive malignant melanoma. Immunohistochemical stains performed on the original scalp specimen showed biphasic immunohistochemical profile. A population of neoplastic cells was strongly positive for the melanocytic markers Melan-A, HMB-45, and tyrosinase and showed weak focal immunoreactivity for S-100. A second population of cells was strongly immunoreactive for keratin (wide-spectrum polyclonal antibody) and BerEp4. To our knowledge, this is the first description of a malignant basomelanocytic tumor complicated by metastatic melanoma.

Basal Cell Carcinoma↗
PubMed2004

Antipsoriatic drug anthralin induces EGF receptor phosphorylation in keratinocytes: requirement for H(2)O(2) generation.

Even though anthralin is a well-established topical therapeutic agent for psoriasis, little is known about its effects and biochemical mechanisms of signal transduction. In contrast to a previous report, we found that anthralin induced time- and concentration-dependent phosphorylation of epidermal growth factor receptor in primary human keratinocytes. Four lines of evidence show that this process is mediated by reactive oxygen species. First, we found that anthralin induces time-dependent generation of H(2)O(2). Second, there is a correlation between a time-dependent increase in anthralin-induced epidermal growth factor receptor phosphorylation and H(2)O(2) generation. Third, the structurally different antioxidants n-propyl gallate and N-acetylcysteine inhibited epidermal growth factor receptor phosphorylation induced by anthralin. Fourth, overexpression of catalase inhibited this process. The epidermal growth factor receptor-specific tyrosine kinase inhibitor PD153035 abrogated anthralin-induced epidermal growth factor receptor phosphorylation and activation of extracellular-regulated kinase 1/2. These findings establish the following sequence of events: (1) H(2)O(2) generation, (2) epidermal growth factor receptor phosphorylation, and (3) extracellular-regulated kinase activation. Our data identify anthralin-induced reactive oxygen species and, more specifically, H(2)O(2) as an important upstream mediator required for ligand-independent epidermal growth factor receptor phosphorylation and downstream signaling.

Acetylcysteine↗
PubMed2004

Suprabasal expression of human amphiregulin in the epidermis of transgenic mice induces a severe, early-onset, psoriasis-like skin pathology: expression of amphiregulin in the basal epidermis is also associated with synovitis.

The expression of amphiregulin (AR) in the basal epidermis of transgenic mice [keratin 14 promoter AR gene (K14-ARGE)] has been previously shown to induce an early-onset and severe skin pathology, with many similarities to psoriasis. In this study, it is demonstrated that involucrin enhancer/promoter-dependent expression of human AR (INV-AR) in the suprabasal epidermis of transgenic mice also produces a cutaneous psoriasis-like phenotype. INV-AR mice possess a limited lifespan and scaling, papillomatous, erythematous skin with partial alopecia. INV-AR mouse histopathology also revealed epidermal hyperkeratosis, parakeratosis, acanthosis, and an exaggerated dermal vasculature. A dermal and epidermal infiltrate was also evident and consisted of both neutrophils and CD3(+) T lymphocytes. The histology of synovial joints in both the INV-AR mice and the K14-ARGE mice of our previous investigation was examined. The histologic examination revealed that 3-week-old INV-AR transgenic mice displayed normal knee joint histology, while 2- to 3-week-old K14-ARGE transgenic mice frequently displayed synovitis, as exemplified by the presence of a mixed leukocytic infiltration, increased vascularization, and enhanced deposition of fibrous matrix in the knee synovium. These results demonstrate that AR overexpression in both the basal and suprabasal epidermis of transgenic mice induces a phenotype that mimics cutaneous psoriasis, while basal AR expression is also associated with synovial inflammation, a precursor to the psoriasis-associated arthropathy, psoriatic arthritis. Collectively, the results implicate epidermal AR expression as a possible mediator of innate cutaneous immunity and epidermal proliferation and also as a potential trigger of both cutaneous psoriasis and psoriatic arthritis.

Age of Onset↗
PubMed2004

A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice.

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with gluten sensitivity. It presents as a papulovesicular rash and is often associated with enteropathy. The rash resolves when the patient is placed on a gluten-free diet and/or dapsone. DH, as well as celiac disease, is tightly associated with DQ2 and DQ8. A novel mouse model for DH is described that utilizes the NOD background and the HLA-DQ8 transgene. The addition of DQ8 contributes sensitivity to gliadin, and the addition of the NOD background contributes to autoimmunity and pathogenesis. Fifteen NOD DQ8+ mice of 90 that were sensitized to gluten developed blistering pathology similar to that seen in DH. Neutrophil infiltration of the dermis, deposition of IgA at the dermal-epidermal junction, and a complete reversal of the blistering phenomenon with the administration of a gluten-free diet with or without dapsone were observed. None of the 3 blistering mice examined had small-bowel pathology. This animal model of DH will be useful to determine the specificity of the IgA deposits, as well as the pathogenic mechanisms that occur in the skin as a result of gluten ingestion.

Animals↗
PubMed2003

A novel vitamin D-regulated immediate-early gene, IEX-1, alters cellular growth and apoptosis.

1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3) inhibits the expression of an immediate-early gene, IEX-1, which is involved in the regulation of cellular growth and apoptosis in a variety of cells. 1alpha,25(OH)2D3 alters the subcellular localization of IEX-1 by causing an efflux of IEX-1 from the nucleus, and the sterol decreases the expression of IEX-1 messenger RNA in cells via a novel DR3 repeat-type DNA response element.

Apoptosis↗
PubMed2003

Localization and regulation of pregnancy-associated plasma protein a expression in healing human skin.

Pregnancy-associated plasma protein A (PAPP-A) is an IGF-binding protein-4 (IGFBP-4) metalloproteinase that cleaves inhibitory IGFBP-4 to amplify local IGF-I bioavailability in vitro. Thus it has functional implications in injury/repair responses. In this study we determined PAPP-A expression in healing human skin. Wounds were induced with a scalpel on the forearms of three normal subjects and were allowed to heal by first intention. Biopsies obtained on d 0, 2, 8, and 14 were processed for immunohistochemical detection of PAPP-A, IGF-I, and IGFBP-4. In uninjured skin (d 0), strong staining for PAPP-A was present in the epidermis, sweat and sebaceous gland epithelial cells, hair follicles, and blood vessels; no PAPP-A was detected in dermal fibroblasts or with mature collagen bundles. IGF-I localized strongly to epithelial cells of skin glands was weak to moderate in epidermis and blood vessels, and was absent in dermal cells. Weak focal staining for IGFBP-4 was found within uninjured epidermis. During wound healing, PAPP-A expression was induced in dermal granulation tissue within and adjacent to the injury. PAPP-A was present in dermis on d 2 and was increased in intensity and extent on d 8 and 14. PAPP-A expression also increased in the epidermis. PAPP-A expression in cells of granulation tissue colocalized with alpha-smooth actin staining of myofibroblasts and new blood vessels as well as with CD68 staining of macrophages and was associated with the compact, newly synthesized collagen of the healing wound. IGF-I staining was enhanced in the epidermis localized to the area of the incision and in granulation tissue associated with lymphoid cells. IGFBP-4 staining of the epidermis remained unchanged during wound healing, but was induced in the fibroblastic cells of granulation tissue over time. These data demonstrate localized and regulated expression of PAPP-A in human skin and suggest that PAPP-A may play an important role in an integrated IGF system in wound healing and tissue remodeling in vivo.

Actins↗