Eleanor A. Knopp

Serum Amyloid A and Lipoprotein Retention in Murine Models of Atherosclerosis

Objective—Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix. Methods and Results—Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)−/− and apoE−/− mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE−/−, r=0.76; LDLR−/−, r=0.86), apoA-I areas (apoE−/−, r=0.88; LDLR−/−, r=0.80), apoB areas (apoE−/−, r=0.74; LDLR−/−, r=0.89), and perlecan areas (apoE−/−, r=0.83; LDLR−/−, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE−/− and LDLR−/− mice demonstrated that SAA was present on both apoA-I–containing and apoB-containing lipoproteins. Conclusions—In chow-fed apoE−/− and LDLR−/− mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.

Nephrogenic systemic fibrosis: early recognition and treatment.

Nephrogenic systemic fibrosis (NSF) is a progressive, debilitating, and emotionally distressing disease that can affect patients with renal dysfunction. Prevention, early recognition and early treatment are essential to limiting its impact. The most significant risk factors for developing NSF are chronic or significant acute kidney disease (usually necessitating dialysis) and the administration of gadolinium‐containing contrast agents (GCCA). Early symptoms include swelling, redness, pruritus, and pain in the limbs, sometimes with muscle weakness. Early signs are edema, erythema, and occasionally palpable warmth of the involved extremities; there may be florid scleral telangiectasia resembling conjunctivitis. We must redouble our efforts to avoid the administration of GCCA to patients with renal insufficiency. The most effective treatment for NSF to date is maximization of renal function via medical therapy or transplantation. There are data to support a beneficial effect from extracorporeal photopheresis, and all patients can gain from physical therapy.

Murine phospholipid hydroperoxide glutathione peroxidase: cDNA sequence, tissue expression, and mapping

Phospholipid hydroperoxide glutathione peroxidase (PHGPx), also known as glutathione peroxidase 4 (GPX4), is a 19-kDa, monomeric enzyme that protects cells from lipid peroxide-mediated damage by catalyzing the reduction of lipid peroxides. PHGPx is synthesized in two forms, as a 194-amino acid peptide that predominates in gonadal tissue and localizes to mitochondria, and as a 170-amino acid protein that predominates in most somatic tissues and localizes to the cytoplasm. With the rapid amplification of cDNA ends (RACE) procedure, an 876-bp PHGPx cDNA was amplified from mouse testis, and a 767-bp PHGPx cDNA was amplified from mouse heart. The cDNA sequences were identical except that the testis cDNA contained an additional 109 bp at its 5′ end. With a partial cDNA with complete homology to both the testis and myocardial PHGPx cDNAs, the murine tissue distribution of PHGPx mRNA expression was determined by Northern blotting. Highest level of PHGPx expression was found in the testis, followed by the kidney, heart and skeletal muscle, liver, brain, lung, and spleen. Northern blotting performed with a cDNA specific for the longer PHGPx transcript demonstrated that this longer PHGPx transcript was present only in the testis. A 1.4-kb PHGPx genomic fragment was amplified from murine kidney DNA and used to map the PHGPx gene by linkage analysis of restriction fragment length variants (RFLVs). The murine PHGPx gene (Gpx4) was mapped to a region of murine Chromosome (Chr) 10, located 43 cM from the centromere, that is syntenic with the human locus, which is located at the terminus of the short arm of human Chr 19. This information may be valuable in characterizing the role of PHGPx in modulating susceptibility to lipid peroxide-mediated injury in inbred murine strains and for targeted disruption of the gene.

NSF: WHAT WE KNOW AND WHAT WE NEED TO KNOW: Nephrogenic Systemic Fibrosis: Early Recognition and Treatment

Nephrogenic systemic fibrosis (NSF) is a progressive, debilitating, and emotionally distressing disease that can affect patients with renal dysfunction. Prevention, early recognition and early treatment are essential to limiting its impact. The most significant risk factors for developing NSF are chronic or significant acute kidney disease (usually necessitating dialysis) and the administration of gadolinium‐containing contrast agents (GCCA). Early symptoms include swelling, redness, pruritus, and pain in the limbs, sometimes with muscle weakness. Early signs are edema, erythema, and occasionally palpable warmth of the involved extremities; there may be florid scleral telangiectasia resembling conjunctivitis. We must redouble our efforts to avoid the administration of GCCA to patients with renal insufficiency. The most effective treatment for NSF to date is maximization of renal function via medical therapy or transplantation. There are data to support a beneficial effect from extracorporeal photopheresis, and all patients can gain from physical therapy.

Somatic ATP2A2 mutation in a case of papular acantholytic dyskeratosis: mosaic Darier disease

Papular acantholytic dyskeratosis, also known as acantholytic dermatosis of the vulvocrural (or anogenital) area, is an uncommon eruption reported predominantly in women. This entity manifests with pruritic papules in the groin/anogenital area and less commonly on the chest. The pathobiology of papular acantholytic dyskeratosis is uncertain. A 62‐year‐old woman presented with multiple verrucous‐appearing lesions in the groin and on the chest showing acantholytic dyskeratosis on histopathology. Given histological similarity of these papular acantholytic dyskeratosis lesions to Darier disease due to inherited ATP2A2 mutation, we screened affected and normal tissue and peripheral blood in our patient for mutations in ATP2A2. We found an identical ATP2A2 p.706D>N mutation in multiple independent papular acantholytic dyskeratosis lesions that was not present in uninvolved skin or peripheral blood DNA. These findings establish somatic mosaicism of ATP2A2 mutations as a genetic cause for papular acantholytic dyskeratosis.

Population-Based Analysis of Histologically Confirmed Melanocytic Proliferations Using Natural Language Processing

Importance Population-based information on the distribution of histologic diagnoses associated with skin biopsies is unknown. Electronic medical records (EMRs) enable automated extraction of pathology report data to improve our epidemiologic understanding of skin biopsy outcomes, specifically those of melanocytic origin. Objective To determine population-based frequencies and distribution of histologically confirmed melanocytic lesions. Design, Setting, and Participants A natural language processing (NLP)-based analysis of EMR pathology reports of adult patients who underwent skin biopsies at a large integrated health care delivery system in the US Pacific Northwest from January 1, 2007, through December 31, 2012. Exposures Skin biopsy procedure. Main Outcomes and Measures The primary outcome was histopathologic diagnosis, obtained using an NLP-based system to process EMR pathology reports. We determined the percentage of diagnoses classified as melanocytic vs nonmelanocytic lesions. Diagnoses classified as melanocytic were further subclassified using the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) reporting schema into the following categories: class I (nevi and other benign proliferations such as mildly dysplastic lesions typically requiring no further treatment), class II (moderately dysplastic and other low-risk lesions that may merit narrow reexcision with <5-mm margins), class III (eg, melanoma in situ and other higher-risk lesions warranting reexcision with 5-mm to 1-cm margins), and class IV/V (invasive melanoma requiring wide reexcision with ≥1-cm margins and potential adjunctive therapy). Health system cancer registry data were used to define the percentage of invasive melanoma cases within MPATH-Dx class IV (stage T1a) vs V (≥stage T1b). Results A total of 80 368 skin biopsies, performed on 47 529 patients, were examined. Nearly 1 in 4 skin biopsies were of melanocytic lesions (23%; n = 18 715), which were distributed according to MPATH-Dx categories as follows: class I, 83.1% (n = 15 558); class II, 8.3% (n = 1548); class III, 4.5% (n = 842); class IV, 2.2% (n = 405); and class V, 1.9% (n = 362). Conclusions and Relevance Approximately one-quarter of skin biopsies resulted in diagnoses of melanocytic proliferations. These data provide the first population-based estimates across the spectrum of melanocytic lesions ranging from benign through dysplastic to malignant. These results may serve as a foundation for future research seeking to understand the epidemiology of melanocytic proliferations and optimization of skin biopsy utilization.

Palifermin-Associated Papular Eruption

BACKGROUND Palifermin is a recombinant human keratinocyte growth factor that is used to reduce the duration and severity of oral mucositis in patients undergoing hematopoietic stem cell transplantation after myelotoxic therapy. Cutaneous adverse reactions associated with keratinocyte growth factor are reported to be rash, pruritus, and erythema. OBSERVATIONS After receiving palifermin following autologous hematopoietic stem cell transplantation and treatment with melphalan, a patient developed erythema and lichenoid papules that were distributed primarily in intertriginous areas. A biopsy specimen of the papules showed a striking resemblance to verrucae, but in situ hybridization studies were negative for human papillomavirus. Immunohistochemical staining with antibodies to Ki-67 and cytokeratin 5/6 showed increased keratinocyte proliferation in lesional skin. CONCLUSIONS After treatment with palifermin, a papular eruption clinically resembling lichen planus or plane warts, with histologic features of verruca plana, and intertriginous erythema may occur. In this case, neither eruption required treatment, and spontaneous resolution was observed over days to weeks. Histopathologic staining patterns of Ki-67 and cytokeratin 5/6 may be useful in identifying adverse reactions to palifermin therapy.

Vegetative Plaques and Hemorrhagic Pustules

A man with a history of chronic renal insufficiency (baseline creatinine level, 2.8mg/dL) presented for evaluation of a painful forehead erythematous eruption and associated headache. (To convert creatinine to micromoles per liter, multiply by 88.4.) Three days prior to symptom onset he underwent a contrast-enhanced computed tomographic (CT) scan to evaluate abdominal pain. On the central forehead was a tender 5-cm reddish brown plaque composed of numerous coalescing vesicles and hemorrhagic pustules with intermixed serous and hemorrhagic crust. Similar vesicles and pustules were present on the nasal bridge and tip, the bilateral conchal bowls, and on the scalp (Figure, A). Two days later, the patient developed several 0.5to 1.0-cm purpuric macules and hemorrhagic vesicles on the bilateral hands and nail beds. Initial blood tests revealed a white blood cell count of 6400 cells (range, 4000 to 11 000/μL; to convert to ×109/L, multiply by 0.001). The patient denied any new medications, any known contacts with or exposures to individuals who were ill, and any history of skin disease. A punch biopsy of the forehead plaque was performed (Figure, B and C). What is your diagnosis?

Centrofacial Balamuthiasis: case report of a rare cutaneous amebic infection

Free‐living amebae are ubiquitous in our environment, but rarely cause cutaneous infection. Balamuthia mandrillaris has a predilection for infecting skin of the central face. Infection may be restricted to the skin or associated with life‐threatening central nervous system (CNS) involvement. We report a case of a 91‐year‐old woman, who presented with a non‐healing red plaque over her right cheek. Several punch biopsies exhibited non‐specific granulomatous inflammation without demonstrable fungi or mycobacteria in histochemical stains. She was treated empirically for granulomatous rosacea, but the lesion continued to progress. A larger incisional biopsy was performed in which amebae were observed in hematoxylin‐eosin stained sections. These were retrospectively apparent in the prior punch biopsy specimens. Immunohistochemistry and polymerase chain reaction studies identified the organisms as Balamuthia mandrillaris. Cutaneous infection by B. mandrillaris is a rare condition that is sometimes complicated by life‐threatening CNS involvement and which often evades timely diagnosis due to its rarity and nonspecific clinical manifestations. Moreover, these amebae are easily overlooked in histopathologic sections because of their small number and their resemblance to histiocytes. Dermatopathologists should be familiar with the histopathologic appearance of these organisms and include balamuthiasis and other amebic infections in the differential diagnosis of granulomatous dermatitis.

Aplasia cutis congenita of the scalp

We read with great interest the recent article by Yilmaz et al on an infant with a large full thickness skin and skull defect on the scalp. The infant suffered from other malformations which proved to be fatal. According to Frieden classification the patient was classified in group 4 (3). Aplasia cutis congenita is a rare disorder that is characterized by the absence of skin in a single or multiple areas, more frequently on the scalp. Occasionally the underlying structures, such as the skull and meninges, are affected (2). Genetic factors, teratogens and trauma have been suggested as etiological factors, whereas it has been associated with various syndromes (1).