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Summary Background Reactive oxygen species (ROS) contribute to the cell dysfunction and tissue damage that result from glucolipotoxicity in diabetes. ROS formation in cells causes oxidative stress, thereby activating oxidative damage-inducing genes. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to play an essential role in the vital defence mechanisms that help cells cope with oxidative stress. Aim To compare Nrf2 protein expression in nondiabetic skin tissue with that in diabetic skin tissue. Methods Nrf2 expression was evaluated by Western blotting, reverse transcription (RT)-PCR, and immunohistochemical staining in diabetic and nondiabetic skin tissues. Dinitrophenylhydrazone derivatives of protein carbonyls in the oxidized proteins were measured by oxyblotting analysis. Cytoplasmic and nuclear Nrf2 protein expression was determined to identify the activity and level of Nrf2. Results Protein oxidation, a marker of oxidative stress, was found to be increased in diabetic skin tissue. In subcellular fraction analysis, Nrf2 protein was detected in the nuclei and cytoplasm of nondiabetic skin tissues, and the Nrf2 protein band was identified from among the multiple bands detected, using small interfering RNA-mediated Nrf2 gene silencing. Compared with nondiabetic tissue, diabetic skin tissue showed simultaneous downregulation of Nrf2 at both the mRNA and protein levels. Nuclear condensation, loss of nuclei, and vacuolization were seen in some parts of the specimen by haematoxylin and eosin staining of diabetic skin tissue. Immunohistochemical staining of Nrf2 confirmed the RT-PCR and Western blotting results. Conclusions Collectively, our data show that expression of Nrf2 is clearly downregulated in diabetic skin tissue, and suggest that Nrf2 may be necessary for protection against glucose-induced oxidative stress.

Angiosarcomas of the small intestine are rare and present non-specifically. They usually manifest with abdominal discomfort, altered bowel habits, anaemia and gastrointestinal bleeding. Diagnosis is often challenging and occurs at an advanced tumour stage. We describe a case of a terminal ileum angiosarcoma masquerading as an appendiceal abscess, and discuss salient clinicopathological features in diagnosing and managing this disease.

Obesity in the USA continues to be a medical problem of epidemic proportions, affecting one-third of American adults. This increase in body weight and body mass index (BMI) is a risk factor for insulin resistance; individuals with insulin resistance are at increased risk for the development of type 2 diabetes and cardiovascular disease. The identification of effective dietary treatments (e.g. low-carbohydrate diet, low-fat diet) for patient populations with insulin resistance remains controversial. While a variety of dietary approaches will result in weight and cardiac risk factor reduction, individuals who have been identified as insulin-resistant may derive additional short-term weight loss results from a low-carbohydrate diet compared to a low-fat diet.

To compare the ablation volume, local tumour progression rate and complication rate of radiofrequency ablation (RFA) for small hepatocellular carcinomas (HCCs) using 15-G and 17-G single electrodes.This retrospective study was approved by the institutional review board and informed consent was waived. We reviewed percutaneous RFA cases for HCCs using 15-G or 17-G electrodes without multiple overlapping ablations. A total of 36 pairs of HCCs matched according to tumour size and active tip length were included. We compared ablation volume and complication rate between the two electrode groups. Cumulative local tumour progression rates were estimated using the Kaplan–Meier method and compared using the log-rank test.Tumour size and ablation time were not significantly different between the 15-G and 17-G groups (p50.661 and p50.793, respectively). However, ablation volume in the 15-G electrode group was larger than that in the 17-G group (14.465.4cm3 vs 8.762.5cm3; p,0.001). No statistical difference in complication rates between the two electrode groups was found. The 10- and 20-month local tumour progression rates were not significantly different between the two groups (2.8% and 5.6% vs 11.1% and 19.3%; p50.166).Ablation volume by the 15-G electrode was larger than that by the 17-G electrode. However, local tumour progression rate and complication rate were not significantly different between the two electrode groups.RFA of HCC using a 15-G electrode is useful to create larger ablation volumes than a 17-G electrode.

Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery. It has been postulated that MSCs have hematopoiesis-supportive properties. Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT. Seven patients received UCB and third-party UCB-MSCs. Hematopoietic recovery and transplantation outcomes were compared with historic controls. There was no acute toxicity associated with the infusion of MSCs. The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26). In addition, there was no engraftment failure in the MSC group. The incidence of acute and chronic GVHD was comparable between the two groups. However, veno-occlusive disease and TRM did not occur in the MSC group. Third-party UCB-MSCs infusion was safe and feasible. MSCs may also enhance the engraftment of UCBT and prevent rejection. In addition, MSCs may have a role in decreasing TRM. Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse.

Optimum dose ratios of rimabotulinumtoxinB (BTX-B) and onabotulinumtoxinA (BTX-A) have not been determined for forehead wrinkles.To compare the efficacy and safety of BTX-B and BTX-A for the treatment of forehead lines.Twenty-two women (mean age, 40 years) with symmetrical moderate to severe forehead lines were randomized to receive single intramuscular injections of BTX-A and BTX-B on either side of the forehead, at a potency ratio of 1 : 70 or 1 : 100. Subjects were followed-up for 16 weeks. Four physicians evaluated patients' photographs according to the 4-point Facial Wrinkling Grade (FWG). Clinical Improvement Scale (CIS) was calculated by subtracting FWG score at each visit from that at baseline. Patient satisfaction scores and adverse events were also recorded.Both BTX-A and BTX-B were effective for the treatment of forehead lines. At both potency ratios, BTX-A had a longer duration of action than BTX-B, while BTX-B led to faster improvement than BTX-A. There was no significant difference in CIS between 700 U and 1000 U BTX-B treatments. Adverse effects were mild and transient.Both BTX-A and BTX-B were effective and well tolerated for the treatment of forehead wrinkles at potency ratios of 1 : 70 and 1 : 100.

Deep cutaneous mycoses can cause significant morbidity and mortality, especially in immunocompromised patients. There have been few studies focusing on deep cutaneous mycoses and there are no data from Asian countries. This study aimed to investigate clinical characteristics, underlying predisposing factors, aetiological organisms and outcomes in patients with deep cutaneous mycoses. A retrospective medical record review of patients with deep cutaneous mycoses treated at a tertiary referral centre in Korea from 1999 to 2010. Forty-one cases of deep cutaneous mycosis were identified (median age: 49). Most patients (32/41) had impaired immunological status, and seven of the remaining nine had a history of physical trauma. Neutropenia and long-term use of antibiotics were detected in 13 and 12 patients respectively. Nodular skin lesions were the most common type (17/41) and the morphology of the lesions varied. Fungal organisms were identified by culture and histopathology of skin specimens. Candida (16/41) was the most common organism, followed by Aspergillus, Alternaria, Fusarium (4/41 each). Systemic antifungal treatment was successful in 28 patients, while nine patients died from the fungal infection. Our study may lead to improved insights into deep cutaneous mycoses as their incidence is increasing and they vary in different clinical settings.

Giant congenital melanocytic naevi (GCMN) are known risk factors for the development of melanoma. However, melanoma risk among Asians is rarely evaluated.To evaluate the clinical characteristics and risk of melanoma development from GCMN in Koreans, we performed a nationwide retrospective cohort study in Korea. GCMN were defined as those comprising ≥5% body surface area in children or measuring ≥20cm in adults.In total, 131 patients with GCMN were enrolled, with a mean age of 10·3years (range: birth-70years).The posterior trunk was the most common site (67, 51·1%), followed by lateral trunk, anterior trunk, legs, both anterior and posterior trunk, buttocks, and arms. Satellite naevi were present in 69 cases (52·7%), and axial areas were more commonly involved in patients with satellite naevi than in those without satellite lesions. Atypical features such as rete ridge elongation and bridges were seen, and, among these, pagetoid spread and ballooning cell changes were more common in patients4years old. Proliferative nodules were found in three cases. Melanomas had developed in three of 131 patients (2·3%; a 6-year-old girl, a 14-year-old girl and a 70-year-old man), and the incidence rate was 990 per 100000 person-years. Melanomas in these three patients consisted of two cutaneous melanomas and one extracutaneous meningeal melanoma.We should be aware of melanoma development from GCMN, and lifelong follow-up is required due to the risk of melanoma arising in GCMN.

The clinicopathologic characteristics of malignant lymphomas vary according to geography. The aim of this study was to determine the relative frequency of cutaneous lymphomas and to examine the clinical relevance of the WHO classification in Korean cases of cutaneous lymphoma. The Korean Dermatopathology Research Group conducted a clinicopathologic review of a nationwide collection of 80 cutaneous lymphomas, diagnosed at 23 institutes over a recent 3-year period. The clinical records, haematoxylineosin-stained slides and immunohistochemical stains from 80 patients with malignant lymphomas of the skin were reviewed. In our study, the most frequent cutaneous lymphoma was mycosis fungoides. Compared with Western countries, Korea had higher rates of NK/T cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma and a much lower rate of B-cell lymphoma. The occurrence rates for various subtypes of malignant lymphoma in Korea are distinct from those in Western countries. The EORTC classification is not fully appropriate in dealing with Korean cases of cutaneous lymphoma, because NK/T cell lymphoma is not included in the EORTC classification for cutaneous lymphoma.

Disseminated microsporidiosis is diagnosed uncommonly in patients not infected with human immunodeficiency virus (HIV). We present a case of disseminated microsporidiosis in a renal transplant recipient who was seronegative for HIV. Chromotrope-based stains were positive for microsporidia in urine, stools, sputum, and conjunctival scrapings. Electron microscopy, immunofluorescence, polymerase chain reaction, and cultures of renal tissue identified the organism as Encephalitozoon cuniculi. The patient was treated with oral albendazole and topical fumagillin with clinical improvement. In addition, she underwent a transplant nephrectomy and immunosuppressive therapy was withdrawn. Follow-up samples were negative for microsporidia. However, the patient developed central nervous system manifestations and died. An autopsy brain tissue specimen demonstrated E. cuniculi by immunofluorescent staining. Disseminated microsporidiosis must be considered in the differential diagnosis of multiorgan involvement in renal allograft recipients.

Variations in practice patterns are markers for the quality of patient care in general medicine, but little is known about variation in care delivered to cancer patients. This study's purpose was to describe chemotherapy use, variations in chemotherapy delivery, and the incidence of complications in community practice settings.Data describing adjuvant chemotherapy for patients with early-stage breast carcinoma (ESBC) were collected from an ongoing Oncology Practice Pattern Study at 13 large managed care, academic, and community practices (1111 patients). Data collection included information about diagnoses and adjuvant chemotherapy treatments, laboratory results, supportive care, complications, and treatment modifications.The median patient age was 50 years, and most patients had zero to three positive lymph nodes. Chemotherapy regimens consisting of cyclophosphamide, methotrexate, and 5-fluororacil (CMF) and of doxorubicin and cyclophosphamide (AC) accounted for 76% of the adjuvant therapies used. Overall, 30% of patients had delivered average relative dose intensities/= 85% of the referenced targets. Delivered summation dose intensities (SDIs) frequently were well below targeted SDIs. Neutropenia-related dose modifications occurred for 27.6% of patients and recurred with a 60.7% rate. AC was the regimen delivered with a dose intensity closest to the referenced target. However, patients who were treated with AC regimens and with regimens consisting of cyclophosphamide, doxorubicin, and 5-fluorouracil had significantly higher rates of chemotherapy-related complications compared with patients who were treated with CMF regimens in the most recent treatment years.Adjuvant chemotherapy for patients with ESBC frequently is not administered as referenced in off-protocol community settings. Variation in the delivered SDI raises concerns about potential treatment outcomes and warrants strategies to identify patients who are at risk for complications early in therapy.

Records from 653 patients treated between 1991 and 1998 in the Oncology Practice Patterns Study (OPPS) were analyzed to determine contemporary chemotherapy delivery patterns in patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Of the 653 patient records reviewed, 90 (14%) omitted an anthracycline or mitoxantrone (Novantrone) from primary therapy. Among patients receiving CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) or CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone), 134 (27%) of 492 received an average relative dose intensity of less than 80% of the literature-referenced dose, due either to an inadequate planned or delivered dose. Of 181 advanced-stage patients with responsive disease, 28 (15%) failed to receive at least six treatment cycles. Overall, 283 (43%) of 653 patients potentially received suboptimal chemotherapy due either to choice of regimen or chemotherapy delivered. Patient ageor = 65 years and cardiac comorbidity appeared to have the greatest influence on a physician's decision regarding chemotherapy administration. Among the 492 patients who received CHOP or CNOP, 235 (48%) experienced a delay or reduction in chemotherapy dose (usually neutropenia-related), 100 (20%) developed mucositis, and 116 (24%) were hospitalized for febrile neutropenia. Growth factor was administered to 261 patients (53%), and its primary prophylactic use was associated with a significant reduction in the incidence of hospitalizations for febrile neutropenia in all patient subgroups receiving appropriate chemotherapeutic dose intensity (P = .02). This assessment of chemotherapy delivery to patients with intermediate-grade NHL showed significant variation from current standards. Further analysis of factors influencing chemotherapy delivery might improve therapeutic outcomes.

Renal angiomyolipoma is a benign tumor histologically characterized by proliferation of spindle cells, epithelioid cells, and adipocytic cells in concert with many thick-walled blood vessels. To add further diagnostic confusion, an epithelioid cell-predominant variant of renal angiomyolipoma has recently been described. HMB-45 immunoreactivity correlates with ultrastructural striated organelles that closely resemble premelanosomes, although no evidence of melanogenesis has been documented in this tumor.To further characterize the immunophenotypic and ultrastructural profile of renal angiomyolipoma based on phenotypic cell type (epithelioid, spindle, and adipocytic cell).Formalin-fixed, paraffin-embedded tissues from 27 renal angiomyolipomas and 8 renal cell carcinomas were immunostained with monoclonal antibodies to the melanoma-associated antigens HMB-45, HMB-50, NKI/C3 (CD63), and tyrosinase; the smooth muscle-related antigens calponin and muscle-specific actin (HHF-35); S100; and cytokeratin (CK). All renal angiomyolipomas were also immunostained with a polyclonal antibody to renin. Ultrastructural examination was performed on 9 selected cases.All renal angiomyolipomas stained positive for HMB-45, HMB-50, NKI/C3, muscle-specific actin (HHF-35), and calponin. Overall, HMB-45, HMB-50, and NKI/C3 preferentially stained the epithelioid cells. Tyrosinase staining was present in 50% of the renal angiomyolipomas with adequate tissue for staining (12 of 24 cases); positive staining and intensity paralleled HMB-45, HMB-50, and NKI/C3. Muscle-specific actin (HHF-35) and calponin preferentially stained the spindle cells. The adipocytic cells stained positive for both melanoma-associated antigens and smooth muscle antigens. Epithelioid cells, spindle cells, and adipocytic cells were CK, S100, and renin negative. Ultrastructural findings paralleled immunohistochemical staining patterns. Premelanosome-like organelles and electron dense granules were more readily detected in the epithelioid cells within the tumor, whereas ultrastructural characteristics of smooth muscle cells were more easily found in the spindle cells. All renal cell carcinomas stained positive for CK, NKI/C3 staining was variable, and all were negative for HMB-45, HMB-50, smooth muscle actin (HHF-35), and calponin.In renal angiomyolipoma, the epithelioid and spindle cells have preferential staining patterns for melanoma-associated antigens versus smooth muscle antigens, respectively. Positivity in renal angiomyolipoma for HMB-50, NKI/C3, and tyrosinase, in addition to HMB-45, provides evidence for the presence of different melanoma-associated gene products. Immunophenotypic overlap of the 3 histologically distinct renal angiomyolipoma cell populations suggests a common cell line, supporting a unitarian concept for renal angiomyolipoma. Ultrastructural characteristics of the 3 renal angiomyolipoma cell phenotypes parallel the immunophenotype, giving further support to a common cell line. Our study lends further credence to the perivascular epithelioid cell concept as proposed by Bonetti and colleagues.

Diltiazem hydrochloride is a widely used calcium channel blocking agent. While a few cases of diltiazem-associated photosensitivity have been reported, no cases of photodistributed hyperpigmentation are known.Four cases of photodistributed hyperpigmentation associated with the long-acting formulation of diltiazem hydrochloride (Cardizem CD) are presented. All patients were African American women, with a mean age of 62 years. The mean duration of diltiazem administration prior to the development of hyperpigmentation was 8 months. The hyperpigmentation was slate-gray and reticulated. Phototesting during diltiazem therapy revealed a decreased minimal erythema dose to UV-A in 1 patient. Histopathologic examination showed lichenoid dermatitis with prominent pigmentary incontinence. Electron microscopic examination of the tissue revealed multiple melanosome complexes. Discontinuation of diltiazem therapy resulted in the gradual resolution of the hyperpigmentation.Long-term administration of diltiazem may be associated with characteristic reticulated, slate-gray hyperpigmentation on sun-exposed areas. Discontinuation of the therapy results in resolution of the eruption.

Churg Strauss granuloma (cutaneous extravascular necrotizing granuloma) is a distinct entity which is associated with systemic immunoreactive or autoimmune diseases in a majority of cases. Typically, Churg Strauss granuloma presents as symmetrical papules or nodules on the extremities. There are two histological patterns: the classic pattern reveals palisading granuloma with central degenerated collagen, interspersed polymorphonuclear leukocytes, and leukocytoclastic debris; the focal basophilic necrosis pattern does not show palisading granuloma. We report two cases of Churg Strauss granuloma with different histopathological patterns.

To help understand the pathogenesis of herpes family virus ocular infection among patients positive for HIV, the authors compared the rates of detection of herpes family virus DNA from the conjunctiva of patients who are positive and negative for human immunodeficiency virus (HIV) using the polymerase chain reaction (PCR).Cross-sectional study.The conjunctival scrapings of 30 patients positive for HIV and 30 patients negative for HIV were examined.PCR was used to assay for the presence of herpes simplex virus type 1 (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA (n = 240 samples).The rate of detection of virus DNA in the two groups, controlling for age, gender, and race, was measured.HSV and VZV DNA were not detected in any of the HIV-positive or HIV-negative samples. CMV DNA was detected in 20% (6 of 30) of patients positive for HIV and was undetected in control subjects negative for HIV (P = 0.01). EBV DNA was detected in 40% (12 of 30) of patients positive for HIV and in 47% (14 of 30) of control subjects negative for HIV (P = 0.58).There was no difference in the frequency of detection of HSV, VZV, or EBV DNA from the conjunctiva of patients positive or negative for HIV. Only CMV DNA was detected at a significantly higher rate in the conjunctiva of patients positive for HIV compared with control subjects negative for HIV. These different rates of peripheral virus shedding may be one possible explanation for the different rates of clinical infection among the herpes family viruses among patients positive for HIV.

We report the case of a 31-year-old woman with a rare presentation of syringoma resembling confluent and reticulated papillomatosis of Gougerot-Carteaud. The lesions have been unresponsive to treatment with topical steroids and retinoic acid.

Six kindreds in which pheochromocytomas were present as manifestations of the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type II were studied. The patients underwent bilateral total adrenalectomy with the finding that the pheochromocytomas were bilateral, multifocal, and associated with distinct medullary hyperplasia and reduction in the normal corticomedullary ratio-- features not usually seen in patients with sporadic pheochromocytoma. These findings were exemplified in recent cases of a 34-year-old woman and a 40-year-old man who both had undergone total thyroidectomy for medullary carcinoma of the thyroid. Diagnoses of pheochromocytoma were made by catecholamine studies, computerized tomography, and 131I meta-iodobenzylguanidine (MIBG) scan. Bilateral adrenalectomy was performed with the finding of multiple bilateral pheochromocytomas and adrenal medullary hyperplasia. As in hereditary medullary carcinoma of the thyroid, the histologic findings in pheochromocytomas of the MEN II syndrome are consistent with Knudson's two-mutational-event theory for the initiation of neoplasia, with adrenal medullary hyperplasia representing the manifestation of the first or genetic mutational event and being present invariably in the hereditary cases.

The presence or absence of myoepithelial cells (ME) has been considered as an important feature in the differential diagnosis of benign and malignant papillary lesions of the breast. We evaluated the distribution of myoepithelial cells in formalin-fixed paraffin-embedded tissue sections of 25 papillomas and 18 papillary carcinomas by ABC immunoperoxidase technique with antibodies to muscle actin (HHF-35) and high molecular weight (HMW) keratin (clone 34BE12, cytokeratins 1, 5, 10, and 14; reacting preferentially with ME cells) and an antiserum to S-100 protein. Also included in the study were eight cases of micropapillary ductal carcinoma in situ (DCIS) having a few fibrovascular cores and five peripheral papillomas with accompanying ductal carcinoma in situ or atypical hyperplasia. The antibodies to muscle actin were sensitive and relatively specific for ME cells of the breast and uniformly labeled ME cells in all 25 papillomas. ME cells were absent or extremely sparse in papillary carcinomas. They were present focally in some of the fibrovascular cores of the micropapillary DCIS, and a mixed pattern was observed in peripheral papillomas with areas of carcinoma. HMW keratin was variably expressed in ME cells in most cases with positive internal controls and was present in several normal ductal and papilloma epithelial cells but not in epithelial cells of papillary carcinomas. HMW keratin, although less specific for ME cells, was a useful adjunct because of its reactivity with ME cells as well as hyperplastic epithelial cells in papillomas, which resulted in a combined positive reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

The ultrastructure of a myocardial tumor, referred to by a variety of names, which most currently is myocardial fibroma, has been studied. Although the tumor cells did not have the structure associated with protein synthesizing cells or active fibroblasts, there was evidence that they were participating in formation of the abundant stroma rich in collagen and elastic fibers in varying stages of maturity. The morphology of the stromal elements was similar to that in the surrounding myocardium and that described in the "normal" heart but differed from the elastica described in fibroelastosis.

Synthesis of a calcium-binding amino acid, gamma-carboxyglutamic acid, is a vitamin K-dependent enzymatic process. Warfarin inhibits gamma-carboxyglutamic acid synthesis and, therefore, might diminish the calcification of porcine bioprosthetic valves. To evaluate this, we studied 40 porcine bioprosthetic valves removed because of spontaneous degeneration; 17 patients were treated with warfarin (prothrombin time greater than or equal to 1.5 control) and 23 were untreated. Gross visualization of calcification corresponded closely to x-ray visualization of calcification in explanted valves. No grossly visible calcification or only a single localized nodule was shown in 11 of 17 valves (65%) in treated patients and in only five of 23 valves (22%) in untreated patients (p less than 0.02). Histologic examination showed no calcium or only fine specks of calcium in nine of 13 valves (69%) among warfarin-treated patients and three of 19 valves (16%) from untreated patients. Warfarin, therefore, administered in usual clinical doses, appeared to diminish calcification in spontaneously degenerated porcine bioprosthetic valves.