National Outcomes of Liver Transplantation for Model for End-Stage Liver Disease Score ≥40: The Impact of Share 35.

In certain regions of the United States in which organ donor shortages are persistent and competition is high, recipients wait longer and are critically ill with Model for End-Stage Liver Disease (MELD) scores ≥40 when they undergo liver transplantation. Recent implementation of Share 35 has increased the percentage of recipients transplanted at these higher MELD scores. The purpose of our study was to examine national data of liver transplant recipients with MELD scores ≥40 and to identify risk factors that affect graft and recipient survival. During the 12-year study period, 5002 adult recipients underwent deceased donor whole-liver transplantation. The 1-, 3-, 5- and 10-year graft survival rates were 77%, 69%, 64% and 50%, respectively. The 1-, 3-, 5- and 10-year patient survival rates were 80%, 72%, 67% and 53%, respectively. Multivariable analysis identified previous transplant, ventilator dependence, diabetes, hepatitis C virus, age >60 years and prolonged hospitalization prior to transplant as recipient factors increasing the risk of graft failure and death. Donor age >30 years was associated with an incrementally increased risk of graft failure and death. Recipients after implementation of Share 35 had shorter waiting times and higher graft and patient survival compared with pre-Share 35 recipients, demonstrating that some risk factors can be mitigated by policy changes that increase organ accessibility.

Cytomegalovirus prophylaxis in solid organ transplantation.

Human Cytomegalovirus is a commonly identified herpesvirus that establishes a state of latent infection in the majority of the population by adulthood. A coordinated immune response involving both the innate and adaptive immune system prevents active viral replication and disease. Cellular immunity appears particularly important to control of viremia requiring both a CMV-specific CD4+ and CD8+ T cell response. Solid organ transplant recipients are particularly susceptible to CMV related disease due to the immunosuppression necessary to prevent organ rejection, with patients receiving T cell depleting therapies being at highest risk. The deleterious outcomes of CMV in organ transplant recipients result from both direct cytopathic and indirect immune-modulatory effects of CMV viral replication. The recognition of the negative effects of CMV in solid organ transplantation has resulted in the routine prophylaxis of organ recipients with antiviral nucleoside analogues. The appropriate duration of therapy is still controversial although guidelines do exist. The ability to assay an individual immune response to CMV should allow for tailored duration of therapy in the future.

Sonography in pathologies of scalp and hair.

Disorders of the scalp often result in severe cosmetic interference with quality of life, creating the need for optimal medical surveillance. We tested the latest generation of ultrasound machines in patients with scalp pathology and prepared a cross-sectional library encompassing a wide assortment of conditions. Normative data on the sonographic anatomy of scalp and human hair, and important methodological considerations, are also included.

Expanding the donor kidney pool: utility of renal allografts procured in a setting of uncontrolled cardiac death.

The chronic shortage of deceased kidney donors has led to increased utilization of donation after cardiac death (DCD) kidneys, the majority of which are procured in a controlled setting. The objective of this study is to evaluate transplantation outcomes from uncontrolled DCD (uDCD) donors and evaluate their utility as a source of donor kidneys. From January 1995 to December 2004, 75,865 kidney-alone transplants from donation after brain death (DBD) donors and 2136 transplants from DCD donors were reported to the United Network for Organ Sharing. Among the DCD transplants, 1814 were from controlled and 216 from uncontrolled DCD donors. The log-rank test was used to compare survival curves. The incidence of delayed graft function in controlled DCD (cDCD) was 42% and in uDCD kidneys was 51%, compared to only 24% in kidneys from DBD donors (p < 0.001). The overall graft and patient survival of DCD donors was similar to that of DBD donor kidneys (p = 0.66; p = 0.88). Despite longer donor warm and cold ischemic times, overall graft and patient survival of uDCD donors was comparable to that of cDCD donors (p = 0.65, p = 0.99). Concerted efforts should be focused on procurement of uDCD donors, which can provide another source of quality deceased donor kidneys.

Pulsatile perfusion reduces the incidence of delayed graft function in expanded criteria donor kidney transplantation.

The use of expanded criteria donors (ECD) has been proposed to help combat the discrepancy between organ availability and need. ECD kidneys are associated with delayed graft function (DGF) and worse long-term survival. The aim of this study is to evaluate the impact of pulsatile perfusion (PP) on DGF and graft survival in transplanted ECD kidneys. From January 2000 to December 2003, 4618 ECD kidney-alone transplants were reported to the United Network for Organ Sharing. PP was performed on 912 renal allografts. The prognostic factors of DGF were analyzed using multivariate logistic regression analysis. Risk factors for reduced allograft viability were greater in donors and recipients of PP kidneys. Three-year graft survival of ECD kidneys preserved with PP was similar to cold storage (CS) kidneys. The incidence of DGF in PP kidneys was significantly lower than CS kidneys (26% vs. 36%, p < 0.001). Despite having a greater number of risk factors for reduced graft viability, the ECD-PP kidneys had similar graft survival compared to ECD-CS kidneys. The use of PP, by decreasing the incidence of DGF, may possibly lead to lower overall costs and increased utilization of donor kidneys.

Iatrogenic pseudoaneurysms of the extrahepatic arterial vasculature: management and outcome.

BACKGROUND: Pseudoaneurysms of the extrahepatic arterial vasculature are relatively uncommon lesions following surgery and trauma. In this report we analyze the presentation, management and outcomes of these vascular lesions. Of the related surgical procedures, the reported incidence is highest following laparoscopic cholecystectomy. We hereby analyze the literature on this subject and report our experience, specifically with extrahepatic pseudoaneurysms, drawing an important distinction from intrahepatic pseudoaneurysms. METHODS: From September 1995 until July 2004, six patients, including three males and three females with a mean age of 67 years, were treated for seven extrahepatic arterial pseudoaneurysms. Patients were evaluated by endoscopy, ultrasound, computerized tomography, and angiography. Management included coil embolization or arterial ligation and/or hepatic resection. RESULTS: The mean pseudoaneurysm size was 4.9-cm (range 1.0-11.0-cm) and the locations included the right hepatic artery (n = 5), inferior pancreaticoduodenal artery (n = 1), and gastroduodenal artery (n = 1). All six patients had prior surgical or percutaneous procedures. Median latency period between the original procedure and treatment of pseudoaneurysm was 17 weeks (range one month-16 years). Clinical features ranged from the dramatic presentation of hypotension secondary to intraperitoneal aneurysmal rupture to the subtle presentation of obstructive jaundice secondary to pseudoaneurysm mass effect. The range of patient presentations created diagnostic challenges, proving that accurate diagnosis is made only by early consideration of pseudoaneurysm. Management was ligation of the right hepatic artery (n = 4) and embolization of the pseudoaneurysms (n = 2). Post-treatment sequelae included liver failure requiring liver transplant (n = 1), intrahepatic biloma requiring percutaneous drainage (n = 1) and cholangitis with right hepatic duct strictures requiring right lobectomy and biliary reconstruction (n = 1). These complications followed arterial ligation, with no complications resulting from embolization. All six patients are alive and well after a mean follow-up of 53 months. CONCLUSIONS: Our six patients demonstrate the diversity and unpredictability with which a pseudoaneurysm of the extrahepatic arterial vasculature may present in terms of initial symptoms, prior procedures, and the latency period between presentation and prior procedure. Through our experience and an analysis of the literature, we recommend a diagnostic and management approach for these patients.

Malignant melanoma.

CONTEXT: The rapidly developing fields of melanoma research are revolutionizing the current concepts on melanoma etiology and pathogenesis and are introducing newer diagnostic techniques and potential therapeutic approaches. OBJECTIVES: To present the most current concepts on the etiology and pathogenesis of melanoma and to introduce the recent diagnostic techniques and the potential therapeutic approaches. METHODS: Data sources were reports on melanoma published in the English language literature and observations made using specimens available at Harvard University, Johns Hopkins Medical Center, Albany Medical College, Loyola University Medical Center, and University of Tennessee Health Science Center. RESULTS: Studies on melanoma containing chromosomal or genetic evaluation were selected for further analysis. Current clinical and pathologic categories with the reported genetic abnormalities were related to the latest information on pigment biology. The data extracted were used to develop a conceptual framework on the pathogenesis of melanoma; the generated model was then evaluated and used to suggest potential therapeutic approaches. CONCLUSIONS: (1) Melanoma is not genetically homogeneous, and the existing differences between the pathologic categories, particularly in areas such as type of growth phase (radial vs vertical growth), total vertical dimension, ulceration of primary tumor, and metastatic process, have profound prognostic and therapeutic implications. (2) Chromosomal aberrations and gene mutations are found in sporadic and familial melanomas; among the most important are those affecting the 9p21, which contains the p16 locus, a site known to be critical for normal progression of the cell cycle. Aberrant p16 expression is associated with more aggressive behavior. (3) Melanoma cells possess a remarkable repertoire of biosynthetic capacities represented by the production of hormones, growth factors, and their receptors that may sustain and accelerate tumor development and progression. For example, expression of the tumoral products alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone is regulated in vitro by ultraviolet light, a known carcinogen. (4) Melanomas differ from other tumors in their intrinsic capability to express melanogenic enzymes with the corresponding structural proteins to actually synthesize melanin. Melanogenesis-related proteins are rapidly entering the clinical arena, being used not only as diagnostic markers, but also as potential targets for melanoma therapy.

Decreased bioavailability of vitamin D in obesity.

BACKGROUND: Obesity is associated with vitamin D insufficiency and secondary hyperparathyroidism. OBJECTIVE: This study assessed whether obesity alters the cutaneous production of vitamin D(3) (cholecalciferol) or the intestinal absorption of vitamin D(2) (ergocalciferol). DESIGN: Healthy, white, obese [body mass index (BMI; in kg/m(2)) > or = 30] and matched lean control subjects (BMI

Immunological responses to ultraviolet light B radiation in Black individuals.

Immunological factors are important participants in the pathogenesis of experimental skin tumors. We therefore studied cutaneous immune responses in subjects with either low natural incidence (Black individuals), or a high frequency rate (White individuals) of skin cancer. We performed whole body irradiation with a low dose of ultraviolet light B (UV-B) and evaluated peripheral lymphocytes. UV-B irradiation was associated with small but significant changes in lymphocyte phenotype frequency. In White subjects this consisted of an increased number of CD19 (B cells) and CD 4/29 (inducer of helper T cells); Black subjects had a slight decrease in CD3 (T cells). Natural killer activity, not affected by UV-B in White subjects, increased significantly in Black subjects. UV-B was devoid of immunological effects in vitro for any of the parameters tested. As expected, the low UV-B dose used in this study induced increases of serum vitamin D3 concentrations in White subjects, with lack of response in the Black subjects. We conclude that Black individuals selectively exhibit an increase in Natural Killer activity in response to irradiation with low dose UV-B. This race group-specific immune response to ultraviolet radiation appears to require mediation by the skin. Enhanced Natural Killer activity could underlie at least partly the resistance in Black individuals to the development of photodependent skin cancer.

Translocation of hepatitis B virus core particles through nuclear pores in transformed yeast cells.

In our previous transmission electron microscopic study of hepatitis B virus core antigen in transformed yeast cells, we observed core particles passing through the nuclear pores. We have now analyzed 1,421 nuclear pores in transformed yeast, and conclude that 1) translocation of core particles from the nucleus to the cytoplasm occurs through the nuclear pores; 2) translocation sites are located in the center of nuclear pores; 3) at least 95% of pores are involved in the translocation process; 4) proteins as large as 28 nm in diameter can cross the envelope; 5) translocation does not stop, but rather becomes more active during nuclear division in yeast cells.

Compensation for the interracial variance in the cutaneous synthesis of vitamin D.

We investigated the homeostatic compensation for the lower cutaneous synthesis of vitamin D in heavily melanized persons. Vitamin D2 (50,000 IU) was administered in a single oral dose to 24 young adults, 12 blacks and 12 whites, matched for age, gender, and socioeconomic status. We also included a group of eight healthy elderly white adults as representatives of a population with a nonracial mechanism for decreased cutaneous vitamin D synthesis. Plasma determinants were performed under basal conditions and at 6, 10, and 24 hours after vitamin D intake. Basal 25-hydroxyvitamin D (25-OH-D) levels were significantly lower in blacks (12.5 +/- 2.2 ng/ml (mean +/- SEM)) and in elderly whites (19.2 +/- 1.9 ng/ml), compared with young whites (30.2 +/- 3.0 ng/ml (p < 0.0001)); levels of basal 1,25-dihydroxyvitamin D (1,25(OH)2 -D) did not differ between groups. The vitamin D blood curve was similar between groups after the oral vitamin D2 load. Increases in 25-OH-D were 91.7 +/- 15.9% in blacks, 18.8 +/- 5.2% in young whites, and 28.6 +/- 6.9 in elderly whites; 1,25(OH)2-D levels increased slightly and did not differ between groups, although in blacks the change over time was significant (p < 0.05). As a whole, the study populations exhibited a strong relation between basal and peak 25-OH-D (r = -0.80; p < 0.001). Levels of intact parathyroid hormone and serum calcium of blacks and young whites did not differ within or between groups throughout the test.(ABSTRACT TRUNCATED AT 250 WORDS)

Neoplastic erythema nodosum.

We performed immunohistologic studies on a 75-year-old white woman with erythema nodosum (EN) and a systemic lymphoma. A skin biopsy specimen from an EN lesion showed lobular and septal pannicular infiltration by atypical lymphocytes. The cutaneous lymphocytic infiltrate was composed of a monoclonal population of B cells with lambda light chains. Atypical lymphocytes were also seen in the peripheral blood, and flow cytometry showed a predominance of the same phenotype of B cells with lambda light chains. Chemotherapy for systemic B-cell lymphoma resulted in the simultaneous resolution of EN and the lymphoma. This is the first documentation of EN representing direct cutaneous invasion by a B-cell lymphoma.

Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin.

We investigated the presence of proopiomelanocortin (POMC) products in sections of skin from normal subjects and patients with neoplastic and non-neoplastic cutaneous disorders. Antibodies specific against adrenocorticotropin, beta-melanotropin, and beta-endorphin were used for detection and characterization of cell types bearing POMC peptides. POMC products were not observed in sections of normal skin from the corporal (non-scalp) areas (six cases), whereas the hair follicles of scalp skin exhibited positive immunostains that were readily apparent (four cases). POMC products were frequently detected in corporal skin affected by diseases (13 of 26 cases), for example, psoriatic keratinocytes, the inflammatory infiltrate in scarring alopecia, nevocytes, the epithelial cell nests of basal cell carcinoma, and melanoma cells. Further tests were performed in keloids, a primary reactive skin disorder, to evaluate whether POMC accumulation represented a disease-related phenomenon or an expression of normal cutaneous reactivity. POMC products were consistently detected (10 of 11 cases) in the keratinocytes and mononuclear cells at keloid lesions. Thus these observations indicate that POMC products may accumulate locally in lesional skin representing, presumably, a novel cutaneous response to injury. The broad spectrum of POMC products detected suggests that these arise from production in situ (expression of the POMC gene itself) by human skin.

Kinetic and thermodynamic studies of the conversion of previtamin D3 to vitamin D3 in human skin.

The thermoisomerization of previtamin D3 to vitamin D3 is the last step in the synthesis of vitamin D3 in human skin. Kinetic and thermodynamic studies of this reaction in human skin and an organic solvent revealed that not only the equilibrium of the reaction was shifted in favor of vitamin D3 formation in human skin (equilibrium constant K at 37 degrees C = 11.44) compared to hexane (K = 6.15), but also the rate of the reaction was increased by more than 10-fold in human skin (T1/2 at 37 degrees C = 2.5 h) when compared to hexane (T1/2 = 30 30 h). This extraordinarily fast reaction rate was also confirmed in vitro in chicken skin and in vivo in human subjects. The enthalpy change for the reaction determined by the van't Hoff plot was delta H degree = -21.58 kJ mol-1 in human skin and delta H degree = -15.60 kJ mol-1 in hexane. Arrhenius plots showed that the activation energies for both the forward and the reverse reactions were lower in human skin (Ea1 = 71.05 kJ mol-1 and Ea2 = 92.63 kJ mol-1) than in hexane (Ea1 = 84.90 kJ mol-1 and Ea2 = 100.5 kJ mol-1). Activation parameters for the reaction in human skin and in hexane were also reported. Subcellular fractionation of human epidermal tissue revealed that most epidermal 7-dehydrocholesterol and previtamin D3 were in the membrane fraction, while only 20% were in the cytosol. The interaction of previtamin D3 with intracellular lipids and/or proteins in skin may be responsible for the increased vitamin D3 formation rate in the skin.

Human plasma transport of vitamin D after its endogenous synthesis.

Transport of vitamin D3 from its sites of cutaneous synthesis into the circulation has been assumed to be via the plasma vitamin D binding protein (DBP). We studied vitamin D transport from the skin in seven healthy volunteers who received whole body irradiation with 27 mJ/cm2 dosage of ultraviolet B light (290-320 nm). Samples of venous blood were collected serially in EDTA and immediately chilled. In KBr, plasma samples were ultracentrifuged to provide a rapid separation of proteins of density < and > 1.3 g/ml. Upper and lower phases and serial fractions were analyzed for vitamin D3 (extraction, HPLC), cholesterol (enzyme assay), and human DBP (hDBP) (radial immunodiffusion). Total plasma vitamin D (basal level < 1 ng/ml) increased by 10 h and peaked at 24 h (9 +/- 1 ng/ml). 98% of the D3 remained at the density > 1.3 layers for up to 7 d, whereas cholesterol (> 85%) was detected at density < 1.3 and all of the hDBP was at density > 1.3. In three volunteers who each ingested 1.25 mg of vitamin D2, the total plasma D2 increased to 90 +/- 32 ng/ml by 4 h, and the D2 was evenly distributed between the upper and lower layers at 4, 8, and 24 h after the dose, indicating a continuing association of the vitamin with chylomicrons and lipoproteins, as well as with hDBP. Actin affinity chromatography removed D3 from plasma of irradiated subjects, indicating the association of the D3 with DBP. These findings indicate that endogenously synthesized vitamin D3 travels in plasma almost exclusively on DBP, providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol observed after depot, parenteral administration of vitamin D. In contrast, the association of orally administered vitamin D with chylomicrons and lipoproteins allows for receptor-mediated, rapid hepatic delivery of vitamin D, and the reported rapid but less-sustained increases in plasma 25-hydroxycholecalciferol.

Acne and related disorders.

Acne vulgaris is the clinical expression of inflammation of the pilosebaceous unit. Factors known to predispose to the development of acne include increased sebum, which is acted on by Propionobacterium acnes to generate inflammatory substances, and retention hyperkeratosis, which causes obstruction of the sebaceous follicle. Therapeutic modalities for acne include topical and systemic antibiotics, comedolytic agents (such as benzoyl peroxide and topical retinoids) and systemic retinoids. Acne scars may be treated surgically using procedures such as dermabrasion and dermal injections of bovine collagen or simple scar excision, scar punch elevation, or punch grafting.

The association of potentially lethal neurologic syndromes with scleromyxedema (papular mucinosis).

Two patients with scleromyxedema who had progressive neurologic impairment are described. One patient died, and one required prolonged mechanical ventilation. A review of the literature has produced 24 other cases of scleromyxedema in which neurologic changes were prominent.