Transabdominal Intrapericardial Approach in Liver Transplantation for Unresectable Primary Hepatic Functioning Paraganglioma With Invasion Into Hepatic Veins and Suprahepatic Vena Cava: A Surgical and Anesthesia Management Challenge.

Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome.

Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes.

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.

Extracorporeal Photopheresis Improves Survival in Hematopoietic Cell Transplant Patients with Bronchiolitis Obliterans Syndrome without Significantly Impacting Measured Pulmonary Functions.

We carried out the first matched retrospective cohort study aimed at studying the safety and efficacy of extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT). Medical records of 1325 consecutive adult patients who underwent HCT between 2005 and 2015 were reviewed. Seventy-four patients (median age, 51 years) with a diagnosis of BOS were included in the study. After propensity-score matching for BOS severity, 26 patients who underwent ≥3 months of ECP were matched to 26 non-ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs. The rate of decline in FEV1 percentage predicted (FEV1PP) decreased after ECP initiation (and after index date in the non-ECP group), with no significant difference between the 2 groups (P = .33). On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched related donor HCT (HR, .1; 95% CI, .03 to .5; P = .002), ECP (HR, .1; 95% CI, .01 to .3; P = .001), and slower rate of decline in FEV1PP before the ECP/index date (HR, .7; 95% CI, .6 to .8; P = .001) were associated with a better overall survival. At last follow-up, non-ECP-treated patients were more likely to be on >5 mg daily dose of prednisone (54% versus 23%; P = .04) and had a greater decline in their Karnofsky performance score (mean difference, -9.5 versus -1.6; P = .06) compared with ECP-treated-patients. In conclusion, compared with other BOS-directed therapies, ECP was found to improve survival in HCT patients with BOS, without significantly impacting measured pulmonary functions. These findings need prospective validation in a larger patient cohort.

Effect of a See and Treat clinic on skin cancer treatment time.

BACKGROUND: Many plastic surgery departments in Australasia have experienced increasing referrals for management of skin lesions. This has driven a demand for new strategies to decrease patient waiting time and administrative costs. The aim of this study was to determine if a purpose-built See and Treat skin cancer clinic could provide a faster skin cancer treatment pathway with comparable clinical outcomes and acceptability to patients. METHODS: This was a prospective observational study of patients treated through the See and Treat clinic with a retrospective control cohort. The prospective 'See and Treat' cohort included a consecutive series of 106 patients, while the retrospective cohort included a consecutive series of 200 patients. Patient demographics, time from referral to surgery and operative measures were analysed. One hundred patients in the prospective cohort completed an anonymous satisfaction survey regarding their treatment. RESULTS: The average time from referral to surgery was reduced from 121 days in the retrospective cohort to 60 days in the See and Treat cohort (P < 0.001). Rates of complete excision of malignant and premalignant lesions were not different between the two groups, being 93% (178/191) and 91% (76/84), respectively (P = 0.609). Ninety-five percent (95/100) of patients were satisfied with their See and Treat experience overall. CONCLUSION: We show that a considerable reduction in the time between referral and surgery can be achieved through a See and Treat clinic without compromise of the success of surgical treatment. Moreover, such a treatment pathway has been shown to be acceptable, and largely preferable, to patients.

Mayo clinic experience of lung transplantation in pulmonary lymphangioleiomyomatosis.

OBJECTIVES: Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that generally results in progressive decline in lung function. Despite advancement of pharmacological therapy for LAM, lung transplantation remains an important option for women with end-stage LAM. METHODS: Patients with LAM undergoing lung transplantation at the Mayo Clinic campuses in Rochester, Minnesota and Jacksonville, Florida since 1995 were retrospectively reviewed. RESULTS: Overall, 12 women underwent lung transplantation. Nine of 12 (75%) underwent double lung transplant. The mean age was 42 ± 8 years at the time of transplant. One patient (8%) had a chylothorax and 7 (58%) had recurrent pneumothoraces, 4 (33%) of which required pleurodesis. All had diffuse, cystic lung disease on chest CT consistent with LAM which was confirmed in the explant of all patients. The average length of ICU and hospital stays were 5 ± 4 and 19 ± 19 days, respectively. Mild to moderate anastomotic ischemia was evident in all patients but resolved with time. No patient was treated with sirolimus pre-transplant. Seven patients received sirolimus post-transplant; however, clinical benefit was documented in only 2 patients, 1 of which was treated for large retroperitoneal cysts with ureteral obstruction and another with persistent chylothorax and retroperitoneal lymphangioleimyomas. Five patients are deceased. The median survival by Kaplan-Meier analysis was 119 months with a median follow-up of 68 months (range 2-225 months). CONCLUSIONS: Lung transplant remains a viable treatment for patients with end-stage LAM. The role of sirolimus peri-transplantation remains ill-defined.

Increased gravitational force reveals the mechanical, resonant nature of physiological tremor.

KEY POINTS: Physiological hand tremor has a clear peak between 6 and 12 Hz, which has been attributed to both neural and resonant causes. A reduction in tremor frequency produced by adding an inertial mass to the limb has usually been taken as a method to identify the resonant component. However, adding mass to a limb also inevitably increases the muscular force required to maintain the limb's position against gravity, so ambiguous results have been reported. Here we measure hand tremor at different levels of gravitational field strength using a human centrifuge, thereby increasing the required muscular force to preserve limb position without changing the limb's inertia. By comparing the effect of added mass (inertia + force) versus solely added force upon hand acceleration, we conclude that tremor frequency can be almost completely explained by a resonant mechanical system. ABSTRACT: Human physiological hand tremor has a resonant component. Proof of this is that its frequency can be modified by adding mass. However, adding mass also increases the load which must be supported. The necessary force requires muscular contraction which will change motor output and is likely to increase limb stiffness. The increased stiffness will partly offset the effect of the increased mass and this can lead to the erroneous conclusion that factors other than resonance are involved in determining tremor frequency. Using a human centrifuge to increase head-to-foot gravitational field strength, we were able to control for the increased effort by increasing force without changing mass. This revealed that the peak frequency of human hand tremor is 99% predictable on the basis of a resonant mechanism. We ask what, if anything, the peak frequency of physiological tremor can reveal about the operation of the nervous system.

Preparation for and physiological responses to competing in the Marathon des Sables: a case report.

A case study into the preparation and physiological responses of competing in the Marathon des Sables (MDS) was conducted by preparing a male competitor for, and monitoring him during, his first attempt at the race. The aims of this case report were to (a) prepare and monitor an ex-Olympic, male rower (S1) during the 2010 race and; (b) compare his physiological responses and race performance to that of the current MDS record holder (S2). S1 (age 37 y; body mass 94.0 kg; height 1.92 m; VO(2peak) 66.0 ml·kg⁻¹·min⁻¹) and S2 (age 37 y; body mass 60.8 kg; height 1.68 m; VO(2peak) 65.9 ml·kg⁻¹·min⁻¹) completed a heat test and S1 subsequently underwent 7 d of heat acclimation prior to the MDS. Gastro-intestinal temperature (Tgi) and heart rate (HR) were measured for S1 during Stages 2, 4, and 5 of the MDS and pre- and post-stage body mass, and urine specific gravity were measured for all stages. Race time and average speeds were collected for S1 and S2. Total race times for S1 and S2 were 25:29:35 and 19:45:08 h:min:s. S1's mean (± 1 SD) percentage HR range (%HRR=[HR-HRmin]/[HRmax-HRmin]x100) was 66.1 ± 13.4% and Tgi ranged between 36.63-39.65°C. The results provide a case report on the physiological responses of a highly aerobically-trained, but novice ultra-endurance runner competing in the MDS, and allow for a comparison with an elite performer.

CD8(+) T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-γ, IL-13, IL-17, and IL-22.

Although CD4(+) T cells are known to contribute to the pathology of atopic dermatitis (AD) and psoriasis, the role of CD8(+) T cells in these diseases remains poorly characterized. The aim of this study was to characterize the cytokine production of T cells from AD and psoriasis skin. We found that CD4(+) T cells isolated from AD skin were largely Th2 (T helper type 2) biased, in agreement with prior reports. However, we also observed large numbers of CD8(+) T cells producing IL-13, IFN-γ, and IL-22. We observed increased numbers of CD8(+) T cells isolated from AD skin, and immunohistochemistry studies confirmed the presence of CD8(+) T cells in the dermis and epidermis of AD skin lesions. Surprisingly, T-cell cytokine production was similar in the lesional and nonlesional skin of patients with AD. T cells from psoriatic lesional skin predominantly produced IFN-γ, IL-17, and IL-22, in agreement with prior studies. However, in addition to Th17 cells, we observed high percentages of CD8(+) T cells that produced both IL-22 and IL-17 in psoriatic skin lesions. Our findings demonstrate that CD8(+) T cells are a significant and previously unappreciated source of inflammatory cytokine production in both AD and psoriasis.

Morphological features of coronary arteries and lesions in hearts from five species of sharks collected from the northwestern Atlantic Ocean.

Morphological features of coronary arteries and incidental lesions are reported from hearts in five species of sharks, the shortfin mako shark, Isurus oxyrhinchus Rafinesque, thresher shark Alopias vulpinus (Bonaterre), blue shark, Prionace glauca L., the smooth dogfish, Mustelus canis (Mitchill), and spiny dogfish, Squalus acanthias L. Sharks were collected from the northwestern Atlantic between June and August from 1996 to 2010. They were necropsied dockside and the hearts were preserved in buffered formalin. Routine sections including ventricle/conus arteriosus and the atrio-ventricular junctions were embedded in paraffin, stained with common histological and immunohistochemical methods and examined by brightfield microscopy. Myointimal hyperplasia, medial myo-myxomatous hyperplasia and bifurcation pads were observed commonly, and medial muscle reorientation and epicardial myeloid tissues were rare. All the above features differed in severity, prevalence and distribution depending on anatomical site and shark species/size. Morphometric analysis indicated that myomyxomatous hyperplasia is associated with luminal narrowing of blood vessels. As suggested previously, the described morphological features are most likely physiological responses to blood flow characteristics. Vascular and cardiac lesions were uncommon and included, granulomatous proliferative epicarditis with fibroepitheliomas, myxomatous epicardial expansions, medial arterial vacuolation, myocardial fibrosis, acute ventricular emboli and parasitic granulomas. The lesions of embolism, proliferative and granulomatous epicarditis and myocardial fibrosis were in all sharks associated with capture events including retained fishing hooks. The significance and aetiopathogenesis of medial vacuolation and epicardial myxomatous expansions remains unclear.

Expression and immune function of tenascin-C.

Our immune system is designed to protect us from danger. Upon pathogen invasion and tissue injury, activation of both innate and adaptive immunity enables us to combat infection and to repair tissue damage. Tenascin-C is a large, extracellular matrix glycoprotein that has a very tightly controlled pattern of expression. Little or no tenascin-C is expressed in most healthy adult tissues; however, it is rapidly and transiently induced at sites of tissue injury and infection. Persistent tenascin-C expression is associated with pathologies such as chronic, non-healing wounds, autoimmune diseases, cancer, and fibrotic diseases. We discuss the myriad roles that this multifunctional molecule plays during the immune response, with a focus on how tissue levels of tenascin-C are regulated and the consequences of misregulated tenascin-C expression in immune regulated disease pathogenesis.

The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study.

Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8(+) T cells, suggesting that host B cells play a role in maintaining pathological CD8(+) T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42).

Beyond the enhanceosome: cluster of novel κB sites downstream of the human IFN-ß gene is essential for lipopolysaccharide-induced gene activation.

The expression of interferon-ß (IFN-ß) in virus-infected HeLa cells established a paradigm of multifactorial gene regulation, in which cooperative assembly of transcription factors (TFs) at the composite DNA element (enhanceosome), is central for amplification of weak activating signals provided by individual TFs. However, whether the same TFs and the same DNA element are essential for IFN-ß induction in response to bacterial stimuli are less well understood. Here we report that rapid and transient transcription of IFN-ß in response to TLR4 stimulation with bacterial lipopolysaccharide (LPS) follows nuclear factor-κB (NF-κB) RelA activation and recruitment to the IFN-ß genomic locus at multiple spatially separated regulatory regions. We demonstrate that the IFN-ß enhanceosome region is not sufficient for maximal gene induction in response to LPS and identify an essential cluster of homotypic κB sites in the 3' downstream of the gene. The cluster is characterized by elevated levels of histone 3 lysine 4 mono-methylation, a chromatin signature of enhancers, and efficiently binds RelA-containing NF-κB complexes in vitro and in vivo. These findings demonstrate that IFN-ß gene activation via multifactorial enhanceosome assembly is potentiated in LPS-stimulated cells by NF-κB interactions with all functional κB sites in the locus.

Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function.

BACKGROUND: Type 2M von Willebrand disease (VWD) is characterized by a qualitative defect in von Willebrand factor (VWF) and diagnosed by a disproportionate decrease in VWF ristocetin cofactor activity (VWF:RCo) as compared with VWF antigen (VWF:Ag). OBJECTIVE: We report here on the spurious diagnosis of VWD in a patient with a sequence variation in the ristocetin-binding domain of VWF. PATIENTS/METHODS: The index case had a VWF:RCo of 11 IU dL(-1), with VWF:RCo/VWF:Ag ratio of 0.09. DNA sequencing revealed a novel P1467S mutation in a known ristocetin-binding region of the A1 domain. Because of the discrepancy between the laboratory findings, consistent with type 2M VWD, and the patient's lack of bleeding symptoms, further studies were performed to determine whether this mutation affected VWF function or merely reduced its ability to interact with ristocetin. RESULTS: Studies with recombinant VWF showed normal platelet binding with botrocetin, but a significant decrease in binding in response to ristocetin. Ristocetin-induced binding to recombinant GPIb was also absent, but normal binding was seen when a gain-of-function GPIb construct was used in the absence of ristocetin. VWF function under shear stress was normal when analyzed with a cone and plate(let) analyzer. CONCLUSIONS: The decreased VWF:RCo seen with the P1467S sequence variation likely represents an artifact as a result of the use of ristocetin to measure VWF activity. The normal VWF function in other assays correlates with the lack of hemorrhagic symptoms, and suggests the need for more physiologically relevant assays of VWF function.

The role of transposable elements in the regulation of IFN-lambda1 gene expression.

IFNs lambda1, lambda2, and lambda3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-beta gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-lambda gene expression. Studies of virus induction of IFN-lambda1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-lambda1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-kappaB binding sites. Remarkably, these sites, which bind efficiently to NF-kappaB and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-kappaB RelA protein significantly reduces the level of the IFN-lambda1 gene expression. We conclude that IFN-lambda1 gene expression requires NF-kappaB, and we propose a model for IFN-lambda1 gene regulation, in which IRF and NF-kappaB activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-lambda1 and IFN-beta promoters and directly implicate transposable elements in the regulation of the IFN-lambda1 gene by NF-kappaB.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

Health-related quality of life in children with sickle cell disease: child and parent perception.

Health-related quality of life (HRQL) is an outcome that may be used to measure the impact of sickle cell disease on the child and their family but has not been routinely assessed in this disease. The objective of this study was to describe the HRQL of children with sickle cell disease as reported by the parent and the child, to compare the relationship between the two, and to determine the association of parent, child and disease characteristics on HRQL. Ninety-five parents completed the Child Health Questionnaire (CHQ)-Parent Form28 and 53 children completed the CHQ-Child Form87. Compared with the child report, parents reported worse HRQL in the overall perception of health, physical functioning, behaviour and self esteem domains of HRQL (P < 0.005). Parent and child reports of HRQL correlated strongly in assessment of the impact of bodily pain (r = 0.58) on HRQL and moderately in physical functioning (r = 0.44), behaviour (r = 0.45), general health (r = 0.44), self esteem (r = 0.40) and changes in health (r = 0.33) domains. Disease status, neurobehavioral co-morbidities, and parent education were associated with the HRQL of the child. Both the parent and child perspectives are needed to fully understand the impact of sickle cell disease on the HRQL of the child and effect of this disease on the family.

Sleep deprivation, energy expenditure and cardiorespiratory function.

Participants in the sport of adventure racing often choose to go without sleep for a period of greater than 24 h while partaking in prolonged submaximal exercise. This study examined the effect of 30 h of sleep deprivation and intermittent physical exercise, on the cardiorespiratory markers of submaximal exercise in six subjects. Six subjects with the following physical characteristics participated in the study (mean +/- SD): age 22 +/- 0.3 years, height 180 +/- 5 cm, body mass: 77 +/- 5 kg, VO2peak 44 +/- 5 ml. kg (-1). min (-1). Three subjects engaged in normal sedentary activities while three others cycled on a cycle ergometer at 50 % VO2peak for 20 min out of every two hours during thirty hours of sleep deprivation. One week later sleep deprivation was repeated with a cross over of subjects. Every four hours, subjects completed assessments of cardiorespiratory function during 50 % VO2peak cycling. A 3 x 8 repeated measures ANOVA revealed a significantly lower heart rate with sleep deprivation (p < 0.05), but no other significant effects (p > 0.05) on respiratory gas exchange variables. Neither sleep deprivation, nor a combination of sleep deprivation and five hours of moderate intensity cycling, appear to be limiting factors to the physiological capacity to perform submaximal exercise.