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.

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.

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.

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 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.

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.

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).

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.

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.

Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.

Heparin-induced thrombocytopenia/thrombosis (HITP) is thought to be mediated by immunoglobulins that activate platelets in the presence of pharmacologic concentrations of heparin, but the molecular basis for this relatively common and often serious complication of heparin therapy has not been established. We found that plasma from each of 12 patients with HITP contained high titer (> or = 1:200) antibodies that reacted with immobilized complexes of heparin and platelet factor 4 (PF4), a heparin-binding protein contained in platelet alpha-granules. Recombinant human PF4 behaved similarly to PF4 isolated from platelets in this assay system. Complexes formed at an apparent heparin/PF4 molecular ratio of approximately 1:2 (fresh heparin) and approximately 1:12 (outdated heparin) were most effective in binding antibody. Immune complexes consisting of PF4, heparin, and antibody reacted with resting platelets; this interaction was inhibited by a monoclonal antibody specific for the Fc gamma RII receptor and by excess heparin. Human umbilical vein endothelial cells, known to express heparin-like glycosaminoglycan molecules on their surface, were recognized by antibody in the presence of PF4 alone; this reaction was inhibited by excess heparin, but not by anti-Fc gamma RII. Antibodies reactive with heparin/PF4 were not found in normal plasma, but IgG and IgM antibodies were detected at dilutions of 1:10 (IgG) and 1:50 (IgM) in 3 of 50 patients (6%) with other types of immune thrombocytopenia. These findings indicate that antibodies associated with HITP react with PF4 complexed with heparin in solution or with glycosaminoglycan molecules on the surface of endothelial cells and provide the basis for a new hypothesis to explain the development of thrombocytopenia with thrombosis or disseminated intravascular coagulation in patients sensitive to heparin.

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.

The biology of social attachments: opiates alleviate separation distress.

The possibility that brain opiate systems participate in the control of social affect was assessed by determining capacity of low doses of exogenous opiates (0.125-0.50 mg/kg oxymorphone, and 0.10-0.50 mg/kg morphine sulfate) to reduce distress vocalizations of socially isolated puppies. Low doses of opiates were capable of profoundly reducing crying as well as the motor agitation they exhibit during brief periods of social isolation. Since reductions in crying could be obtained with morphine in the absence of any gross behavioral disturbances, the possibility is entertained that brain opiates may function to control the intensity of emotions arising from social separation. Possible parallels between the biological nature of narcotic addiction and the formation of social bonds are discussed.

The effect of recipient lung size on lung physiology after heart-lung transplantation.

We studied the postoperative course of lung volumes in 32 heart-lung transplant recipients relative to the predicted total lung capacity of the individual donors, to assess the degree of inaccuracy likely to result from the radiological method of matching of donor and recipient lung sizes. There was a tendency for recipients with large preoperative lung volumes--from, for example, emphysema--to receive smaller lungs, while those with smaller volumes from pulmonary vascular disease received bigger donor lungs, but no immediate problems were incurred. After an initial fall in total lung capacity, the postoperative value of the total lung capacity approached the recipients' pretransplant value about one year after the operation irrespective of the size of the donor lungs. This suggests that chest wall compliance is the major determinant of postoperative lung volume and not the donor lung size or compliance. Exact matching of donors' and recipients' lung sizes may not be necessary, and if required can be simply achieved by comparing the measured total lung capacity in the recipient with the predicted value of the donor based on sex, age, and height.

Risk factors for obliterative bronchiolitis in heart-lung transplant recipients.

Obliterative bronchiolitis is the major cause of death of long-term survivors of heart-lung transplantation. Of our first 75 patients who have received heart-lung transplantation, 38 have been followed for a year or longer. Eight patients developed clinical evidence of obliterative bronchiolitis within 15 months of transplantation, of whom four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. One further patient died before one year after chronic rejection. All nine patients had evidence on transbronchial biopsy of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy, and the other eighteen are well and without fibrosis on transbronchial biopsy. Studies of the 274 biopsies obtained from 38 patients confirmed rejection on 182 occasions with more frequent, more persistent, and more severe rejection in the chronic rejection group than in the without-fibrosis or lung fibrosis groups. Opportunistic infection resulted in pneumonia on 19 occasions, and were most commonly found in lung fibrosis patients. We conclude that obliterative bronchiolitis is the likely outcome in patients with early, poorly controlled, severe rejection.

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

Infection and reactivation with cytomegalovirus strains in lung transplant recipients.

Cytomegalovirus pneumonia is a major cause of morbidity and death following lung transplantation (LT) (1). The case fatality rate is highest in the CMV-seronegative recipients (R-) of organs from seropositive donors (D+), which suggests that transmission of CMV may occur with the graft (1), but in seropositive recipients (R+) the comparative importance of reactivation of endogenous virus and reinfection with donor virus is poorly understood.