Heart Transplantation in Systemic Sclerosis: New Impulses for Conventional Scleroderma Transplantation Regimen and Scleroderma Diagnostic Monitoring: 2 Case Reports.

BACKGROUND: Although low (but increasing) rates of lung/lung-heart transplantations of scleroderma (systemic sclerosis [SSc]) patients have been reported, exclusive heart transplantation is a rare approach for treatment of heart failure due to SSc. CASES: We report on 2 cases of SSc patients receiving a heart transplantation (HTx) due to severe and progressive right heart failure without pulmonary artery hypertension. One patient received a hepatitis C virus (HCV)-positive donor heart and recovered excellently from viral transmission after administration of a direct-acting antiviral (DAA) regimen. This is the first published case of an SSc patient who underwent HTx using an HCV-positive donor heart. The clinical course of both patients was monitored by different serum SSc biomarkers. Only xylosyltransferase activity proved to be a promising biomarker for disease stage determination and therapeutic monitoring, precisely reflecting fibrotic remodeling and successful organ recovery. CONCLUSIONS: Successful implementation of the 2 cases described here demonstrates that HTx is a safe and effective therapeutic option for defined SSc sub-patient groups despite the progressive character of the underlying disease. In the future, xylosyltransferase activity might be conducive to simplify the identification of patients with low systemic involvement but a strong indication for single heart transplantation. Finally, we demonstrate that treatment of HCV viral transmission from HCV-positive donor to organ recipient using DAA gives us new opportunities to consider HCV-positive donor organs for HTx and might reveal new possibilities to ease the lack of donor organs.

Observation of Efficient Lower Hybrid Current Drive at High Density in Diverted Plasmas on the Alcator C-Mod Tokamak.

Efficient lower hybrid current drive (LHCD) is demonstrated at densities up to n[over ¯]_{e}≈1.5×10^{20} m^{-3} in diverted plasmas on the Alcator C-Mod tokamak by operating at increased plasma current-and therefore reduced Greenwald density fraction. This density exceeds the nominal "LH density limit" at n[over ¯]_{e}≈1.0×10^{20} m^{-3} reported previously, above which an anomalous loss of current drive efficiency was observed. The recovery of current drive efficiency to a level consistent with engineering scalings is correlated with a reduction in density shoulders and turbulence levels in the far scrape-off layer. Concurrently, rf wave interaction with the edge and/or scrape-off-layer plasma is reduced, as indicated by a minimal broadening of the wave frequency spectrum measured at the plasma edge. These results have important implications for sustaining steady-state tokamak operation and indicate a pathway forward for implementing efficient LHCD in a reactor.

Two-dimensional AXUV-based radiated power density diagnostics on NSTX-U.

A new set of radiated-power-density diagnostics for the National Spherical Torus Experiment Upgrade (NSTX-U) tokamak have been designed to measure the two-dimensional poloidal structure of the total photon emissivity profile in order to perform power balance, impurity transport, and magnetohydrodynamic studies. Multiple AXUV-diode based pinhole cameras will be installed in the same toroidal angle at various poloidal locations. The local emissivity will be obtained from several types of tomographic reconstructions. The layout and response expected for the new radially viewing poloidal arrays will be shown for different impurity concentrations to characterize the diagnostic sensitivity. The radiated power profile inverted from the array data will also be used for estimates of power losses during transitions from various divertor configurations in NSTX-U. The effect of in-out and top/bottom asymmetries in the core radiation from high-Z impurities will be addressed.

High-resolution tangential absolute extreme ultraviolet arrays for radiated power density measurements on NSTX-U.

The radiated-power-density diagnostic on the equatorial midplane for the NSTX-U tokamak will be upgraded to measure the radial structure of the photon emissivity profile with an improved radial resolution. This diagnostic will enhance the characterization and studies of power balance, impurity transport, and MHD. The layout and response expected of the new system is shown for different plasma conditions and impurity concentrations. The effect of toroidal rotation driving poloidal asymmetries in the core radiation from high-Z impurities is also addressed.

Human xylosyltransferase-I - a new marker for myofibroblast differentiation in skin fibrosis.

Skin fibrosis is a severe type of fibrotic disorder emerging in terms of hypertrophic scars or systemic sclerosis. Key event of fibrogenesis is the transition of fibroblasts to matrix-producing myofibroblasts. In the presence of fibrotic triggers, for instance secretion of profibrotic growth factors like transforming growth factor-ß1 (TGF-ß1) or mechanical strain, myofibroblasts persist. Current research focuses on discovering innovative myofibroblast biomarkers which are regulated in fibrotic development and accessible for antifibrotic inhibition. Here, we consider the suitability of xylosyltransferase-I (XT-I) as a myofibroblast biomarker in skin fibrosis. XT-I catalyzes the initial step of glycosaminoglycan biosynthesis. Its increase in enzymatic activity is known to refer only to manifested diseases which are characterized by an abnormal rate of proteoglycan biosynthesis. In this study, treatment of normal human dermal fibroblasts (NHDF) with TGF-ß1 was followed by increased relative XYLT1 mRNA expression. Remarkably, this upregulation was strongly dependent on myofibroblast content, increasing during fibrogenesis. Moreover, XT activity increased time-dependently in response to progressive myofibroblast transformation. XYLT1 expression was inhibited by TGF-ß receptor I (ALK5) inhibitor SB431542. In contrast, XYLT2 expression was only marginally affected by TGF-ß1 as well as ALK5 inhibition. Our results strengthen the significance of XT expression and activity in fibrotic remodeling. Therefore, we propose XT activity, in addition to α-SMA expression, as a new biomarker for myofibroblast differentiation and fibrotic development. Further studies are now needed to evaluate the option to control and inhibit fibrotic remodeling by interfering with XT expression.

Occupational risk factors for acute leukaemia: a case-control study.

A case-control study has been performed for occupational risk factors of acute leukaemia, based on 185 cases more than 30 years old and 513 matched controls. There was a significant excess of polyvalent farming and electronic engineers among professions of cases, and, in addition of metal workers when considering the professions pursued for more than 5 years. The corresponding exposures were analysed through a detailed questionnaire, and assessed by an industrial hygienist after blinding the case-control status. The odds ratios (OR) were computed after adjustment on matching variables and prior chemo- or radiotherapy treatment, and after stratification for the level and total duration of exposure. There was no excess of professional exposure to ionizing radiation among cases. A significant relationship was observed between acute leukaemia and high or medium exposure to benzene, as well as over 10 years high or medium exposure to exhaust gas. In addition a significant relationship was observed with exposure to pesticides--insecticides and/or weed killers--and to electric and magnetic fields (EMF). The relationship with pesticides was significant when considering high or medium exposure to weed killers and more than 10 years exposure to both subtypes of pesticides. The relationship with pesticides and EMF remained significant when confounding factors were taken into consideration and after adjustment on co-exposure to benzene. The cytological studies showed that acute leukaemias following exposure to benzene (high or medium) and to EMF were only of myelogenous subtypes, whereas those following exposure to pesticides were divided between lymphoblastic and myeloblastic subtypes. Cytogenetic studies failed to show increased frequency of chromosomal abnormalities, as described in acute leukaemias secondary to anti-cancer treatments. Our study adds credence to the hypothesis that pesticides and EMF are leukaemogenic agents, together with benzene.

Depot-specific features of adipocyte progenitors revealed by primary cultures plated at low density.

Variation in growth across an animal's fat depots derives, at less in part, from inter-depot differences in pre-adipocytes. However, because of technical difficulties that have impeded the study of pre-adipocytes in primary culture, these differences are not well defined. Adipose tissue stromal cell fractions that contain pre-adipocytes grow readily in culture but invariably include cells plated at various stages of maturity. Consequently, crucial events in relatively immature cells are often obscured by activities of cells that are more mature. Therefore, one aim of the present study was to diminish the impact of cells plated near maturity by maximizing the density of immature cells. This was accomplished by the plating of stromal-vascular (SV) cell fractions at low density. Since immature pre-adipocytes proliferate much more rapidly than do mature pre-adipocytes, they become predominant. This approach made it possible for a variety of differences to be seen between cells from retroperitoneal (RP) and epididymal (Epi) tissues: Epi, but not RP, cells were seen to assemble in multi-layer clumps; multiplication was found to remain constant through at least one subculture in RP cells, but not in Epi cells; and, in a variety of ways, RP cells showed more differentiation than Epi cells. The reasons for these differences remain to be determined, but just the fact that they exist suggests that important dissimilarities among pre-adipocytes (including those responsible for nonuniform growth of fat depots) can be revealed and studied in primary cell culture.

Protection against fat cell hyperplasia in a hibernator, Glis glis.

Dormice, Glis glis, were fed a high-fat diet for 11 mo in one experiment: in another experiment they were fed a high-fat diet for 5 mo, either at room temperature (21.5 degrees C) or in a warm room (27 degrees C). Only in the latter group did adipocyte hyperplasia occur; this was significant in all the fat depots studied (inguinal, retroperitoneal, and gonadal). In the other groups there was no evidence of fat cell hyperplasia, despite weight gains from approximately 160 g (peaks on chow diet) to approximately 250 g (maximums on high-fat diet). Instead, fat cell size, assessed from biopsies of the inguinal area, became considerably enlarged. Taken together with earlier data from other species, the results suggest that hibernators are protected against fat cell hyperplasia. In dormice this protection appears to be present at all phases of their seasonal weight cycles. For species that experience several cycles of weight gain and loss in their lives, it may be adaptive to avoid increases in adipocyte number.

Resistance to adipocyte hyperplasia in ground squirrels given high-fat diets.

Mammalian hibernators prepare for the winter by depositing fat in existing fat cells. There is little, if any, production of new fat cells. This is curious because equivalent fat deposition in rats is associated with substantial fat cell production. To determine whether degree of weight gain, diet composition, or some special mechanism militating against adipocyte hyperplasia may underlie the absence of adipocyte hyperplasia in hibernators, male Richardson's ground squirrels, Spermophilus richardsonii, were fed a fattening high-fat diet for either 5 mo or 1 yr. The 5-mo high-fat feeding period caused peak body weights to increase 36% relative to the peak body weights seen in control animals fed ordinary chow. Despite this increase, there was no apparent increment in fat cell number in any of the major fat depots. Animals fed the diet for 1 yr reached body weights similar to those of the 5-mo group but showed significant adipocyte hyperplasia in all fat depots studied. Thus adult ground squirrels are clearly capable of enlarging their pool of mature fat cells, but they fail to do so, at least at certain times, in response to conditions of weight gain that cause considerable adipocyte hyperplasia in rats.

Dietary and species influence on potential of plasma to stimulate differentiation and lipid accumulation in cultured adipocyte precursors.

Sera and plasma from different species and from rats of various dietary statuses were compared with regard to effects on proliferation, glycerophosphate dehydrogenase (GPDH) activity, and lipid-filing of rat adipocyte precursors converting to adipocytes in primary cell culture. All of the tested sera and plasma samples were comparably supportive of cell multiplication, but their effects on elevation of GPDH activity (a key event in adipocyte differentiation) and lipid-filling varied greatly. Plasma supported a much greater increase in GPDH activity than serum, while serum from cats supported a much lower increase than serum from humans, calves, goats, or rats. Dietary status of rats did not affect the potential of plasma to support GPDH activity, but did affect plasma support of lipid-filing. A higher than normal degree of lipid-filling was promoted by plasma from rats fed a high-fat, high-sugar diet, while a lower than normal degree was promoted by plasma from fasted rats. Lipid-filling was also found to vary in response to changes in content of very low density lipoprotein (VLDL) in human plasma. This suggests that the influence of diet on the potential of plasma to promote adipocyte lipid-filling may be mediated by the effect of diet on plasma VLDL. The absence of a diet-dependent effect of plasma either on multiplication of adipocyte precursors or on degree of elevation of GPDH activity leaves unresolved the mechanism by which diet affects adipocyte production in animals.

Cycles of body fat in hibernators.

This paper reviews data on seasonal changes in body fat of mammalian hibernators. It then presents data on the fat cell number and size in the retroperitoneal and gonadal fat depots of dormice, Glis glis, over the course of their body weight cycles. Enlargement of fat cell size is the principal way that hibernators get fat. The hibernator cycle may provide a way of discovering whether regulation of fat level is achieved through regulation of total mass of fat or through regulation of the size of existing adipocytes.

Diet-dependent hyperplastic growth of adipose tissue in hypothalamic obese rats.

Accelerated production of fat cells is often seen in dietary obesity in rats but not in obesity occurring in response to damage to the medial area of the hypothalamus (MH). The basis for this difference was examined. MH damage (MHD) was produced in rats by either electric current or small knife cuts. Rats were then fed either chow or a high-fat high-sugar diet (HFS) for up to 6 mo. Fat cell production did not accelerate during the 1st 16 wk after MHD in rats fed only chow, but acceleration clearly occurred in rats fed HFS during only 4 wk. At 18 wk after MHD rats fed only chow showed evidence of accelerated fat cell production. However, there was greater acceleration after MHD in HFS-fed rats held to the same weight gain as chow-fed rats. Rats allowed to freely eat HFS for 6 mo after MHD showed extremely large increases in body weight and fat cell number. The plateau in body weight often seen in rats fed only chow after MHD did not occur. Because HFS-feeding promoted unimpeded production of fat cells, accelerated weight gain induced by MHD could continue indefinitely. These findings suggest that enlargement of fat cells and components of the diet act synergistically in the promotion of adipocyte hyperplasia in adult rats and also suggest that accelerated weight gain after MHD is not due to elevation of a set point for body weight or body fat.

Effects of castration on adipose tissue growth and regrowth in the male rat.

Adipose tissue has been found to regrow in the male rat following surgical removal (lipectomy) of inguinal subcutaneous depots, but the degree of regrowth has varied widely across experiments. It is possible that at least part of the disparity of previous findings occurred because of differences among the experiments in the testicular integrity of experimental animals. To address this possibility, the present study examined effects of castration on adipose tissue regrowth in rats treated either as weanlings or as young adults. Male Sprague-Dawley rats, at either 4 or 15 weeks of age, were subjected to one of four surgical procedures: bilateral lipectomy of the inguinal subcutaneous depots; castration; lipectomy and weight gain, but castrated rats achieved a higher ratio of adipose weight to body weight than noncastrated rats. In rats lipectomized but not castrated at 15 weeks of age, partial regeneration and a small increase in growth of noninguinal subcutaneous adipose tissue combined to produce substantial restoration of adipose mass. The same surgery in 4-week-old rats did not result in significant restoration because growth of noninguinal subcutaneous adipose tissue was reduced. In rats that were both castrated and lipectomized, regrowth of adipose tissue was substantial regardless of age at time of surgery. Thus, castration is seen to impede body weight gain while sparing ordinary growth of adipose tissue and facilitating regrowth of adipose tissue following lipectomy. Since adipose tissue regrowth varied with age only in noncastrated rats, it appears to be facilitated as well by testicular maturation.

Demonstration of de novo production of adipocytes in adult rats by biochemical and radioautographic techniques.

Adult rats of various strains show small increases in the number of adipocytes in the epididymal (Epi) fat pad and large increases in the retroperitoneal (RP) fat depot when they are fed a high-fat, high-sugar diet ( HFS ). In the present study, radioautographic techniques are used to demonstrate that these increases result from replication and differentiation of adipocyte precursors. In addition, both in vivo and in vitro biochemical techniques are used to demonstrate that HFS -induced acceleration of DNA synthesis differs between Epi and RP depots. Measures of levels of incorporation of radiolabeled thymidine into DNA in rats fed HFS for 4 weeks reveal significant elevation in the RP depot but not in the Epi pad. Analysis of radioautographs indicates that formation of precursors may be accelerated in the RP depot as early as the first week of HFS -feeding. Results obtained from the in vitro biochemical assay are of interest with regard to possible clinical application since current in vivo techniques for quantitative assessment of precursor synthesis cannot be applied directly to the study of adipose tissue growth in man. While data obtained from the in vitro assay contains a relatively high degree of variation, the information it provides is in general agreement with that provided by the in vivo assay.

Meal-taking behavior is related to predisposition to dietary obesity in the rat.

The hypothesis that early nutritional experience can determine endogenous patterns of meal-taking behavior and thereby affect predisposition to dietary obesity was tested by raising male Sprague-Dawley rats in litters of 4, 8, and 20, and examining their meal patterns and responsiveness to a high-fat, high-sugar (HFS) diet in adulthood. At 9 months of age, half the rats from each litter size group were given the HFS diet for 16 weeks, while the other half were continued on laboratory chow. As expected, HFS-fed rats gained more weight and developed larger fat depots and more and larger fat cells than did chow-fed controls. Analysis of meal-taking behavior just prior to the introduction of HFS-feeding allowed some of the rats to be classified as "gorgers" or "nibblers" according to their average daily meal size. While on lab chow, gorgers and nibblers showed no differences in body weight gain, but upon being switched to the HFS diet, gorgers gained significantly more weight than did nibblers, and showed a greater degree of fat depot enlargement. These findings suggest that patterns of meal-taking behavior can predict the magnitude of and may contribute to the development of dietary obesity.

Effects of severe long-term food deprivation and refeeding on adipose tissue cells in the rat.

To determine whether it is possible to use diet to cause a loss of adipocytes, adipose tissue cellularity was examined in adult male rats subjected to unusually prolonged semistarvation. After 1 wk of total fast, rats were given a nutritionally inadequate glucose-electrolyte diet for up to 7 wk. This caused a 49% reduction of body weight, up to a 99% reduction in the weight of adipose tissue, and significant losses of total adipose tissue DNA content. Nevertheless, there was no evidence that fat cells had been lost. The number of fat cells in the right epididymal depots of the food-deprived rats equaled both the number seen in left depots after refeeding and the number seen in corresponding depots of nonfasted controls. Adipose tissue DNA synthesis, which declined 88% below control values during fasting, did increase as much as 2,000% above control values during refeeding. However, autoradiographs showed that the increase reflects only the replacement of lost endothelial and nonadipocyte mesenchymal cells; no labeled fat cell nuclei were found. Thus, severe, long-term food deprivation followed by refeeding causes loss and recovery of stromal-vascular cells in adipose tissue but no loss of fat cells.

A virally induced obesity syndrome in mice.

An obesity syndrome was found in a number of mice infected as young adults with canine distemper virus, a morbillivirus antigenically related to measles. Body weights of obese animals 16 to 20 weeks after infection were comparable to those reported for genetically obese mice and for mice rendered obese by hypothalamic lesions. The total number of adipocytes in specific fat deposits was greater in obese animals than in their lean littermates. This hyperplasia was accompanied by moderate cell enlargement. Pancreatic islet tissue was also hypercellular in the obese mice. Brain tissue from the obese mice showed no overt pathology, and immunofluorescence staining for viral antigens was negative. There may be a selective, virus-induced disruption of critical brain catecholamine pathways.

Alterations in rat adipose tissue morphology induced by a low-temperature environment.

Rats raised in the cold showed an unusual pattern of adipose tissue morphology. Male Sprague-Dawley rats were maintained in a 5 degrees C environment for up to 24 wk and the cellularity of their major adipose depots was determined. Normal age-related increases in adipocyte number were absent in two major fat depots (retroperitoneal and inguinal), whereas there was a supranormal increase in a third (epididymal). This pattern of hyperplasia contrasts sharply with that seen in rats fed highly palatable high-fat or high-carbohydrate diets in which retroperitoneal depots show the most hyperplasia and epididymal pads the least. Such variations of response across depots suggest that the features of adipose tissue responsible for adipocyte proliferation in the various depots may not be homogeneous both in their nature and in their distribution.