S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)

Cutaneous lupus erythematosus (CLE) is a rare inflammatory autoimmune disease with heterogeneous clinical manifestations. To date, no therapeutic agents have been licensed specifically for patients with this disease entity, and topical and systemic drugs are mostly used ‘off‐label’. The aim of the present guideline was to achieve a broad consensus on treatment strategies for patients with CLE by a European subcommittee, guided by the European Dermatology Forum (EDF) and supported by the European Academy of Dermatology and Venereology (EADV). In total, 16 European participants were included in this project and agreed on all recommendations. Topical corticosteroids remain the mainstay of treatment for localized CLE, and further topical agents, such as calcineurin inhibitors, are listed as alternative first‐line or second‐line topical therapeutic option. Antimalarials are recommended as first‐line and long‐term systemic treatment in all CLE patients with severe and/or widespread skin lesions, particularly in patients with a high risk of scarring and/or the development of systemic disease. In addition to antimalarials, systemic corticosteroids are recommended as first‐line treatment in highly active and/or severe CLE. Second‐ and third‐line systemic treatments include methotrexate, retinoids, dapsone and mycophenolate mofetil or mycophenolate acid, respectively. Thalidomide should only be used in selected therapy‐refractory CLE patients, preferably in addition to antimalarials. Several new therapeutic options, such as B‐cell‐ or interferon α‐targeted agents, need to be further evaluated in clinical trials to assess their efficacy and safety in the treatment of patients with CLE.     

Multicenter Analysis of Clinicopathologic Features of Intraductal Papillary Mucinous Tumor of the Pancreas: Is It Possible to Predict the Malignancy Before Surgery?

Background Despite recently increasing numbers of reports on intraductal papillary mucinous tumors (IPMTs), difficulties still remain in terms of diagnosis, treatment, and prognosis. The purpose of this multicenter study was to evaluate the clinicopathologic features of IPMT in Korea and to suggest predictive criteria for malignancy in IPMT.Methods We retrospectively reviewed the clinicopathologic data of 208 patients who underwent operations for IPMT between 1993 and 2002 at 28 institutes in Korea.Results Of the 208 patients (mean age, 61 years), 147 were men and 61 were women. A total of 124 patients underwent pancreatoduodenectomy, 42 underwent distal pancreatectomy, 17 underwent total pancreatectomy, and 25 underwent limited pancreatic resection. There were 128 benign cases (adenoma, n = 62; borderline, n = 66) and 80 malignant cases (noninvasive, n = 29; invasive, n = 51). A significant difference in 5-year survival was observed between the benign and malignant groups (92.6% vs. 65.3%; P = .006). Of the six factors (age, location, duct dilatation, mural nodule, main duct type, and tumor size) that showed statistical differences by univariate analysis between the benign and malignant groups, three were significant by multivariate analysis—namely, mural nodule (P = .009), tumor size (P = .023), and a dilated duct size (P = .010).Conclusions A significant proportion of IPMTs are malignant, although the overall prognosis of IPMT is superior to that of ordinary pancreatic cancer. Radical surgery is recommended for IPMT with the predictors of malignancy: mural nodule, tumor size (30 mm), and dilated duct size (12 mm).     

Recurrence of hepatitis B is associated with cumulative corticosteroid dose and chemotherapy against hepatocellular carcinoma recurrence after liver transplantation.

The incidence of hepatitis B (HB) recurrence after a liver transplantation has been reduced by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine. However, the long-term incidence of recurrence is <10%, and the factors associated with HB recurrence are unclear. This study analyzed the factors associated with HB recurrence in 203 recipients who underwent liver transplantation for HB in 3 major centers in Korea over 4 years. Eighty-five patients (41.9%) had a hepatocellular carcinoma (HCC). Preoperative active virus replicators with the HBeAg(+) (46.8%) and/or hepatitis B virus DNA(+) (39.4%) were observed in 136 patients (67.0%). The HB prophylaxis consisted of either HBIG monotherapy (n = 95, HBIG group) or combination therapy with lamivudine (n = 108, combination group). HB recurrence was defined as the appearance of the HBsAg. The follow-up period was 28.3 +/- 13.1 months (mean +/- SD). HB recurred in 21 patients (10.3%) after transplantation. The time from transplantation to recurrence was 16.3 +/- 9.4 months. Pre-LT DNA positivity was more prevalent in HBIG group (55.8%) than in the combination group (39.8%) (P = 0.015). However, the incidence of HB recurrence was similar in the HBIG (6.3%) and combination group (13.8%), as well as between the active replicators (12.5%) and nonreplicators (4.1%) (P < 0.05). There was a far higher incidence of HB recurrence in patients receiving corticosteroid pulse therapy (21.0% vs. 7.9%), patients who experienced HCC recurrence (31.3% vs. 8.6%), and patients receiving chemotherapy to prevent HCC recurrence (25.0% vs. 4.4%) (P < 0.05). The cumulative corticosteroid dose was higher in patients who experienced recurrence of HB (P = 0.002). Multivariable analysis confirmed the effect of the cumulative corticosteroid dose and chemotherapy to be risk factors. Liver transplantation for HB is safe, with low recurrence rates if adequate prophylaxis is used. However, the cumulative corticosteroid dose and the chemotherapy used for HCC were risk factors for HB recurrence, so careful monitoring for HB recurrence is needed in these patients.     

The importance of hydrology in routing terrestrial carbon to the atmosphere via global streams and rivers

The magnitude of stream and river carbon dioxide (CO₂) emission is affected by seasonal changes in watershed biogeochemistry and hydrology. Global estimates of this flux are, however, uncertain, relying on calculated values for CO₂ and lacking spatial accuracy or seasonal variations critical for understanding macroecosystem controls of the flux. Here, we compiled 5,910 direct measurements of fluvial CO₂ partial pressure and modeled them against watershed properties to resolve reach-scale monthly variations of the flux. The direct measurements were then combined with seasonally resolved gas transfer velocity and river surface area estimates from a recent global hydrography dataset to constrain the flux at the monthly scale. Globally, fluvial CO₂ emission varies between 112 and 209 Tg of carbon per month. The monthly flux varies much more in Arctic and northern temperate rivers than in tropical and southern temperate rivers (coefficient of variation: 46 to 95 vs. 6 to 12%). Annual fluvial CO₂ emission to terrestrial gross primary production (GPP) ratio is highly variable across regions, ranging from negligible (<0.2%) to 18%. Nonlinear regressions suggest a saturating increase in GPP and a nonsaturating, steeper increase in fluvial CO₂ emission with discharge across regions, which leads to higher percentages of GPP being shunted into rivers for evasion in wetter regions. This highlights the importance of hydrology, in particular water throughput, in routing terrestrial carbon to the atmosphere via the global drainage networks. Our results suggest the need to account for the differential hydrological responses of terrestrial–atmospheric vs. fluvial–atmospheric carbon exchanges in plumbing the terrestrial carbon budget.

The Earth’s water, carbon, and energy fluxes follow seasonal variations in the Earth’s solar radiation and climate variability (1, 2). As an integral part of terrestrial landscapes, streams and rivers receive significant water and carbon inputs from terrestrial and wetland ecosystems, which are further processed along the river to ocean continuum (3). As the largest carbon flux mediated by fluvial systems, carbon dioxide (CO₂) emission from stream and river surfaces (4–7) is double the lateral carbon transport to oceans (8), yet its spatial and temporal variations are not fully resolved. Stream and river CO₂ evasion changes considerably across space and time due to biogeochemical responses to climatic factors (3), the physics governing the transfer of gas across the water–air interface (9), and seasonal variations in the spatial extent of drainage networks (10, 11). However, seasonal variability of the flux has not been determined at the global scale, limiting our ability to understand controls at the macrosystem level.The rate at which streams and rivers exchange CO₂ with the atmosphere is determined by three factors: dissolved CO₂ concentration (often expressed as an equivalent atmospheric partial pressure [pCO₂]), water surface gas transfer velocity (k), and water surface area. To estimate flux at the monthly scale, all three factors need to be resolved at the same or finer temporal scale(s). To date, existing spatially explicit estimates of riverine CO₂ emission at the global scale (4, 12) relied exclusively on pCO₂ calculated from carbonate equilibria and historical archives of pH and alkalinity measurements. While these data have reasonable spatial coverage, the carbonate equilibria method is subject to inflated pCO₂ estimates due to biased pH measurements (13) and alkalinity contribution from organic acids (14), particularly in low–ionic strength waters. These errors, although reducible within individual datasets (15), are difficult to correct for when scaling globally. This problem has significantly undermined calculations and understanding of the flux at the global scale. More importantly, although global estimates of the stream and river surface area and gas transfer velocity at mean annual discharge have been achieved (4, 16), their seasonal extent, a major driver of within-year variability of riverine CO₂ flux, has not. This is largely because a temporally resolved reach-scale representation of global river hydrology has not been available until recently (17), and new understandings of aquatic surface area extent and water–air gas transfer rates are necessary to incorporate temporal variability into the riverine CO₂ flux estimate.We compiled a dataset of present-day direct pCO₂ measurements in global streams and rivers from the literature. The dataset has 5,910 individual measurements of different months that cover all major freshwater ecoregions of the world (18), despite a small percentage (∼0.5%) of measurements from southern temperate rivers (SI Appendix, Fig. S1). The dataset further has pCO₂ measurements in all months from each freshwater ecoregion (open water months for the polar freshwater ecoregion) except oceanic islands and large river deltas that make up only 0.4% of the global land area (SI Appendix, Fig. S1). These observations allowed for robust validation of the study’s results. Riverine pCO₂ was statistically modeled against a set of watershed properties (SI Appendix, Table S1) in order to understand biogeochemical and geophysical controls on pCO₂. Predictions of pCO₂, k, and surface area were based on a new representation of the global river networks (the Global Reach-Level A Priori Discharge Estimates for Surface Water and Ocean Topography [GRADES] river networks) (17), which contains daily discharge estimates at ∼3 million individual river reaches over a 35-y period. Monthly CO₂ flux estimates were achieved by coupling monthly pCO₂ estimates driven by monthly watershed properties to monthly k and surface area estimates driven by the GRADES discharge. Spatial and temporal variability of the flux was finally investigated to demonstrate a strong modulation of the terrestrial (and wetland) carbon routing to the atmosphere via streams and rivers by hydrology.     

Antihypertensive effects of L-tryptophan are not mediated by brain serotonin

L-Tryptophan produces a significant antihypertensive effect in spontaneously hypertensive rats while D-tryptophan does not change blood pressure. Both isomers of tryptophan significantly increase brain serotonin to the same extent at a time when the antihypertensive effect of L-tryptophan is maximal. Thus, the antihypertensive effects of L-tryptophan do not appear to be mediated by brain serotonin.     

The sarcomeric Z-disc: a nodal point in signalling and disease

The perception of the Z-disc in striated muscle has undergone significant changes in the past decade. Traditionally, the Z-disc has been viewed as a passive constituent of the sarcomere, which is important only for the cross-linking of thin filaments and transmission of force generated by the myofilaments. The recent discovery of multiple novel molecular components, however, has shed light on an emerging role for the Z-disc in signal transduction in both cardiac and skeletal muscles. Strikingly, mutations in several Z-disc proteins have been shown to cause cardiomyopathies and/or muscular dystrophies. In addition, the elusive cardiac stretch receptor appears to localize to the Z-disc. Various signalling molecules have been shown to interact with Z-disc proteins, several of which shuttle between the Z-disc and other cellular compartments such as the nucleus, underlining the dynamic nature of Z-disc-dependent signalling. In this review, we provide a systematic view on the currently known Z-disc components and the functional significance of the Z-disc as an interface between biomechanical sensing and signalling in cardiac and skeletal muscle functions and diseases.     

Construction and characterization of Listeria monocytogenes mutants with in-frame deletions in the response regulator genes identified in the genome sequence

Two-component systems are widely distributed in prokaryotes where they control gene expression in response to diverse stimuli. To study the role of the sixteen putative two-component systems of Listeria monocytogenes systematically, in frame deletions were introduced into 15 out of the 16 response regulator genes and the resulting mutants were characterized. With one exception the deletion of the individual response regulator genes has only minor effects on in vitro and in vivo growth of the bacteria. The mutant carrying a deletion in the ortholog of the Bacillus subtilis response regulator gene degU showed a clearly reduced virulence in mice, indicating that DegU is involved in the regulation of virulence-associated genes.     

Deletion of the gene encoding p60 in Listeria monocytogenes leads to abnormal cell division and loss of actin-based motility

Protein p60 encoded by the iap gene is regarded as an essential gene product of Listeria monocytogenes. Here we report, however, the successful construction of a viable iap deletion mutant of L. monocytogenes EGD. The mutant, which produces no p60, shows abnormal septum formation and tends to form short filaments and hooked forms during logarithmic growth. These abnormal bacterial cells break into almost normal sized single bacteria in the late-stationary-growth phase. The iap mutant is strongly attenuated in a mouse model after intravenous injection, demonstrating the importance of p60 during infection, and the invasiveness of the Deltaiap mutant for 3T6 fibroblasts and Caco-2 epithelial cells is slightly reduced. Upon uptake by epithelial cells and macrophages, the iap mutant escapes from the phagosome into the cytosol with the same efficiency as the wild-type strain, and the mutant bacteria also grow intracellularly at a rate similar to that of the wild-type strain. Intracellular movement and cell-to-cell spread are drastically reduced in various cell lines, since the iap-negative bacteria fail to induce the formation of actin tails. However, the bacteria are covered with actin filaments. Most intracellular bacteria show a nonpolar and uneven distribution of ActA around the cell, in contrast to that for the wild-type strain, where ActA is concentrated at the old pole. In an iap(+) revertant strain that produces wild-type levels of p60, intracellular movement, cell-to-cell spread, and polar distribution of ActA are fully restored. In vitro analysis of ActA distribution on the filaments of the Deltaiap strain shows that the loss of bacterial septum formation leads to ActA accumulation at the presumed division sites. In the light of data presented here and elswhere, we propose to rename iap (invasion-associated protein) cwhA (cell wall hydrolase A).     

A natural musaceas plant extract inhibits proteasome activity and induces apoptosis selectively in human tumor and transformed, but not normal and non-transformed, cells

Animal studies have demonstrated that a dietary polyphenol known as tannic acid (TA) exhibits anticarcinogenic activity in chemically induced cancers. Most recently, we have reported that TA and ester-bond containing green tea polyphenols are potent proteasome inhibitors in vitro and in vivo. We hypothesize that CellQuest, a patented formula which contains high level of TA obtained from a musaceas (plantain) plant extract, will inhibit the tumor cell proteasome activity. Here, we report that a partially purified CellQuest fraction, S3, potently inhibits the proteasomal chymotrypsin-like activity of Jurkat T cell extracts in a concentration-dependent manner. Inhibition of the proteasome by S3 in leukemia Jurkat T, simian virus 40-transformed and prostate cancer LNCaP cells results in accumulation of ubiquitinated proteins and the natural proteasome substrate p27Kip1, followed by induction of apoptosis. In contrast, non-transformed, immortalized human natural killer cells and normal human fibroblasts are resistant to S3-mediated proteasome inhibition and apoptosis induction. Our present study suggests that CellQuest targets and inhibits the proteasome selectively in tumor cells, which may contribute to the claimed anticancer activity.     

Adverse drug reaction monitoring in Jena: Relevance of polymorphic drug metabolizing enzymes for inducing adverse drug reactions

Inter-subject variability in therapeutic drug response and drug toxicity is a major problem in clinical practice. In this field genetic polymorphisms of drug metabolizing enzymes play an important role. In a multicenter study supported by the German Federal Institute for Drugs and Medical Devices (BfArM, Z 12.01-68502-201) adverse drug reactions (ADRs) leading to hospital admission to departments of internal medicine have been registered and evaluated. The aim of the presented part of the study was to look for evident differences in genotypes for polymorphic drug metabolizing enzymes between adverse drug reaction cases and controls. All cases found in the local area – Jena and Weimar – were genotyped for N-acetyl-transferase 2 (NAT2), cytochrom P450 (CYP) 2D6 and 2C19 in comparison to a control population of the same region. The investigation on genotype was carried out for about 2 years (2000–2002). 254 blood samples from patients of the ADR study were analyzed. The genotype of drug metabolizing enzymes was determined by means of polymerase chain reaction using allel specific primers or restriction enzyme analysis. Within all ADRs cases genotyped, no exceptional frequencies for slow acetylators or poor metabolizers (PM) of CYP2D6 or CYP2C19 were found. About 65% of the individuals with ADR genotypically displayed a slow acetylator state. 6.3% PM for CYP2D6, including CYP2D6*3, *4 and *6 alleles, and 2.0% PM frequency for CYP2C19 (*2) have been found in ADR cases. A direct connection between PM genotype and the ADR observed may be assumed only in few of them. Further investigations on genotype and ADR-associated drugs require a much larger sample of patients to obtain more data allowing to focus an association on specific drugs, ADR and polymorphisms genotype of drug metabolizing enzymes might be useful.