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Pregenomic hepatitis B virus RNA (HBV pgRNA) is a potential biomarker in the management of HBV infected patients. However, prior to the use in routine clinical practice potential confounders of test results need to be identified. This study investigates the stability of HBV pgRNA under various storage conditions. HBV-RNA level of 26 HBV patients were determined using the Roche cobas® 6800/8800 investigational HBV-RNA assay. Plasma and serum were stored for 6,48,169 h at 4,25 and 42 °C, respectively. Additionally, 10 serum and plasma samples underwent 4 or 11 cycles of freezing (-80 °C) and thawing (25 °C). A significant decline in mean pgRNA concentration compared to baseline was observed after storage for 48 h at 25 °C as well as after 6 h of storage at 42 °C. Accordingly, sub-analyses of predefined pgRNA baseline concentrations (≤ 10 cp/mL, > 10-100 cp/ml, > 100 cp/mL) revealed significant changes in pgRNA level after storage at 25 and 42 °C. No effect of freezing and thawing on pgRNA level was observed. A qualitative detection of HBV pgRNA is feasible in samples with > 100 cp/mL up to 48 h under storage temperatures of 4-42 °C. For most stable quantitative HBV pgRNA values storage at 4 °C should be preferred., (© 2024. The Author(s).)

T cells are the key players of the adaptive immune response. They coordinate the activation of other immune cells and kill malignant and virus-infected cells. For full activation T cells require at least two signals. Signal 1 is induced after recognition of MHC/peptide complexes presented on antigen presenting cells (APCs) by the clonotypic TCR (T-cell receptor)/CD3 complex whereas Signal 2 is mediated via the co-stimulatory receptor CD28, which binds to CD80/CD86 molecules that are present on APCs. These signaling events control the activation, proliferation and differentiation of T cells. In addition, triggering of the TCR/CD3 complex induces the activation of the integrin LFA-1 (leukocyte function associated antigen 1) leading to increased ligand binding (affinity regulation) and LFA-1 clustering (avidity regulation). This process is termed "inside-out signaling". Subsequently, ligand bound LFA-1 transmits a signal into the T cells ("outside-in signaling") which enhances T-cell interaction with APCs (adhesion), T-cell activation and T-cell proliferation. After triggering of signal transducing receptors, adapter proteins organize the proper processing of membrane proximal and intracellular signals as well as the activation of downstream effector molecules. Adapter proteins are molecules that lack enzymatic or transcriptional activity and are composed of protein-protein and protein-lipid interacting domains/motifs. They organize and assemble macromolecular complexes (signalosomes) in space and time. Here, we review recent findings regarding three cytosolic adapter proteins, ADAP (Adhesion and Degranulation-promoting Adapter Protein), SKAP1 and SKAP2 (Src Kinase Associated Protein 1 and 2) with respect to their role in TCR/CD3-mediated activation, proliferation and integrin regulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dadwal, Mix, Reinhold, Witte, Freund, Schraven and Kliche.)

Background: Evidence shows that having a bowel management program prevents rehospitalization postacute rehabilitation discharge for persons with a spinal cord injury (SCI). Peer mentors have been used to assist patients in managing their care., Purpose: The aim of the study was to illustrate how interprofessional collaboration led to utilizing resources of the inpatient rehabilitation facility's peer mentor program and incorporating peer mentors into bowel education for persons with SCI., Methods: A descriptive case review of a continuous quality improvement (CQI) project, using an eight-item Likert scale evaluation survey with three open-ended questions to assess the utility of incorporating peer mentors into bowel education., Findings and Conclusions: Twenty-seven of the 28 participants responded to the survey. Results showed that the education program was useful, should be continued, and include the peer mentors. Responses from open-ended questions included themes related to knowledge, adherence, and taking charge of one's own care. Interprofessional collaboration and involvement of peer mentors as copresenters in SCI bowel education were feasible.

The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.

Background: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA)., Methods: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated., Results: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment., Conclusions: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.

Background and aim  The advent of direct-acting antivirals has revolutionized treatment of chronic hepatitis C with very high cure rates and excellent tolerability compared to interferon-based hepatitis C virus (HCV) treatment. However, long-term effects of interferon-free cure of HCV infection on the metabolic condition of patients have not been investigated so far. Methods  We investigated weight development during and after antiviral treatment of hepatitis C. In a prospective single-center cohort study, interferon-free antiviral treatment was initiated in 284 patients. Each patient's weight was monitored 1 year before the start of treatment, at baseline (BL), end of treatment (EOT), follow-up week 24 (FU24), and follow-up week 48 (FU48). Results  Weight gain after HCV cure was observed in 20 %, 33 %, and 44 % of patients at EOT, FU24, and FU48, respectively. The mean overall weight change at FU48 compared to baseline was 1.45 kg (95 % CI 0.44; 2.46, p = 0.02, compared to the pretreatment period). Multivariate regression revealed age as the only factor predicting weight change at FU48 (B - 0.107, 95 % CI, - 0.202 to - 0.011, p = 0.03), while gender, cirrhosis, diabetes mellitus, ribavirin, and body mass index had no influence. In the subgroup of patients younger than 60 years, mean weight gain at FU48 compared to baseline was 2.8 kg (95 % CI, 1.23 - 4.4). In contrast, patients 60 years and older had a mean weight change of - 0.04 kg (95 % CI, - 1.12 to 1.03, p = 0.005). Conclusions  Cure of HCV by interferon-free antiviral treatment was associated with weight gain in up to 44 % of patients during long-term follow-up. Weight gain occurred predominantly in patients younger than 60 years. The precise mechanism of weight gain remains to be elucidated., Competing Interests: Conflict of interest: BS received travel grants from Abbvie, MSD, Shionogi and Gilead. CHZS received a travel grand from Gilead and speaker fees from Gilead, MSD and Roche. MPM received consulting fees from Roche, BMS, Gilead, Boehringer Ingelheim, Novartis Tibotec, Vertex, GSK, MSD, grant/research support from Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Merck/MSD and lecture fees from Merck/MSD, Roche, BMS, Gilead. MC received research support from Merck, Roche, Gilead and speaking and/or consulting fees from Abbvie, BMS, Gilead, Merck, Novartis, Roche. HW received research support from Roche, BMS, Novartis, Abbott and speaking and/or consulting fees from Abbvie, Abbott, Achillon, BMS, Boehringer, Gilead, GSK, Merck, Novartis, Roche, Siemens, Transgene. All remaining authors declare that they have no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

This prospective study investigated viral and host markers after stopping long-term therapy with nucleos(t)ide analogues in noncirrhotic patients with hepatitis B e antigen-negative chronic hepatitis B. After stopping therapy, 13 of 15 patients experienced a virological relapse. Rebound of hepatitis B virus DNA and hepatitis B core-related antigen was associated with induction of plasma tumor necrosis factor, interleukin (IL) 10 , IL-12p70, CXCL10 and subsequent decline in hepatitis B surface antigen (HBsAg), with 20% HBsAg loss after long-term follow-up. The peak levels of hepatitis B virus DNA and hepatitis B core-related antigen after cessation of therapy were positively correlated with the level of HBsAg decline at week 48. Thus, stopping or interrupting NA treatment should be further investigated as a strategy to accelerate HBsAg loss., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Exceptional aging, defined as reaching age 85 years, shows geographic inequalities that may depend on local environmental conditions. Links between particulate pollution-a well-recognized environmental risk factor-and exceptional aging have not been investigated., Objectives: We conducted a nationwide analysis of ~28 million adults in 3,034 United States counties to determine whether local PM2.5 levels (particulate matter < 2.5 μm in aerodynamic diameter) affected the probability of becoming 85- to 94-year-olds or centenarians (100- to 104-year-olds) in 2010 for individuals who were 55-64 or 70-74 years old, respectively, in 1980., Methods: We used population-weighted regression models including county-level PM2.5 from hybrid land-use regression and geostatistical interpolation, smoking, obesity, sociodemographic, and age-specific migration variables., Results: On average, 2,295 and 71.4 per 10,000 of the 55- to 64- and 70- to 74-year-olds in 1980, respectively, remained in the 85- to 94- and 100- to 104-year-old population in 2010. An interquartile range (4.19 μg/m3) increase in PM2.5 was associated with 93.7 fewer 85- to 94-year-olds (p < 0.001) and 3.5 fewer centenarians (p < 0.05). These associations were nearly linear, were stable to model specification, and were detectable below the annual PM2.5 national standard. Exceptional aging was strongly associated with smoking, with an interquartile range (4.77%) increase in population who smoked associated with 181.9 fewer 85- to 94-year-olds (p < 0.001) and 6.4 fewer centenarians (p < 0.001). Exceptional aging was also associated with obesity rates and median income., Conclusions: Communities with the most exceptional aging have low ambient air pollution and low rates of smoking, poverty, and obesity. Improvements in these determinants may contribute to increasing exceptional aging. Citation: Baccarelli AA, Hales N, Burnett RT, Jerrett M, Mix C, Dockery DW, Pope CA III. 2016. Particulate air pollution, exceptional aging, and rates of centenarians: a nationwide analysis of the United States, 1980-2010. Environ Health Perspect 124:1744-1750; http://dx.doi.org/10.1289/EHP197., Competing Interests: The authors declare they have no actual or potential competing financial interests.

Objective: To analyze associations of short-term exposure to fine particulate matter (diameter ≤ 2.5 µm [PM2.5]), a measurable component of urban pollution, with the event date of fever onset for patients with Kawasaki disease (KD) residing in 7 metropolitan regions., Study Design: A case-crossover study design was used. Time trends, seasonality, month, and weekday were controlled for by matching. We assembled PM2.5 exposure measurements from urban monitors and imputed PM2.5 to provide day-to-day temporal variability and resolution for time series indexes of exposures. Selected exposure windows (to 14 days) of PM2.5 were examined., Results: A total of 3009 KD events were included for which the subject resided within a study metropolitan area and the event date occurred during years with available PM2.5. The estimated ORs (with 95% CIs) of an event of KD associated with a 10 µg/m(3) PM2.5 lagged moving average concentration of lagged exposure period (ie, concurrent, preceding day[s]) revealed no evidence of a consistent, statistically significant, positive association between elevated PM2.5 exposure and increased risk of KD. Extended analysis with stratification by city, sex, age, ethnic origin, incomplete or complete clinical manifestations, the presence of coronary aneurysm, and intravenous immunoglobulin resistance did not provide evidence of a consistent, statistically significant, positive association between elevated exposure to PM2.5 and increased risk of KD for any of the strata studied., Conclusions: This multicity study failed to establish a risk of the event of KD with short-term fine particulate exposure. Our negative findings add to the growing field of environmental epidemiology research of KD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Fine particulate matter (PM2.5) is a measurable component of ambient pollution, and positive associations of short-term PM2.5 exposure with the clinical presentation of systemic onset juvenile idiopathic arthritis (SJIA) in young children have been described in a regional cohort. Our objective was to further establish associations between short-term pollution exposures and the reported clinical event of SJIA onset in cases residing from multiple metropolitan regions., Methods: A case-crossover study design was used to analyse associations of short-term PM2.5 exposures with the event of SJIA symptom onset from cases residing in five metropolitan regions. Time trends, seasonality, month, and weekday were controlled for by matching. Selected exposure windows (to 14 days) of PM2.5 were examined., Results: Positive, statistically significant associations between PM2.5 concentrations and elevated risk of SJIA were not observed. The most positive associations of short-term PM2.5 exposure with SJIA were in children <5.5 years (RR 1.75, 95% CI 0.85-3.62). An ad hoc extended pooled analysis including previously reported cases from Utah's metropolitan areas identified an increased risk of SJIA for children <5.5 years (RR = 1.76, 95% CI 1.07-2.89 per 10 μg/m3 increase in 3-day lagged moving average PM2.5)., Conclusions: In this multi-city, multi-period study small, statistically insignificant PM2.5-SJIA associations are observed. However, as found in prior study, the PM2.5-SJIA association is most suggestive in preschool aged children. Larger numbers of SJIA cases spatially located in geographic areas which experience a greater day to day ambient particulate burden may be required by the analysis to demonstrate effects.

Magnons are the elementary excitations of a magnetically ordered system. In ferromagnets, only a single band of low-energy magnons needs to be considered, but in ferrimagnets the situation is more complex owing to different magnetic sublattices involved. In this case, low lying optical modes exist that can affect the dynamical response. Here we show that the spin Seebeck effect (SSE) is sensitive to the complexities of the magnon spectrum. The SSE is caused by thermally excited spin dynamics that are converted to a voltage by the inverse spin Hall effect at the interface to a heavy metal contact. By investigating the temperature dependence of the SSE in the ferrimagnet gadolinium iron garnet, with a magnetic compensation point near room temperature, we demonstrate that higher-energy exchange magnons play a key role in the SSE.

Background: Successful antiviral treatment of decompensated hepatitis B with HBV polymerase inhibitors is associated with improvement of liver function. To what extent liver function also improves in cirrhotic patients with chronic hepatitis C receiving novel interferon-free (IFN-free) therapies is unknown., Aim: To study liver function in cirrhotic HCV patients receiving IFN-free therapies., Methods: We here studied 80 consecutive patients with advanced HCV associated liver cirrhosis including 34 patients (43%) with Child B/C cirrhosis and 42 patients (53%) with platelet counts of <90.000/μL receiving different combinations of direct acting antivirals without interferon [sofosbuvir/ribavirin (n = 56), sofosbuvir/simeprevir ± ribavirin (n = 15) and sofosbuvir/daclatasvir ± ribavirin (n = 9)]. The majority of patients was infected with HCV genotype 1 (n = 50); HCV genotypes 2, 3 and 4 were present in 4, 24 and 2 patients, respectively., Results: Liver function parameters including albumin, bilirubin, cholinesterase and prothrombin time all improved in the majority of patients during antiviral therapy irrespectively of the underlying HCV genotype, however, with different kinetics. MELD scores improved until post-treatment week 12 in 44% of the patients but worsened in 15%. A sustained virological response was achieved in 63% of the patients. HCV RNA relapse led to moderate ALT increases in 15/23 patients but was not associated with hepatic decompensations., Conclusion: This real-world single centre study showed that interferon-free treatment of hepatitis C patients with advanced liver cirrhosis restores liver function, and may thereby reduce the need for liver transplantations., (© 2015 John Wiley & Sons Ltd.)

Background & Aims: Several real world data demonstrated that eligibility for and tolerability of triple therapy against hepatitis C virus (HCV) infection with a first-wave protease inhibitor is limited. With the approval of sofosbuvir (SOF) effective treatment with and without pegylated interferon (PEG-IFN) has become available for most genotypes. However, no data are available regarding the added benefit of an interferon-free treatment concerning eligibility and tolerability in a real-world scenario. We aimed to assess the eligibility and safety of SOF based therapies in patients with primarily advanced cirrhosis, including decompensated cirrhosis, in a real-world setting., Results: In total, 207 patients were evaluated for a SOF based treatment with and without PEG-IFN. Twenty-six patients did not receive treatment because of safety reasons. Common causes were severe concomitant cardiac disease and advanced renal disease. Autoimmune disease, thrombopaenia, anaemia or hepatic dysfunction did not preclude treatment. Eighty-four patients started treatment, 15 with decompensated cirrhosis. During the first 12 weeks hospitalization occurred in 11 patients most frequently because of typical complications of advanced liver disease. Risk factors for hospitalization were low platelet count and deteriorated liver function. Overall, 982 of 1008 planned treatment weeks (97%) were successfully completed within the first 12 weeks of therapy., Conclusion: With the better safety profile of interferon-free therapies, eligibility for HCV treatment will expand broadly, including patients with decompensated cirrhosis. Current limitations are renal failure and concomitant cardiac disease. Patients with advanced cirrhosis still have a high risk for hospitalization even with interferon-free therapies, but can continue HCV treatment in most cases., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: HCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center., Methods: All consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12., Results: 208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12., Conclusions: P/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.

Background & Objectives: Chronic kidney disease (CKD) is commonly complicated by secondary hyperparathyroidism (SHPT), leading to increased risk of morbidity and mortality. SHPT is a progressive disease often requiring long-term therapy to control parathyroid hormone (PTH) and mineral imbalances. Vitamin D sterols and phosphate binders, used as traditional therapies to lower PTH and phosphorus, may provide inadequate long-term control for many dialysis patients. Cinacalcet, by simultaneously lowering PTH, calcium, phosphorus, and calcium-phosphorus levels, may maintain PTH and mineral balance in these individuals. However, as with traditional therapies, long-term data are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENT: Dialysis subjects from at least one of five lead-in studies (double-blind placebo-controlled, including one extension trial) completing up to 52 wk of either cinacalcet or placebo were eligible for this open-label extension study, including an 8-wk dose titration (initiated at 30 mg/d), followed by 24-wk maintenance and up to 132 wk of follow-up. Final efficacy analysis was at week 180., Results: Three hundred thirty-four of 589 enrolled subjects received cinacalcet from the beginning of the lead-in study. Weekly median PTH values were < or =300 pg/ml (weeks 16 through 180) and median CaxP values were < or =55 mg(2)/dl(2) (weeks 4 through 180). Similar results were exhibited in the 255 subjects who initially received placebo. Among the patients exposed to cinacalcet from the beginning of the lead-in study, 3% of subjects exhibited treatment-related serious adverse events., Conclusions: Cinacalcet effectively maintained PTH, Ca and P reductions in dialysis subjects for up to 180 wk.

Approximately 40 samples of animal feces, drinking water, feed, bedding, pine wood shavings, compost, and manure slurry were collected from two animal research farms (one dairy and one poultry) and analyzed for ceftriaxone-resistant bacteria. Our study revealed that the total percentage of aerobic bacteria with reduced susceptibility to ceftriaxone (minimal inhibitory concentration (MIC) > or = 16 micro g/mL) ranged from 0.9% to 10.8% in dairy feces and from 0.05% to 3.93% in chicken feces. The percentages of ceftriaxone-resistant bacteria (MIC > or = 64 micro g/mL) were in the range of 0.01% - 2.3% in dairy feces and 0.01% - 0.79% in chicken feces. Environmental samples contained a wide range of ceftriaxone-resistant bacterial populations. Among those environmental samples, fresh pine wood shavings used as chicken bedding contained the highest percentages (41.5%) of ceftriaxone-resistant bacteria, as determined by a plating method. A total of 105 ceftriaxone-resistant (MIC > or = 128 micro g/mL) bacterial isolates were isolated from the above samples and tested for resistance to nine antibiotics: ampicillin, ceftriaxone, streptomycin, kanamycin, gentamicin, chloramphenicol, tetracycline, ciprofloxacin, and nalidixic acid. The most prevalent resistance pattern (34.3%) among isolates included resistance to all nine antibiotics. Results from this study suggest that ceftriaxone-resistant bacteria exist in farm environments, and the ceftriaxone resistance was frequently associated with resistance to multiple antibiotics. Environmental sources such as pine wood shavings used as bedding can be a potential reservoir for transmitting the multidrug-resistant bacteria.

Using microsatellites, we investigated population structure and gene flow of the short-lived, wind-dispersed plant species Hypochaeris radicata in a fragmented agricultural landscape where more than 99% of the nutrient-poor grasslands have disappeared over the last century. We sampled populations in the few remaining high density populations in conservation areas, as well as individuals that occurred, with lower densities, in linear landscape elements, at two spatial scales. In a re-inventory of the landscape, after 3 years, both extinctions and colonizations of populations were observed. Contrary to expectations, no differences in genetic diversity between high and low density populations were observed. Both types of populations had relatively high levels of diversity. Overall genetic differentiation (theta) was 0.04 and significantly different from zero (P < 0.01). A significant isolation-by-distance pattern was found when all populations were simultaneously analysed (r = 0.24, P = 0.013). Isolation by distance was (marginally) significant at the small scale (r = 0.32, P = 0.06), whereas nonsignificant at the large spatial scale (r = -0.05, P = 0.66). A maximization-of-explained-variance procedure resulted in a threshold distance of 3.5 km above which populations were effectively genetically isolated. An additional partial exclusion Bayesian-based assignment test showed that overall 32.3% of the individuals were assigned to their population of origin, 48% were assigned to another population in the area and 19.7% were not assigned. Together, these results suggest high levels of gene flow. Seed dispersal contributes to the observed gene flow up to several hundred metres, which is higher than previously modelled using aerodynamic models on seed dispersal of H. radicata. We discuss the consequences of these results for an evaluation of the probability of persistence of this species in the fragmented landscape.

Factor V Leiden is a well-known risk factor for venous thrombosis. The dual role of factor V as a coagulatory and anticoagulatory cofactor permits the assumption that further mutations in the factor V gene are of importance in the study of the risk of thrombosis. Relevant studies to date have given rise to a controversy over this risk for the HR2 haplotype. For the G allele, defined in our work group as a G at the nucleotide positions 2391, 2663, 2684 and 2863, there have been to date no other investigations of thrombotic risk. In a case-control study on 347 patients with deep venous thrombosis (DVT) and 282 controls, we investigated the association of the HR2 haplotype and the G allele with DVT. We found no association between HR2 haplotype and DVT [odds ratio (OR) 0.87; 95% confidence interval (CI) 0.58-1.30; P = 0.537]. The frequency of the G allele was, on the contrary, higher in the control group than among the patients (OR 0.68, 95% CI: 0.53 to 0.89; P = 0.005). The factor V activity of the HR2 carriers was lower than that of the wild type and G allele carriers. The HR2 haplotype exhibited a moderate influence on activated protein C response. This study presented no evidence of thrombotic risk for the HR2 haplotype alone. The results here permit the assumption of a protective effect of the G allele. The source of a possible protective influence of the G allele on thrombotic risk is at present unclear., (Copyright 2003 Lippincott Williams & Wilkins)

During the last decades, transplantation has become an established tool for the treatment of terminal organ failure. Beside immunological factors, hyperlipidemia is the main problem after heart transplantation, causing rapid transplant coronary artery disease (TxCAD) and poor long-term prognosis at the beginning of the transplantation. Heart transplant recipients are now effectively treated with lipid lowering substances, of which HMG-CoA-reductase inhibitors are the most potent. However, treatment with these substances correlates with an increased risk for the development of rhabdomyolysis due to therapy with the immunosuppressive cyclosporine A. Our study monitored the safety and efficacy of treatment with the HMG-CoA reductase inhibitor fluvastatin in heart transplant recipients compared to healthy controls. We investigated 10 patients receiving immunosuppressive therapy consisting of cyclosporine A, prednisone, and azathioprine who had increased concentrations of LDL-cholesterol (LDL-C), and 10 age-matched healthy controls. The patients were treated with 40 mg/day fluvastatin for 4 weeks and 20 mg/day for 4 additional weeks. Control individuals received 40 mg/day fluvastatin for 4 weeks only. Parameters of fluvastatin pharmacokinetics (maximum concentration of the drug (C(max.)), time (t(max.)) to reach C(max.), area under the concentration vs. time curve (AUC(0h-24h)), elimination half-life time (t(1/2))), apparent total body clearance (CL), blood cyclosporine A concentration, plasma lipids, and safety parameters were determined in both study groups at the beginning of the study and after 4 weeks. The latter were determined in the patient group also after 8 and 12 weeks. Treatment with 40 mg/day fluvastatin caused a significant decrease in total cholesterol (patients: 5.47 +/- 1.32 mmol/L vs. 7.30 +/- 1.83 mmol/L; controls: 4.69 +/- 0.64 mmol/L vs. 5.81 +/- 0.72 mmol/L), LDL-C (patients: 3.28 +/- 1.25 mmol/L vs. 5.00 +/- 1.85 mmol/L; controls: 2.58 +/- 0.63 mmol/L vs. 3.50 +/- 0.70 mmol/L), and triglycerides (patients: 1.99 +/- 0.77 mmol/L vs. 2.50 +/- 1.00 mmol/L; controls: 1.24 +/- 0.46 mmol/L vs. 1.72 +/- 0.67 mmol/L) in both study groups, whereas HDL-C was not significantly changed (patients: 1.29 +/- 0.35 mmol/L vs. 1.17 +/- 0.32 mmol/L; controls: 1.55 +/- 0.30 mmol/L vs. 1.53 +/- 0.26 mmol/L). Values of C(max.) and AUC(0h-24h) were higher in the patient group than in the control group (day 1, patients vs. controls, C(max.): 869.4 +/- 604.0 ng/mL vs. 211.9 +/- 113.9 ng/mL; AUC(0h-24h): 1948.8 +/- 1347.9 ng/mL*h vs. 549.4 +/- 247.4 ng/mL*h), whereas the corresponding value of CL was lower in the patient group (33.3 +/- 24.5 L/h vs. 107.9 +/- 95.8 L/h), and the values of t(max.) and t(1/2) showed no differences. In addition, values of C(max.) and AUC(0h-24h) after administration of 40 mg/day fluvastatin for 4 weeks in both groups were slightly higher than at the beginning, whereas the value of CL was slightly lower (day 28, patients vs. controls, C(max.): 1530.4 +/- 960.4 ng/mL vs. 254.7 +/- 199.8 ng/mL; AUC(0h-24h): 2615.3 +/- 1379.4 ng/mL*h vs. 841.8 +/- 421.4 ng/mL*h; CL: day 28, 21.4 +/- 15.3 L/h vs. 61.5 +/- 36.6 L/h). Except for an intermittent increase of creatine kinase, safety parameters showed no increases within the observation period. Our data suggest that fluvastatin effectively lowers plasma concentrations of cholesterol and LDL-C in patients after heart transplantation, however, the metabolism of fluvastatin is affected by concomitant therapy with cyclosporine A. Serum concentrations of fluvastatin should be monitored in cases of concomitant therapy with other substances interfering in the metabolism by competing cytochrome enzymes.

Background: Fluvastatin is an inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, effectively lowering serum cholesterol concentrations. A high-performance liquid chromatography (HPLC) assay was developed that determined the pharmacokinetics of fluvastatin in healthy individuals after administration of 40 and 80 mg fluvastatin., Methods: The method was linear for serum concentrations between 10 ng/mL and 5,000 ng/mL, showing good coefficients of variations and sample stability. After administration of 40 mg fluvastatin, the mean values of the area under the serum concentration vs time curve (AUC), the maximum serum drug concentration (C(max)), the time to reach C(max) (t(max)), and the serum elimination half-life time were 528.5 +/-358.8 ng/mL x h, 149.6 +/-56.0 ng/mL, 60.0 +/-30.0 minutes, and 108.0 +/-67.9 minutes, respectively. The corresponding values for a dose of 80 mg fluvastatin were 1417.7 +/-879.2 ng/mL x h, 1024.7 +/-1085.1 ng/mL, 60.0 +/-21.2 minutes, and 106.0 +/-73.6 minutes, respectively. Doubling of the dose from 40 mg to 80 mg caused an overproportional increase of AUC and C(max)., Results and Conclusion: Results suggest that the measurement of fluvastatin serum concentrations by means of HPLC provides reliable data within the broad range of physiological serum concentrations. The pharmacokinetic data after administration of high doses (80 mg) showed an overproportional increase of AUC and C(max), suggesting a saturation of the hepatic first-pass effect. Thus, in patients treated with additional substances interfering with fluvastatin metabolism, fluvastatin serum concentrations should be analyzed.

Among middle-aged women: The factor beta-lipoproteins is significantly influenced by cigarette smoking and by the intensity of physical activity at leisure time. The factor alpha-lipoproteins is not influenced by these lifestyle factors. The leukocyte count is higher among smokers. It is not significantly associated with other inflammation markers. The pre-diabetic risk profile is improved by physical activity at leisure time and by rigid eating behaviour in stressful situations. The physical activity at leisure time and a rigid eating behaviour in stressful situations play a positive role for mental health, too. Styles of coping with stress, action styles or sense of coherence do not influence the relationships between lifestyle factors and cardiovascular risk factors. Psychosocial resources intensify the relationships between lifestyle and mental health.

In the whole population total cholesterol (TC) was unchanged within two years. The triglyceride (TG) level increased significantly, but HDLC increased too between 1996 and 1998. The increase of TG concentration was significantly in the stable group only, whereas the increase of HDLC concentration was observed in both groups. "Depressed mood" and "anxiety" seem to have a positive influence on the TC levels.

The pattern of circulating monocyte subtypes and the concentration of the soluble intercellular adhesion molecule-1 (ICAM-1) were compared in middle-aged female moderate smokers and lifetime non-smokers. Total leukocyte and monocyte counts were higher in smokers. The pattern of circulating monocytes of smokers was changed toward lower absolute counts of activated (CD16+/CD64+) monocytes and (CD16+/CD14+) monocyte-macrophages and higher counts of nonactivated monocytes. The serum concentration of soluble ICAM-1 was significantly higher in smokers than in non-smokers. It is supposed that even moderate cigarette smoking leads to an activation of the circulating monocytes and their increased adhesion to the endothelium.

Serum selenium concentration was measured in middle-aged Dresden (East Germany) women in 1990 and 1996. In 1990, the serum concentration of selenium in middle-aged women was higher than in men living under the same environmental conditions (0.98 +/- 0.32 vs 0.82 +/- 0.19 micromol/l). In 1996, the serum concentration of selenium in middle-aged women was significantly higher than in 1990 (1.19 +/- 0.34 micromol/l). This increase seems to be caused by the changed foodstuff supply after the reunification of Germany. Selenium values did not correlate with age, blood pressure or daily energy intake. Moderate smoking and menopausal status did not influence the selenium levels. In 1990, the serum concentration of selenium was the highest in those women who consumed the lowest amounts of carbohydrates or fibers, or who had the highest consumption of meat, fresh fish or potatoes.

Unlabelled: LBNF1 cardiac allografts (Tx) are rejected within 36 hr in LEW rats sensitized with BN skin Tx 7 days earlier, compared to 8-day rejection in unmodified hosts. Treatment with cyclosporine or ART-18, an anti-interleukin 2 receptor (IL-2[R]) mAb monoclonal antibody, abrogates accelerated rejection and prolongs mean Tx survival to 42 days and 16 days, respectively. ART-18 given in concert with subtherapeutic dose of CsA extends survival to 25 days. These studies were designed to dissect the early mechanisms leading to ART-18 and/or CsA-mediated abrogation of accelerated Tx injury. No effect of concomitant mAb administration upon CsA through levels was noted in Tx recipients conditioned with both modalities. The beneficial effect of ART-18+CsA treatment was also unrelated to CsA-induced diminished host responses to mAb, as shown by ELISA. In the biodistribution studies 125I-labeled ART-18 accumulated preferentially into host lymphoid tissues and Tx itself and away from the blood. In animals that were concomitantly given "cold" CsA, the clearance of labeled ART-18 from the blood increased further, as did mAb sequestration into the Tx. The sensitized hosts developed high titers of complement-dependent cytotoxic (CDC) antibodies, which peaked at the time of actual Tx loss. ART-18 or CsA alone inhibited CDC, whereas combined therapy decreased further the humoral effects of sensitization. The cell-mediated lymphocytotoxicity assay revealed a similar pattern. CsA, ART-18, and combination therapy each modulated the deposition of IgG, IgM, and C3 in Tx, as shown by immunohistology. However, only CsA or ART-18+CsA therapy abolished or markedly decreased elaboration of IL-2, interferon gamma, and tissue necrosis factor alpha., In Conclusion: (1) the adjunctive low dose of CsA potentiates the inhibitory effects of ART-18 upon humoral and cellular responses, leading to accelerated rejection of cardiac Tx in presensitized rats; (2) the synergistic interaction between both modalities that results in the inhibition of lymphokine production is critical and correlates with long-term Tx survival; (3) the biodistribution patterns of mAb are important--an increased blood level of mAb does not necessarily translate into its higher therapeutic efficacy.

Unlabelled: In this report on 93 patients with limb-threatening leg ischemia the surgical procedures applied were malleolar bypasses (14), sequential bypasses (12) and femoro-distal bypasses with adjunct AV fistulas (67). The first two methods resulted in favourable limb-salvage and patency rates. However the results of such reconstructions essentially depend on the quality of primary and secondary foot arcades. In peripheral calf and foot arterial occlusions we have applied a distal arteriovenous fistula as an adjunct measure to maintain bypass patency in the crural region. 67 patients were operated on according to this method: 30 females and 37 males with an average age of 70.3 years. 29% had rest-pain and 71% had gangrene. The majority had already been operated on at least once. 7 patients had been amputated contralaterally., Results: 79% of the patients had a patent graft after one month. The incidence of limb salvage was 77%. At two years 47% of all grafts are still patent and the incidence of limb-salvage is 52%. However, this operation should be exclusively designed for limb-salvage and for cases with extremely poor run-off.

This study evaluates the critical points in the management of 48 patients with injured arteries of the lower limb between 1980 and 1986. 77% of the traumas were resultant from blunt vehicular traffic mishaps. 13 patients were treated within 6 h, 8 patients later than 6 h, 21 patients later than 24 h post injury. Delays in diagnosis occurred due to lack of or no indication for vascular trauma. Careful physical examination and aggressive use of angiography is essential in improving limb salvage rates, while doppler investigation may lead to improper diagnosis. Overall limb salvage was 69%, however, no reconstruction was possible in 6 cases (13%). 38 of the 42 arterial reconstructions required interposition of venous bypass grafts, four end to end anastomoses. Eleven patients had associated venous injuries, which in nine cases were repaired. Venous ligation in three cases was attributed with increased complication. In three cases ischemia time was shortened by the use of temporary javid shunts for rapid restoration of arterial flow. 50% of the patients were found to require fasciotomy, either pre- or postvascular repair. Early fasciotomy, however was found to be most beneficial. Fractures were treated in 15 cases with the external fixator, in 21 cases with internal fixation. Delayed revascularization after 24 h combined with aggressive debriding of muscle necrosis and the employment of vascularized muscular and skin flaps resulted in a decline in amputation rates and improved functional results.