Precise parameter control of multicycle terahertz generation in PPLN using flexible pulse trains.

The low (sub %) efficiencies so-far demonstrated for nonlinear optical down-conversion to terahertz (THz) frequencies are a primary limiting factor in the generation of high-energy, high-field THz-radiation pulses (in particular narrowband, multicycle pulses) needed for many scientific fields. However, simulations predict that far higher conversion efficiencies are possible by use of suitably-optimized optical sources. Here we implement a customized optical laser system producing highly-tunable trains of infrared pulses and systematically explore the experimental optimization of the down-conversion process. Our setup, which allows tuning of the energy, duration, number and periodicity of the pulses in the train, provides a unique capability to test predictions of analytic theory and simulation on the parameter dependences for the optical-to-THz difference-frequency generation process as well as to map out, with unprecedented precision, key properties of the nonlinear crystal medium. We discuss the agreements and deviations between simulation and experimental results which, on the one hand, shed light on limitations of the existing theory, and on the other hand, provide the first steps in a recipe for development of practical, high-field, efficiency-optimized THz sources.

One-joule 500-Hz cryogenic Yb:YAG laser driver of composite thin-disk design.

We present results on the development of a cryogenic Yb:YAG multi-pass laser amplifier based on a composite thin-disk design and demonstrate one-joule, diffraction limited, chirped 234-ps pulses with 50% optical-to-optical efficiency. High beam quality was obtained for repetition rates up to 400 Hz. The hardware was disassembled and thoroughly inspected after accumulating 80 hours of use at repetition rates from 100 to 500 Hz and exhibited no signs of damage. This laser driver is now commissioned to a dedicated laboratory where a grating compressor is producing 5.2-ps pulses used in the development of a compact x ray source based on inverse Compton scattering.

Pelvic lymphadenectomy in vulvar cancer and its impact on prognosis and outcome.

BACKGROUND: The value of pelvic lymphadenectomy (LAE) has been subject of discussions since the 1980s. This is mainly due to the fact that the relation between lymph node involvement of the groin and pelvis is poorly understood and therewith the need for pelvic treatment in general. PATIENTS AND METHODS: N = 514 patients with primary vulvar squamous cell cancer (VSCC) FIGO stage ≥ IB were treated at the University Medical Center Hamburg-Eppendorf between 1996 and 2018. In this analysis, patients with pelvic LAE (n = 21) were analyzed with regard to prognosis and the relation of groin and pelvic lymph node involvement. RESULTS: The majority had T1b/T2 tumors (n = 15, 78.9%) with a median diameter of 40 mm (11-110 mm). 17/21 patients showed positive inguinal nodes. Pelvic nodal involvement without groin metastases was not observed. 6/17 node-positive patients with positive groin nodes also had pelvic nodal metastases (35.3%; median number of affected pelvic nodes 2.5 (1-8)). These 6 patients were highly node positive with median 4.5 (2-9) affected groin nodes. With regard to the metastatic spread between groins and pelvis, no contralateral spread was observed. Five recurrences were observed after a median follow-up of 33.5 months. No pelvic recurrences were observed in the pelvic nodal positive group. Patients with pelvic metastasis at first diagnosis had a median progression-free survival of only 9.9 months and overall-survival of 31.1 months. CONCLUSION: A relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease, therefore pelvic staging (and radiotherapy) is probably unnecessary in the majority of patients with node-positive VSCC.

Prospective Analyses of Circulating B Cell Subsets in ABO-Compatible and ABO-Incompatible Kidney Transplant Recipients.

Immunosuppressive strategies applied in renal transplantation traditionally focus on T cell inhibition. B cells were mainly examined in the context of antibody-mediated rejection, whereas the impact of antibody-independent B cell functions has only recently entered the field of transplantation. Similar to T cells, distinct B cell subsets can enhance or inhibit immune responses. In this study, we prospectively analyzed the evolution of B cell subsets in the peripheral blood of AB0-compatible (n = 27) and AB0-incompatible (n = 10) renal transplant recipients. Activated B cells were transiently decreased and plasmablasts were permanently decreased in patients without signs of rejection throughout the first year. In patients with histologically confirmed renal allograft rejection, activated B cells and plasmablasts were significantly elevated on day 365. Rituximab treatment in AB0-incompatible patients resulted in long-lasting B cell depletion and in a naïve phenotype of repopulating B cells 1 year following transplantation. Acute allograft rejection was correlated with an increase of activated B cells and plasmablasts and with a significant reduction of regulatory B cell subsets. Our study demonstrates the remarkable effects of standard immunosuppression on circulating B cell subsets. Furthermore, the B cell compartment was significantly altered in rejecting patients. A specific targeting of deleterious B cell subsets could be of clinical benefit in renal transplantation.

Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease.

BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.

Renal Contrast-Enhanced Sonography Findings in a Model of Acute Cellular Allograft Rejection.

Noninvasive methods to diagnose and differentiate acute cellular rejection from acute tubular necrosis or acute calcineurin inhibitor toxicity are still missing. Because T lymphocytes play a decisive role in early states of rejection, we investigated the suitability and feasibility of antibody-mediated contrast-enhanced ultrasound by using microbubbles targeted to CD3(+) , CD4(+) , or CD8(+) T cells in different models of renal disease. In an established rat renal transplantation model, CD3-mediated ultrasound allows the detection of acute rejection as early as on postoperative day 2. Ultrasound signal intensities increased with the severity of inflammation. Further, an early response to therapy could be monitored by using contrast-enhanced sonography. Notably, acute tubular necrosis occurring after ischemia-reperfusion injury as well as acute calcineurin inhibitor toxicity could easily be differentiated. Finally, the quantified ultrasound signal correlated significantly with the number of infiltrating T cells obtained by histology and with CD3 mRNA levels, as well as with chemokine CXCL9, CXCL11, and CCL19 mRNA but not with KIM-1 mRNA expression, thereby representing the severity of graft inflammation but not the degree of kidney injury. In summary, we demonstrate that antibody-mediated contrast-enhanced ultrasound targeting T lymphocytes could be a promising tool for an easy and reproducible assessment of acute rejection after renal transplantation.

GARP inhibits allergic airway inflammation in a humanized mouse model.

BACKGROUND: Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. METHODS: To analyze the therapeutic effects of sGARP, adult NOD/Scidγc(-/-) (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP. RESULTS: In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45(+) cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-ß receptor pathway, mice additionally received anti-TGF-ß receptor II (TGF-ßRII) antibodies. Blocking the signaling of TGF-ß through TGF-ßRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation. CONCLUSION: Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases.

Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases.

INTRODUCTION: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute. MATERIALS AND METHODS: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development. CONCLUSION: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.

Return-to-activity after anatomical reconstruction of acute high-grade acromioclavicular separation.

BACKGROUND: To evaluate return-to-activity (RtA) after anatomical reconstruction of acute high-grade acromioclavicular joint (ACJ) separation. METHODS: A total of 42 patients with anatomical reconstruction of acute high-grade ACJ-separation (Rockwood Type V) were surveyed to determine RtA at a mean 31 months follow-up (f-u). Sports disciplines, intensity, level of competition, participation in overhead and/or contact sports, as well as activity scales (DASH-Sport-Module, Tegner Activity Scale) were evaluated. Functional outcome evaluation included Constant score and QuickDASH. RESULTS: All patients (42/42) participated in sporting activities at f-u. Neither participation in overhead/contact sports, nor level of activity declined significantly (n.s.). 62 % (n = 26) of patients reported subjective sports specific ACJ integrity to be at least the same as prior to the trauma. Sporting intensity (hours/week: 7.3 h to 5.4 h, p = .004) and level of competition (p = .02) were reduced. If activity changed, in 50 % other reasons but clinical symptoms/impairment were named for modified behavior. QuickDASH (mean 6, range 0-54, SD 11) and DASH-Sport-Module (mean 6, range 0-56, SD 13) revealed only minor disabilities at f-u. Over time Constant score improved significant to an excellent score (mean 94, range 86-100, SD 4; p < .001). Functional outcome was not correlated with RtA (n.s.). CONCLUSION: All patients participated in sporting activities after anatomical reconstruction of high-grade (Rockwood Type V) ACJ-separation. With a high functional outcome there was no significant change in activity level (Tegner) and participation in overhead and/or contact sports observed. There was no correlation between functional outcome and RtA. Limiting, there were alterations in time spent for sporting activities and level of competition observed. But in 50 % those were not related to ACJ symptoms/impairment. Unrelated to successful re-established integrity and function of the ACJ it should be considered that patients decided not return-to-activity but are very content with the procedure.

Noninvasive Imaging of Acute Renal Allograft Rejection by Ultrasound Detection of Microbubbles Targeted to T-lymphocytes in Rats.

PURPOSE: We propose CD3-antibody-mediated contrast-enhanced ultrasonography using human T-lymphocytes for image-based diagnosis of acute allograft rejection (AR) established in a rat renal transplantation model. MATERIALS AND METHODS: 15 minutes after tail vein injection of 30 × 10(6) human T-lymphocytes, contrast media/microbubbles conjugated with an anti-human CD3 antibody was applied to uni-nephrectomized 10-week-old allogeneically transplanted male rats (Lewis-Brown Norway (LBN) to Lewis, aTX) and ultrasound was performed to investigate the transplanted kidney as well as the native kidney. In vivo results were confirmed via immunohistochemical stainings of CD3 after post mortem dissection. Syngeneically transplanted rats (LBN to LBN, sTX), rats with ischemia/reperfusion injury (IRI, 45 min. warm ischemia), and rats subjected to acute cyclosporin A toxicity (CSA) (cyclosporine 50 mg/kg BW for 2 days i. p.) served as controls. RESULTS: Accumulation of human T-lymphocytes was clearly detected by antibody-mediated sonography und was significantly increased in allografts undergoing AR (5.41 ±â€Š1.32 A. U.) when compared to native control kidneys (0.70 ±â€Š0.08 A. U.). CD3 signal intensity was low in native kidneys, sTX (0.99 ±â€Š0.30 A. U.), CSA (0.10 ±â€Š0.02 A. U.) and kidneys with IRI (0.46 ±â€Š0.29 A. U.). Quantification of the ultrasound signal correlated significantly with the T-cell numbers obtained by immunohistochemical analysis (R2 = 0.57). CONCLUSION: Contrast-enhanced sonography using CD3-antibodies is an option for quick and highly specific assessment of AR in a rat model of renal transplantation.

[Acute tibial tubercle avulsion fractures]. / Avulsionsverletzungen der proximalen Tibia.

BACKGROUND: The tear-off of the apophysis of the proximal tibia is a rare injury (< 1 % of all apophysal lesions). It mainly affects male adolescents (14,6 years). Main causes are concentric and eccentric stress during sport activity. Morbus Osgood-Schlater seems to be a predisposing factor. AIM: Up-to-date survey of pathogenesis, diagnostics and treatment strategies. MATERIAL AND METHODS: Literature research (level III and IV studies) as well as own results. RESULTS: The affected patients are mostly male (97 %), type III fractures are most frequently seen (48 %). Accompanying injuries are not to be missed (10 %). The treatment usually consists of surgery by means of an open reposition and internal refixation, recently also minimal invasi. The results are mainly very good to good, approximately 95 % reach their old level of activity again. Almost one third of the patients develop a mostly slight complication. CONCLUSION: The acute tear-off of the apophysis of the proximal tibia is an infrequent disease. In dislocated injuries the standard procedure is the open reposition and the internal fixation. Lesions within the knee are particularly to be expected in intraarticular fractures und must not be missed. A very good to good result is to be expected with correct treatment, momentous complications are all together rare.

Epicutaneous immunotherapy with a hypoallergenic Bet v 1 suppresses allergic asthma in a murine model.

BACKGROUND: Due to reduced allergic potency, hypoallergenic variants have been suggested as safer and potentially more efficacious alternative to the corresponding wild-type allergens in allergen-specific immunotherapy. Here, we aimed at investigating the efficacy of recombinant Bet v 1B2, a hypoallergenic folding variant of Bet v 1, in epicutaneous immunotherapy to suppress asthmatic features using a murine model of birch pollen allergy. METHODS AND RESULTS: Before, or after sensitization with rBet v 1 plus ALUMW and intranasal challenges with birch pollen extract, BALB/c mice received epicutaneous immunization (EPI) with rBet v 1, or rBet v 1B2 on their depilated back. Prophylactic EPI with rBet v 1B2, but not with rBet v 1, suppressed serum levels of Bet v 1-specific IgE antibodies and reduced the number of eosinophils and the concentrations of Th2 cytokines in bronchoalveolar lavage. In an established allergic condition, serum levels of Bet v 1-specific IgE antibodies were similar between PBS-treated control mice and EPI-treated mice. However, therapeutic EPI with rBet v 1B2, but not with rBet v 1, significantly suppressed the development of airway inflammation and lung function impairment. CONCLUSION: This study is the first to show the effect of therapeutic EPI with a recombinant form of a hypoallergenic folding variant on the suppression of asthmatic features. Our results suggest that rBet v 1B2 along with its reduced IgE-binding capacity could be a preferred therapeutic allergen than wild-type rBet v 1 in epicutaneous immunotherapy of birch pollen-induced allergic asthma, in particular due to a lower risk of allergic side effect.

Autoantibodies against CD74 in spondyloarthritis.

BACKGROUND: Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Establishing the diagnosis is often difficult, since abnormalities in conventional X-ray develop with a latency of several years and only HLA-B27 is used as a laboratory marker. The goal of our study was to identify new autoantibodies as diagnostic markers of SpA. METHODS: Protein array technology was used to screen for new autoantigens in ankylosing spondylitis. Then, the results were confirmed by ELISA using Class II-associated invariant chain peptide domain of CD74 as antigen. Sera for the ELISA were obtained from 216 patients with axial (n=156) and peripheral (n=60) SpA. Sera of patients with psoriatic arthritis without axial involvement as another subtype of peripheral SpA, rheumatoid arthritis, systemic lupus erythematosus, HIV infection and blood donors served as controls. All donors provided informed consent for the study which was approved by the local ethics committee (project number 4928). RESULTS: Using protein arrays, we detected IgG antibodies against CD74 in SpA sera. Using ELISA technology on sera that had previously been frozen for several years, IgG autoantibodies against CD74 were found in 67% of the SpA patients and were even more frequent in patients with a short disease duration. In the controls, the prevalence of the new autoantibodies was 18/40 (45%) in psoriatic arthritis without axial involvement, 9/80 (11%) in rheumatoid arthritis, 6/40 (15%) in systemic lupus erythematosus, 1/40 (2.5%) in HIV and 1/125 (0.8%) in blood donors. CONCLUSIONS: Antibodies against CD74 could provide an important additional tool for diagnosis of SpA.

Epicutaneous immune modulation with Bet v 1 plus R848 suppresses allergic asthma in a murine model.

BACKGROUND: Combining allergen(s) with an adjuvant is a strategy to improve the efficacy and safety of allergen-specific immunotherapy. Here, we aimed at investigating the adjuvant effects of polyadenylic-polyuridylic acid (poly(A:U)), a TLR3 agonist, and R848 (resiquimod), a TLR7 agonist, in epicutaneous immunotherapy with Bet v 1, the major birch pollen allergen, to intervene in birch pollen allergy. METHODS AND RESULTS: BALB/c mice received epicutaneous immunization (EPI) with recombinant Bet v 1 (rBet v 1) alone, or plus poly(A:U), or R848 on their depilated back using patches. Among the groups, EPI with rBet v 1 and R848 induced detectable levels of IFN-γ-producing CD4(+) T cells in lymph nodes and Bet v 1-specific IgG2a antibodies in the sera of mice. Before or after EPI, mice were sensitized with rBet v 1 plus aluminium hydroxide adjuvant and intranasally challenged with birch pollen extract. Prophylactic EPI with rBet v 1 plus R848 inhibited the production of biologically active Bet v 1-specific IgE antibodies in sensitization. Prophylactic and therapeutic EPI with rBet v 1 plus R848 suppressed lung inflammation upon challenges. Remarkably, only rBet v 1 plus R848 reduced the development of enhanced pause (PenH), a substituted parameter for airway hyper-reactivity, in challenged mice. In contrast to R848, poly(A:U) did not present adjuvant effect on the suppression of asthmatic features. CONCLUSION: Epicutaneous immunization with rBet v 1 plus R848 induced predominant Bet v 1-specific Th1 responses and efficiently suppressed asthmatic features elicited by birch pollen. R848 could be a promising adjuvant in epicutaneous immunotherapy for birch pollen-induced allergic asthma.

Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study.

OBJECTIVES: Early broad-spectrum antimicrobial treatment reduces mortality in patients with septic shock. In a multicenter, prospective observational study, we explored whether delayed appropriate antimicrobial therapy (AAT) influences outcome in Staphylococcus aureus bloodstream infection (SAB). METHODS: Two hundred and fifty-six patients with SAB from ten German study centers were enrolled and followed for 3 months. Predisposing factors, clinical features, diagnostic procedures, antimicrobial therapy, and outcome were recorded. The appropriateness of antimicrobial therapy was judged by a trained physician based on in vitro activity, dosage, and duration of therapy. Therapy was considered to be delayed when more than 24 h elapsed between the first positive blood culture and the start of appropriate therapy. The association of delayed therapy with overall mortality and SAB-related events (i.e., attributable mortality or late SAB-related complications) was assessed by crosstabulation and propensity score-based logistic regression. RESULTS: One hundred and sixty-eight patients received AAT during their hospital stay, of whom 42 (25%) received delayed AAT. The overall mortality and the occurrence of severe sepsis or septic shock were lower in patients with delayed AAT, pointing towards confounding by indication. Adjusted 90-day mortality (adjusted odds ratio [OR] 0.91, 95% confidence interval [CI] [0.39-2.13], p 0.82) and SAB-related events (adjusted OR 1.46, 95% CI [0.47-4.51], p 0.52) also failed to show a significant impact of delayed AAT on outcome. CONCLUSION: In patients with SAB, early AAT may not improve survival. However, confounding by indication is a major challenge when analyzing and interpreting observational studies on the impact of delayed AAT.

Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066).

INTRODUCTION: There was a growing need for practical guidelines for the most common OIs in Germany and Austria under consideration of the local epidemiological conditions. MATERIALS AND METHODS: The German and Austrian AIDS societies developed these guidelines between March 2010 and November 2011. A structured Medline research was performed for 12 diseases, namely Immune reconstitution inflammatory syndrome, Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. Due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. The German version was accepted by the German and Austrian AIDS Societies and was previously published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; German Association of the Scientific Medical Societies). CONCLUSION: The review presented here is a translation of a short version of the German-Austrian Guidelines of opportunistic infections in HIV patients. These guidelines are well-accepted in a clinical setting in both Germany and Austria. They lead to a similar treatment of a heterogeneous group of patients in these countries.

Are the elderly different? Factors influencing mortality after percutaneous coronary intervention with stent implantation.

BACKGROUND: The aim of this study was to investigate factors influencing mortality after percutaneous coronary intervention (PCI) in patients aged ≥ 75 years compared to younger patients. PATIENTS AND METHODS: A total of 1,809 coronary heart disease (CHD) patients after PCI with stent implantation in our hospital were assessed. Kaplan-Meier analyses with log-rank test and Cox regression analyses were performed on three predefined models concerning primary endpoint of all-cause mortality. Model 1 was a univariate analysis of the influence of age dichotomized by age 75 years on the primary endpoint. Model 2 included age and classical cardiovascular risk factors (CVRFs, e.g., body mass index (BMI), smoking, diabetes, and hypertension). Model 3 consisted of age, classical CVRFs, and additional factors (e.g., medication; hemoglobin, peripheral arterial disease (PAD), low-density lipoprotein cholesterol (LDL-C) and creatinine levels, and left ventricular ejection fraction (LVEF)). RESULTS: In the mean follow-up of 137 ± 61 weeks 375 patients died. Age ≥ 75 years was significantly related to mortality in all models. In model 3, previous stroke, PAD, diabetes, elevated levels of serum creatinine, and increased LDL-C were related to elevated mortality, higher hemoglobin levels, and LVEF > 50% were associated with decreased mortality in all patients and in patients < 75 years. In patients ≥ 75 years arterial hypertension was associated with poor outcome (hazard ratio (HR) 7.989, p = 0.040), previous antiplatelet therapy showed reduced mortality (HR 0.098, p = 0.039). CONCLUSION: Although risk factors such as previous stroke, PAD, diabetes, renal insufficiency, and anemia were predictors for death in all patients and patients < 75 years, in the elderly only arterial hypertension increased, whereas treatment with platelet inhibitors decreased mortality.

Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity.

OBJECTIVE: The underlying aetiology of chronic fatigue syndrome is currently unknown; however, in the light of carnitine's critical role in mitochondrial energy production, it has been suggested that chronic fatigue syndrome may be associated with altered carnitine homeostasis. This study was conducted to comparatively examine full endogenous carnitine profiles in patients with chronic fatigue syndrome and healthy controls. DESIGN: A cross-sectional, observational study. SETTING AND SUBJECTS: Forty-four patients with chronic fatigue syndrome and 49 age- and gender-matched healthy controls were recruited from the community and studied at the School of Pharmacy & Medical Sciences, University of South Australia. MAIN OUTCOME MEASURES: All participants completed a fatigue severity scale questionnaire and had a single fasting blood sample collected which was analysed for l-carnitine and 35 individual acylcarnitine concentrations in plasma by LC-MS/MS. RESULTS: Patients with chronic fatigue syndrome exhibited significantly altered concentrations of C8:1, C12DC, C14, C16:1, C18, C18:1, C18:2 and C18:1-OH acylcarnitines; of particular note, oleyl-L-carnitine (C18:1) and linoleyl-L-carnitine (C18:2) were, on average, 30-40% lower in patients than controls (P < 0.0001). Significant correlations between acylcarnitine concentrations and clinical symptomology were also demonstrated. CONCLUSIONS: It is proposed that this disturbance in carnitine homeostasis is reflective of a reduction in carnitine palmitoyltransferase-I (CPT-I) activity, possibly a result of the accumulation of omega-6 fatty acids previously observed in this patient population. It is hypothesized that the administration of omega-3 fatty acids in combination with l-carnitine would increase CPT-I activity and improve chronic fatigue syndrome symptomology.

TB or not TB? Difficulties in the diagnosis of tuberculosis in HIV-negative immigrants to Germany.

BACKGROUND: Immigrants to Germany and their children are at particular risk for tuberculosis (TB). - METHODS: 35 Patients (10 male / 25 female aged 2 - 59 years (median 33 years) originating mostly from high incidence countries in Asia (19 (54.3%)) in Africa (14 (40.0%) and East Europe (2 (5.7%)), attended at the Tropical Medicine Unit were analysed. - RESULTS: Primary clinical presentation was most frequently lymphadenitis (13 (37.1%)). Other organs involved included bones (7 (20.0%)), central nervous system (5 (14.3%)), urogenital organs (3 (8.6%)), lung (3 (8.6%)), mediastinum, (2 (5.7%)) and abdomen (2 (5.7%)). ESR was abnormal in 21/28 (75.0%), CRP in 20/35 (57.1%), and protein electrophoresis in 22/26 (84.6%) cases. The tuberculin skin test was strongly positive in all 15 cases where the test had been performed. Tuberculosis interferon gamma release assay (TB-IGRA) was positive in all 35 cases (100%). PCR for nucleic acids of Mycobacterium (M.) tuberculosis complex was positive in only 7/20 (35.0%) cases. M. tuberculosis was identified in 32/35 (91.4%), M. bovis in 2 (5.7%) cases. 1 case was diagnosed clinically. All patients were negative for HIV. Typical histopathology was seen in the 29 cases, where biopsies had been taken. Chest-X-ray did not reveal specific pulmonary lesions in the majority of cases (22/35 (62.9%)). Diagnosis of TB was mostly delayed (4 to 299 weeks, (median 8)). The most frequent primary suspicion was a malignancy (17/35 (48.6%)) while TB was initially suspected in 5 cases only. Diagnosis of TB is impeded by its multifaceted presentation especially in immigrants.

Cholestatic liver diseases from child to adult: the diversity of MDR3 disease.

The phospholipidfloppase MDR3 (gene symbol: ABCB4) is expressed in the canalicular membrane of hepatocytes and mediates the biliary excretion of phosphatidylcholine, which is required for the formation of mixed micelles in bile. Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC). Here, we report on four new (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) and one known (S27G) MDR3 mutations in eight patients of three families. The patients presented with a wide spectrum of liver diseases. The clinical presentation and decisive laboratory findings or the association to a trend-setting family history led to the identification of the genetic background in these patients. Even the same mutation may be associated with varying disease progression.