Indoleamine-2,3-dioxygenase activity in experimental human endotoxemia

Background: Excessive tryptophan metabolism to kynurenine by the rate-limiting enzyme endothelial indoleamine 2,3-dioxygenase 1 (IDO) controls arterial vessel relaxation and causes hypotension in murine endotoxemia. However, its relevance in human endotoxemia has not been investigated so far. We thus aimed to study changes in blood pressure in parallel with tryptophan and kynurenine levels during experimental endotoxemia in humans. Findings: Six healthy male volunteers were given E. coli lipopolysaccharide (LPS; 4 ng/kg) as a 1-min intravenous infusion. They had levels of soluble E-Selectin and soluble vascular cell adhesion molecule-1 as well as IDO activity assessed as the kynurenine-to-tryptophan plasma ratio by liquid chromatography-tandem mass spectrometry at various time points during a 24 h time course. During endotoxemia, IDO activity significantly increased, reaching peak levels at 8 h after LPS infusion (44.0 ± 15.2 vs. 29.4 ± 6.8 at baseline, P<0.0001). IDO activity correlated inversely with the development of hypotension as shown by random effects linear regression models. Finally, IDO activity exhibited a kinetic profile similar to that of soluble endothelial-specific adhesion molecules. Conclusions: LPS is a triggering factor for the induction of IDO in men. Our findings strongly support the concept that the induction of IDO in the vascular endothelium contributes to hypotension in human sepsis

Elimination of Herpes Simplex Virus-2 and Epstein-Barr Virus With Seraph 100 Microbind Affinity Blood Filter and Therapeutic Plasma Exchange: An Explorative Study in a Patient With Acute Liver Failure

OBJECTIVES Herpes simplex virus (HSV)-2 is a rare cause of hepatitis that can lead to acute liver failure (ALF) and often death. The earlier the initiation of acyclovir treatment the better the survival. With regard to ALF, controlled randomized data support the use of therapeutic plasma exchange (TPE) both as bridge to recovery or transplantation-possibly by modulating the systemic inflammatory response and by replacing coagulation factors. Seraph 100 Microbind Affinity Blood Filter (Seraph; Ex Thera Medical, Martinez, CA), a novel extracorporeal adsorption device, removes living pathogens by binding to a heparin-coated surface was shown to efficiently clear HSV-2 particles in vitro. Here, we tested the combination of Seraph with TPE to reduce a massive HSV-2 viral load to reach a situation in that liver transplantation would be feasible. DESIGN Explorative study. SETTING Academic tertiary care transplant center. PATIENT Single patient with HSV-2-induced ALF. INTERVENTIONS TPE + Seraph 100 Microbind Affinity Blood Filter. MEASUREMENTS AND MAIN RESULTS We report Seraph clearance data of HSV-2 and of Epstein-Barr virus (EBV) in vivo as well as total viral elimination by TPE. Genome copies/mL of HSV-2 and EBV in EDTA plasma were measured by polymerase chain reaction every 60 minutes over 6 hours after starting Seraph both systemically and post adsorber. Also, HSV-2 and EBV were quantified before and after TPE and in the removed apheresis plasma. We found a total elimination of 1.81 × e$^{11}$ HSV-2 copies and 2.11 × e$^{6}$ EBV copies with a single TPE (exchange volume of 5L; 1.5× calculated plasma volume). Whole blood clearance of HSV-2 in the first 6 hours of treatment was 6.64 mL/min (4.98-12.92 mL/min). Despite much lower baseline viremia, clearance of EBV was higher 36.62 mL/min (22.67-53.48 mL/min). CONCLUSIONS TPE was able to remove circulating HSV-2 copies by 25% and EBV copies by 40% from the blood. On the other hand, clearance of HSV-2 by Seraph was clinically irrelevant, but Seraph seemed to be far more effective of removing EBV, implicating a possible use in EBV-associated pathologies, but this requires further study

Minimal change nephrotic syndrome in an 82 year old patient following a tetanus-diphteria-poliomyelitis-vaccination

Abstract Background The most common cause of idiopathic nephrotic syndrome in children and younger adults is the minimal change nephrotic syndrome (MCNS). In the elderly MCNS is relatively uncommon. Over the last decade some reports suggest a rare but possible association with the administration of various vaccines. Case presentation A 82-year old Caucasian female presented with pronounced nephrotic syndrome (proteinuria of 7.1 g/d, hypoproteinemia of 47 g/l). About six weeks prior to admission, she had received a combination vaccination for tetanus, diphtheria and poliomyelitis as a booster-vaccination from her general practitioner. The renal biopsy revealed typical minimal change lesions. She responded well to the initiated steroid treatment. As through physical examination as well as extensive laboratory and imaging studies did neither find any evidence for malignancies nor infections we suggest that the minimal change nephrotic syndrome in this patient might be related to the activation of the immune system triggered by the vaccination. Conclusion Our case as well as previous anecdotal reports suggests that vaccination and the resulting stimulations of the immune system might cause MCNS and other severe immune-reactions. Increased awareness in that regard might help to expand the database of those cases.</p

KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancer

The association between kidney disease and cancer is multifaceted and complex. Persons with chronic kidney disease (CKD) have an increased incidence of cancer, and both cancer and cancer treatments can cause impaired kidney function. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. In addition, the oncology treatment landscape is changing rapidly, and data on tolerability of novel therapies in patients with CKD are often lacking. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and research priorities are described

Obesity, colorectal cancer and MACC1 expression: a possible novel molecular association

Obesity is a major and increasing public health concern, associated with an increased risk of and mortality from several types of cancer including colorectal cancer (CRC), being associated with cancer progression, metastasis and resistance to therapy. It was hypothesized that the expression of cancer/metastasis‑inducing gene metastasis‑associated in colon cancer 1 (MACC1) is increased in obesity, which may constitute a link to obesity‑induced cancer. The present study thus analyzed circulating cell‑free plasma MACC1 expression levels in human obese (vs. normal weight) adult individuals from independent studies, namely the Martin Luther University (MLU) study (n=32) and the Metabolic syndrome study (MetScan, Berlin) (n=191). Higher plasma MACC1 levels were found in obese individuals, increasing with a greater body fat mass and body mass index; these levels were predominantly observed in male and to a lesser extent in female individuals, although the results were not significant. A reduction in body fat mass following dietary intervention and physical exercise decreased the MACC1 expression levels in the MLU study. Furthermore, Wistar rats with diet‑induced obesity exhibited slightly increased plasma MACC1 levels compared with rats of normal weight. The obese Wistar rats exposed to azoxymethane to induce colon cancer exhibited a more severe colon tumor outcome, which was associated with significantly increased MACC1 levels compared with their non‑obese littermates. On the whole, the findings of the present study suggest an association between MACC1 and obesity, as well as with obesity‑induced CRC

An International Partnership of 12 Anatomy Departments - Improving Global Health through Internationalization of Medical Education

Background: At a time of global interconnectedness, the internationalization of medical education has become important. Anatomy as an academic discipline, with its close connections to the basic sciences and to medical education, can easily be connected with global health and internationalization of medical education. Here the authors present an international program based on a partnership between twelve anatomy departments in ten countries, on four continents. Details of a proposed plan for the future direction of the program are also discussed. Objective: The aim is to improve global healthcare by preparing future global healthcare leaders via early international networking, international collaboration and exchange, intercultural experience, and connecting two seemingly distant academic disciplines - anatomy and global health - via internationalization of medical education. Methods: Based in the anatomy course, the program involved early international collaboration between preclinical medical and dental students. The program provided a stepwise progression for learning about healthcare and intercultural topics beyond pure anatomy education - starting with virtual small groups of international students, who subsequently presented their work to a larger international audience during group videoconferences. The above progressed to in-person visits for research internships in the basic sciences within industrialized countries. Findings: Students appreciated the international and intercultural interaction, learned about areas outside the scope of anatomy (e.g., differences in healthcare education and delivery systems, Public and Global Health challenges, health ethics, and cultural enrichment), and valued the exchange travel for basic sciences research internships and cultural experience. Conclusions: This unique collaboration of international anatomy departments can represent a new role for the medical anatomy course beyond pure anatomy teaching - involving areas of global health and internationalization of medical education - and could mark a new era of international collaboration among anatomists.Peer reviewe

Asymmetric Dimethylarginine, Endothelial Nitric Oxide Bioavailability and Mortality in Sepsis

Background: Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxidesynthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelialdysfunction, but the role of ADMA in acute inflammatory states is less well defined.Methods and Results: In a prospective longitudinal study in 67 patients with acute sepsis and 31 controls, digitalmicrovascular reactivity was measured by peripheral arterial tonometry and blood was collected at baseline and 2&ndash;4 dayslater. Plasma ADMA and L-arginine concentrations were determined by high performance liquid chromatography. Baselineplasma L-arginine: ADMA ratio was significantly lower in sepsis patients (median [IQR] 63 [45&ndash;103]) than in hospital controls(143 [123&ndash;166], p,0.0001) and correlated with microvascular reactivity (r = 0.34, R2 = 0.12, p = 0.02). Baseline plasma ADMAwas independently associated with 28-day mortality (Odds ratio [95% CI] for death in those in the highest quartile($0.66 mmol/L) = 20.8 [2.2&ndash;195.0], p = 0.008), and was independently correlated with severity of organ failure. Increase inADMA over time correlated with increase in organ failure and decrease in microvascular reactivity.Conclusions: Impaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potentialmechanism linking increased plasma ADMA with organ failure and death in sepsis

Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 µM; 95% CI 0.74–0.96) compared to those with MSM (0.54 µM; 95%CI 0.5–0.56) and HCs (0.64 µM; 95%CI 0.58–0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0–181; p = 0.01). ADMA was independently associated with decreased exhaled NO (rs = −0.31) and endothelial function (rs = −0.32) in all malaria patients, and with reduced exhaled NO (rs = −0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria

Dimethylarginine Dimethylaminohydrolase-1 Transgenic Mice Are Not Protected from Ischemic Stroke

Methylated arginines are endogenous analogues of L-arginine, the substrate for nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) interferes with NO formation, causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in humans. It is eliminated primarily by enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH).We investigated whether human DDAH-1 (hDDAH-1) transgenicity protects from ischemic tissue damage in temporary middle cerebral artery occlusion (tMCAO) in mice. Infarct sizes did not significantly differ between hDDAH-1 transgenic (TG) mice and wild-type littermates (WT). As expected, ADMA plasma concentrations were significantly decreased, cerebral hDDAH expression and protein significantly increased in transgenic animals. Interestingly, neither brain tissue DDAH activity nor ADMA concentrations were different between TG and WT mice. In contrast, muscular DDAH activity was generally lower than in brain but significantly increased in TG mice.Our study demonstrates that hDDAH-1 transgenic mice are not protected from ischemic cerebral tissue damage in tMCAO. This lack of protection is due to high basal cerebral DDAH activity, which is not further increasable by transgenic overexpression of DDAH