Andrea Griesmacher

Blood coagulation activation and fibrinolysis during a downhill marathon run.

Prolonged physical exercise is associated with multiple changes in blood hemostasis. Eccentric muscle activation induces microtrauma of skeletal muscles, inducing an inflammatory response. Since there is a link between inflammation and coagulation we speculated that downhill running strongly activates the coagulation system. Thirteen volunteers participated in the Tyrolean Speed Marathon (42 195 m downhill race, 795 m vertical distance). Venous blood was collected 3 days (T1) and 3 h (T2) before the run, within 30 min after finishing (T3) and 1 day thereafter (T4). We measured the following key parameters: creatine kinase, myoglobin, thrombin–antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin–α2-antiplasmin complexes, tissue-type plasminogen activator antigen, plasminogen-activator-inhibitor-1 antigen and thrombelastography with ROTEM [intrinsic pathway (InTEM) clotting time, clot formation time, maximum clot firmness, alpha angle]. Thrombin generation was evaluated by the Thrombin Dynamic Test and the Technothrombin TGA test. Creatine kinase and myoglobin were elevated at T3 and further increased at T4. Thrombin–antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin–α2-antiplasmin complexes, tissue-type plasminogen activator antigen and plasminogen-activator-inhibitor-1 antigen were significantly increased at T3. ROTEM analysis exhibited a shortening of InTEM clotting time and clot formation time after the marathon, and an increase in InTEM maximum clot firmness and alpha angle. Changes in TGA were indicative for thrombin generation after the marathon. We demonstrated that a downhill marathon induces an activation of coagulation, as measured by specific parameters for coagulation, ROTEM and thrombin generation assays. These changes were paralleled by an activation of fibrinolysis indicating a preserved hemostatic balance.

High-sensitivity cardiac troponin T compared with standard troponin T testing on emergency department admission: how much does it add in everyday clinical practice?

Background We compared high‐sensitivity cardiac troponin T (hs‐cTnT) and standard cTnT for acute myocardial infarction (AMI) diagnosis in everyday clinical practice of an emergency department (ED). Methods and Results cTnT was measured in 2384 consecutive patients (60±21 years, 52% female) on ED admission. Readmissions to the ED (n=720) and mortality (n=101) were followed for an average period of 239±49 days. There were 53 AMIs (delay, 1 to 96 hours; median, 3 hours), 440 chest pain patients, 286 dyspnea patients, 785 acute or chronic cardiac diseases, and 540 neurological diseases, with the remaining having various internal diseases. The diagnostic performances of hs‐ and standard cTnT were comparable for AMI diagnosis (area under receiver operating characteristics curves [ROC AUC], 0.91±0.02 versus 0.90±0.03; P=0.31). Using the 99th‐percentile cutoff, the sensitivities and specificities for AMI in the whole population were 91% and 74% for hs‐cTnT and 89% and 80% for standard cTnT. hs‐cTnT detected significantly more patients with cardiac diseases (ROC AUC, 0.77±0.01 versus 0.67±0.01; P<0.001). hs‐cTnT and standard cTnT were significant predictors of ED readmissions but not of mortality, but both were not independent predictors of ED readmissions or the combined end point of readmission or mortality in binary logistic regression analysis. Conclusions In unselected ED patients the diagnostic performances of hs‐cTnT and standard cTnT for AMI diagnosis did not differ significantly. hs‐cTnT detected significantly more cardiac diseases. hs‐cTnT and standard cTnT were not independent predictors of ED readmissions and mortality from all causes.

Concordance between results of somatostatin receptor scintigraphy with 111In-DOTA-DPhe1-Tyr3-octreotide and chromogranin A assay in patients with neuroendocrine tumours

PurposeSomatostatin receptor scintigraphy (SRS) and chromogranin A (CgA) assay have successfully been implemented in the clinical work-up and management of neuroendocrine tumour (NET) patients. However, there is still a lack of studies comparing results in these patients. Our aim was to compare directly in NET patients SRS and CgA assay results with special regard to tumour features such as grade of malignancy, primary origin, disease extent and function.MethodsOne hundred twenty consecutive patients with histological confirmed NETs were investigated with 111In-DOTA-DPhe1-Tyr3-octreotide (111In-DOTA-TOC) SRS and CgA immunoradiometric assay. Tumours were classified by cell characteristics [well-differentiated NETs, well-differentiated neuroendocrine carcinomas, poorly differentiated neuroendocrine carcinomas (PDNECs)], primary origin (foregut, midgut, hindgut, undetermined), disease extent (limited disease, metastases, primary tumour and metastases) and functionality (secretory, nonsecretory).ResultsSRS was positive in 107 (89%) patients; CgA levels were increased in 95 (79%) patients. Overall, concordance between SRS and CgA results was found in 84 patients. Positive SRS but normal CgA level were found in 24 patients, with higher prevalence (p < 0.05) in patients with nonsecretory tumours. Conversely, negative SRS but CgA level increased were seen in 12 patients, with higher proportion (p < 0.05) in patients with PDNECs and tumours of hindgut origin.ConclusionsOverall, 111In-DOTA-TOC SRS proved to be more sensitive than CgA in NETs patients. Tumour differentiation, disease extent and presence of liver metastases impact both SRS and CgA results, whereas nonsecretory activity is a negative predictor of only CgA increase. PDNECs and hindgut origin of tumours predispose to discrepancies with negative SRS but increased CgA levels.

Cystatin C is a strong predictor of survival in patients with cirrhosis: is a cystatin C‐based MELD better?

The model of end stage liver disease (MELD) includes serum creatinine, which is a poor surrogate marker of renal function in patients with cirrhosis. Especially in women and patients with advanced disease creatinine underestimates true renal function. Our objective was to assess whether or not the substitution of creatinine by cystatin C improves the prognostic performance of the model.

Biomarkers of bone turnover in diagnosis and therapy of osteoporosis: a consensus advice from an Austrian working group.

SummaryAimReasonable application of laboratory parameters in prevention, diagnosis, treatment and therapy monitoring of osteoporosis.Target groupsPhysicians from different specialist disciplines (general medicine, geriatrics, gynaecology, urology, internal medicine—especially endocrinology and metabolism, nephrology, laboratory medicine, rheumatology, nuclear medicine, orthopaedics, paediatrics, rehabilitation and physical medicine, radiology, social medicine, transplantation medicine, accident surgery), moreover social insurances, hospitals and self-help groups.BackgroundEvaluation of aetiology of bone disorders, widening of the therapeutic spectrum for diseases of bone and knowledge on biochemical markers of bone turnover. Improvements in judging the success of therapy and in monitoring the compliance of patients. Research perspectives.BasesScientific literature and guidelines, consensus meetings.RésuméBasic and specialized laboratory investigations are important in differentiation between primary and secondary osteoporosis for an adequate therapy. Biochemical markers of bone turnover are an additional aid in evaluation of individual fracture risk. These markers identify responders to bone therapy faster than surveillance of bone mineral density, which helps to improve patient’s compliance too. Characteristics, preanalytic precautions and applications are presented for selected markers of bone resorption and formation and for parameters regulating bone metabolism.ZusammenfassungZielSinnvoller Einsatz der Labordiagnostik zur Prävention, Diagnose, Therapie und Therapieüberwachung der Osteoporose.ZielgruppeÄrztinnen und Ärzte für Allgemeinmedizin, Geriatrie, Gynäkologie, Urologie, Innere Medizin (besonders Endokrinologie und Stoffwechsel), Nephrologie, Med. und Chem. Labordiagnostik, Onkologie, Rheumatologie, Nuklearmedizin, Orthopädie, Pädiatrie, Rehabilitation und Physikalische Medizin, Radiologie, Sozialmedizin, Transplantationsmedizin, Unfallchirurgie, sowie Sozialversicherungsanstalten, Krankenanstalten, Selbsthilfegruppen.HintergrundAbklärung der Ätiologie von Knochenerkrankungen. Wachsendes Spektrum der Therapiemöglichkeiten von Knochenerkrankungen und der biochemischen Marker des Knochenstoffwechsels. Verbesserungen in der Beurteilung des Therapieerfolgs und bei der Überwachung der Compliance von Patienten. Forschungsperspektiven.GrundlagenWissenschaftliche Literatur, Leitlinien und Konsens-Gespräche.FazitRoutine- und Spezial-Laboruntersuchungen sind für die Unterscheidung zwischen primärer und sekundärer Osteoporose und für die Wahl einer angemessenen Therapie wichtig. Biochemische Marker des Knochenumbaus sind ein zusätzliches Hilfsmittel bei der Abschätzung des individuellen Frakturrisikos. Mit diesen Markern kann ein Ansprechen auf eine knochenspezifische Therapie rascher erfasst werden als mit der Überwachung der Knochenmineraldichte, dies hilft auch die Compliance der Patienten zu verbessern. Eigenschaften, Präanalytik und Anwendung von ausgewählten Markern für Knochen- Resorption und Anbau und von Parametern, die den Knochenstoffwechsel regulieren, werden präsentiert.

Nodding syndrome in Tanzania may not be associated with circulating anti-NMDA- and anti-VGKC receptor antibodies or decreased pyridoxal phosphate serum levels-a pilot study

BACKGROUND Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D-aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients. METHODS Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti-VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured. RESULTS Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal-phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans. CONCLUSIONS In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found.

Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects.

Essentials It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis.

Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation – a pilot study

Kv1.3‐channels are critically involved in activation and function of effector memory T cells. Blocking Kv1.3‐channels was investigated for its effect on skin rejection in a rat limb‐transplantation‐model. Animals received the Kv1.3‐blocker correolide C systemically or locally as intra‐graft‐treatment in combination with tacrolimus. Systemic (intraperitoneal) administration of correolide C resulted in slight, but significant prolongation of allograft survival compared with untreated and placebo treated controls. In 4/6 correolide C treated animals, histology showed an intact epidermis and a mild infiltrate by day 10. High correolide C plasma trough levels correlated with prolonged allograft survival. A decrease in CD4+ and CD8+ effector memory T cells was observed in allograft skin, peripheral blood and the spleen on day 5. When applied subcutaneously in combination with systemic tacrolimus (30 days+/−anti‐lymphocyte serum) detectable, but insignificant prolongation of graft survival was achieved. 2/5 animals showed an intact epidermis and a mild infiltrate until day 45. Tapering systemic tacrolimus and weaning on day 50 resulted in rejection by day 55, regardless of local correolide C treatment. Subcutaneous injection did not lead to systemic plasma levels. The Kv1.3‐channel is a potential drug target worth exploring in more detail for immunosuppression in vascularized composite allotransplantation.

“Idiopathic Bence-Jones proteinuria”: a new characterization of an old entity

Idiopathic Bence-Jones proteinuria (BJP) is a rare plasma cell dyscrasia, of which the clinical and biological characteristics are yet unclear. Historical data suggested that they are at higher risk of progression to multiple myeloma or other related neoplasms, while recent findings are contradictory. To address these open questions, we evaluated a series of both BJP and monoclonal gammopathy of undetermined significance (MGUS) with production of an intact immunoglobulin plus Bence-Jones proteinuria (MGUS+BJP) with long-term follow-up, regarding their clinical characteristics and progression to multiple myeloma, amyloidosis or other related B cell lymphoproliferative disorders. Two hundred and twenty-nine persons fulfilling the 2004 criteria of MGUS were included in the final analyses: 31 had BJP and 198 had MGUS+BJP. At the time of diagnosis, significantly more persons in the BJP group had renal impairment, anaemia and polyneuropathy. A more detailed analysis revealed discrepancies between the serum and urine light chain type in nine cases, reflecting clonal heterogeneity. The number of disease progressions was higher in MGUS+BJP (n = 30) when compared to BJP (n = 1), with a rate of 1.6 and 0.4 progressions per 100 person-years, respectively. In conclusion, BJP has distinct clinical characteristics and a lower risk of progression when compared to MGUS+BJP. Our data suggest that MGUS+BJP being closer to malignant transformation may be due to the higher portion of genetically heterogeneous, pre-malignant plasma cell subclones.

Immunoglobulin subclass 4 for the diagnosis of immunoglobulin subclass 4‐associated diseases in an unselected liver and pancreas clinic population

AIMS   The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin subclass 4 (IgG(4) )-associated cholangitis (IAC) is based on imaging studies, serology, histology and a response to steroid therapy. The major serological finding is an elevation of the serum IgG(4) concentration. Previous studies have shown that its sensitivity is about 70% and its specificity exceeds 90% at a cut-off of 140 mg/dl in selected patient populations. The aim of the present study was to assess the performance of serum IgG(4) as a diagnostic parameter in an unselected liver and pancreas clinic population. METHODS AND RESULTS   IgG(4) was prospectively determined in 1412 patients and clinical diagnoses were recorded from a review of patient charts. The prevalence of AIP or IAC in the entire cohort was 1.1% (n= 15). The sensitivity of IgG(4) for the diagnosis of AIP and IAC was 80% and the specificity was 86% at a cut-off value of ≥135 mg/dl. The positive predictive value and the negative predictive value were 6% and 99.7%, respectively. The most common differential diagnosis in patients with elevated IgG(4) was liver cirrhosis. CONCLUSION   IgG(4) has a reasonable sensitivity and specificity in a liver and pancreas clinic population, where liver cirrhosis appears to be the most frequent differential diagnosis for elevated IgG(4) concentrations.