Summary Background Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau ...proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. Methods We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50–85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov , number NCT01850238 ; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov , number NCT02031198. Findings This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 53% vaccinated patients 92 individual events). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. Interpretation AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. Funding AXON Neuroscience SE.
Neurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. ...Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients.
We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer's disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer's Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry.
The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 50% of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment.
AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1.
The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov : the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.
The purpose of this study was to find out whether Procalcitoni, Neopterin and C-reactive protein are sensitive and specific markers of intrauterine infection.
We evaluated 155 patients from 26. to ...41. week of pregnancy at the time of delivery. We measured serum concentrations of procalcitonin (PCT), neopterin and C-reactive protein (CRP) from mother's blood sample at the beginning of delivery and from umbilical cord blood after delivery.
In first group occurred in higher percentage (27.41%) preterm delivery (26.-37. week of pregnancy), chorioamnionitis confirmed by histological examination (16.12%) and preterm premature rupture of membranes (24.19%). In this group occured perinatal infection of newborn in 61.29%. In the second group preterm delivery (6.31%) and perinatal infection of newborn (7.36%) occured in lower percentage.
The results suggest that the simultaneous measurement of CRP, PCT and NPT in mother's blood sample before delivery and umbilical cord blood may provide an accurate early diagnosis of infection and then preterm delivery (Tab. 1, Fig. 3, Ref. 18). Full Text (Free, PDF) www.bmj.sk.
Early identification of patients with severe forms of acute pancreatitis (AP) and subsequent management of these high risk patients are the most important aims in order to decrease mortality from AP. ...Procalcitonin (PCT) as a marker for systemic inflammation appears to be a useful marker for early identification of severe forms.
101 patients with confirmed AP have been admitted to department of general surgery. PCT values were measured in each patient on admission and after 12 hours. PCT levels were correlated to the disease's course and prognosis. Results are given through PPV and NPV. Immunoluminometric assay (BRAHMS Diagnostica) was used for measurement.
PPV and NPV for prediction of disease's course were better for PCT than for CRP PPV 64.7% versus 36% and NPV 82,6% versus 79.6% and for prediction of fatal outcome PCT reached 75% and 100% for cut off value 5 ng/ml.
PCT seems to be a useful screening parameter for detecting severe AP and for identifying the patients who need ICU treatment, ATB covering and who can benefit from the novel therapies.
There is still no general agreement as to which patients suffering from attacks of acute biliary pancreatitis should undergo emergent endoscopic retrograde cholangiopancreatography (ERCP) with ...subsequent endoscopic intervention (endoscopic papilotomy, stent placement etc.). Many authors have described large differences in Procalcitonin (PTC) serum levels in patients suffering from biliary pancreatitis as opposed to patients whose acute pancreatitis is based on toxic etiology. Therefore, we have investigated the correlation of Procalcitonin serum levels with the presence of biliary obstruction in patients undergoing ERCP examination.
From 1.8.2004 to 31.3.2005, 97 patients undergoing ERCP were enrolled into the study. Blood samples were taken from each patient just before their ERCP examinations, and PCT serum levels were subsequently correlated to ERCP findings.
ERCP examinations were completed in 90 out of 97 patients. Bile ducts obstructions were confirmed in 61 out of 90 patients and the mean serum level of PTC was 0.078 ng/ml. In the remaining 29 patients ERCP revealed normal findings and the mean PCT value was 0.069 ng/ml. There was no statistical correlation between PCT serum levels and the presence of biliary obstruction on ERCP findings.
The measurement of PCT serum levels is of no help in the identification of patients, who should undergo emergent ERCP due to acute biliary pancreatitis (Tab. 1, Fig. 1, Ref. 6).
Cardiopulmonary bypass and cardiac operations are obligatorily connected with systemic inflammatory reaction. Production of proinflammatory cytokines is responsible also for negative effects on the ...myocardial function.
Follow-up of the dynamic changes of proinflammatory and antiinflammatory cytokine levels in patients with left ventricular dysfunction during the first week after cardiac surgery.
A total of nine patients with a very low left ventricular ejection fraction (22.75 +/- 0.65%) who had undergone cardiac surgery (for coronary artery bypass grafting or aortic valve reconstruction) were investigated during the first after week operation. The preoperative and postoperative plasma levels of tumor necrosis factor (TNF), interleukin-8 (IL-8) and interleukin-10 (IL-10) were estimated by means of ELISA technique.
With respect to the preoperative levels, on the first postoperative day the levels IL-8 (from 9.36 to 16.65 pg/ml) (p < 0.05) and of IL-10 (from 6.93 to 28.09 pg/ml) (p < 0.02) significantly rose with a stepwise decrease down to the seventh day after surgery. From the third to seventh day an insignificant increase in TNF level was also noted.
The results have shown that open heart surgery in patients with a severe left ventricular dysfunction evoked a systemic inflammatory response demonstrated by early increase in proinflammatory cytokine IL-8 and was accompanied by increased level of antiinflammatory cytokine IL-10. Despite stepwise decrease in IL-8 levels, they did not reach the preoperative levels, not even on the seventh postoperative day. (Tab. 1, Fig. 3, Ref. 21.)
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