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IntroductionWe recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted.MethodsWe established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change.ResultsBased on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of −7.9% (95% CI −2.5 to −13.4) for the cardio-renal endpoint, a risk change of −5.1% (−1.2 to −9.0) for the CV endpoint and a non-significant risk change of −19.9% (−42.1 to +2.1) for the renal endpoint.ConclusionsPRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.

The present study investigates the presence and removal of target organic micropollutants in a large Swedish wastewater treatment plant designed for nutrient removal including activated sludge, trickling filters, nitrifying moving bed biofilm reactors (MBBRs) and post-denitrifying MBBRs. A total of 28 organic micropollutants were analysed, at concentrations ranging from few ng/L to µg/L, in the influent and effluent of the different biological reactors in two sampling campaigns. The observed micropollutant removal efficiencies of the wastewater treatment plant varied from insignificant (< 20%) to high (> 90%) between compounds. The activated sludge reactor, being the first in line, contributed to most of the removal from the water phase. Additional removal of a few compounds was observed in the biofilm units, but most of the persistent compounds remained stable through all biological treatments.

The origin of DNA replication of porcine circovirus (PCV) was mapped to a 111-bp fragment. On top of a hairpin, a nonanucleotide (TAGTATTAC) homologous to nonanucleotides of other viruses was identified. Mutation of this element abolishes replication. PCV may be related to a virus family characterized by single-stranded circular DNA genomes, rolling-circle replication, and homology of their rep proteins.

Continuous and comparative studies of the plasma-levels of glutamic-oxaloacetic transaminase (G.O.T.), glutamic-pyruvic transaminase (G.P.T.), and ornithine-carbamyl transferase (O.C.T.), as well as the concentration of bromsulphalein (B.S.P.) showed that in experimentally produced hepatitis contagiosa canis (H.c.c.) the plasma-activity of these enzymes and B.S.P. retention were raised and the increased B.S.P. retention correlated in time with the rises in plasmaenzyme activity.

The levels of glutamic-oxaloacetic transaminase (G.O.T.), glutamicpyruvic transaminase (G.P.T.), and ornithine-carbamyl transferase (O.C.T.) were studied in different organs from healthy dogs. In the liver the activity of G.O.T., G.P.T., and O.C.T. was high. In the heart the G.O.T. level was high, the G.P.T. level lower, and the O.C.T. level very low. The skeletal muscles were found to have a very high G.O.T. level and very low levels of G.P.T. and O.C.T.

Dogs without antibodies were inoculated with virus of canine hepatitis. The conditions taken as a criterion of developed disease were a rise of temperature, leucopenia and increased activity of serum-transaminase enzymes. The urine was examined for the presence of virus and the antibody titre in blood-serum was determined. Urological studies including inulin and PAH clearance, and histological examination of the kidneys were carried out. No renal changes attributable to the virus inoculation were seen.

Electrocardiographic studies have been made in 14 dogs of the cocker spaniel breed, which had uraemia as a result of renal cortical hypoplasia. The predominating E.C.G. changes were increased duration of the QT interval, elevation or depression of the T waves, and, in exceptional cases, increased duration of the QRS complexes and depression of the amplitude of the ST segment and the ST junction. Determinations of serum-electrolytes in the examined cases showed a correlation between increased duration of the QT interval and hypocalcaemia. A correlation was also demonstrated between hyperkalaemia and elevation or depression of the T waves. The electrocardiograms of dogs in which the hypocalcaemia or the hyperkalaemia had been induced were also examined.

The clinical picture of renal cortical hypoplasia in the dog has been studied. Blood analyses including the electrolytes sodium, potassium, calcium and phosphorus are reported in detail. Hyperkalaemia, hypocalcaemia and hyperphosphataemia are present in hypoplastic dogs. Hypercalcaemia, on the other hand, is not seen, and the calcinosis in renal disorders is therefore considered to be caused by dystrophic calcification and not by metastases. The causation of the secondary hyperparathyreoidism is discussed. The presence of anaemia is demonstrated. Finally, a practical example is given to illustrate the competitive effect in the renal tubules between para-amino-hippuric acid (PAH) and diodone.

The blood-pressure in young dogs of the cocker spaniel breed was measured by a direct method. The mean arterial pressure in healthy dogs was 148 mm Hg with a standard deviation of 8.7. Among 10 dogs with renal cortical hypoplasia a raised blood-pressure was not recorded in any case. The hypertrophy of the left side of the heart observed at autopsy is hypothetically explained by the anaemia.

Clearing the haze: Stimulated emission depletion (STED) nanoscopy on single DNA strands reveals details with an up to five‐ to sixfold improved resolution over confocal microscopy (see images). Thus STED nanoscopy allows features to be distinguished down to the persistence length of DNA (ca. 50 nm) without promoting any significant additional photodamage, such as photobleaching or photonicking.

Scharfe Aufnahmen: STED‐Nanoskopie (STED=stimulierte Fluoreszenzverhinderung) von einzelnen DNA‐Strängen visualisiert Strukturen mit einer 5‐ bis 6fach höheren Auflösung als konfokale Mikroskopie (Konf), wie aus dem linken bzw. rechten Bild ersichtlich ist. Die STED‐Technik enthüllt Strukturen der Größenordnung der DNA‐Persistenzlänge (ca. 50 nm), ohne dabei in maßgeblicher Weise Photoschäden wie Bleichen oder DNA‐Bruch zu verursachen.