ABSTRACT
Backgound
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, and leads to a steady loss of kidney function in adulthood. The variable course of ...the disease makes it necessary to identify the patients with rapid disease progression who will benefit the most from targeted therapies and interventions. Currently, magnetic resonance imaging–based volumetry of the kidney is the most commonly used tool for this purpose. Biomarkers that can be easily and quantitatively determined, which allow a prediction of the loss of kidney function, have not yet been established in clinical practice. The glycoprotein Dickkopf 3 (DKK3) which is secreted in the renal tubular epithelium upon stress and contributes to tubulointerstitial fibrosis via the Wnt signaling pathway, was recently described as a biomarker for estimating risk of kidney function loss, but has not been investigated for ADPKD. This study aimed to obtain a first insight into whether DKK3 may indeed improve outcome prediction in ADPKD in the future.
Methods
In 184 ADPKD patients from the AD(H)PKD registry and 47 healthy controls, the urinary DKK3 (uDKK3) levels were determined using ELISA. Multiple linear regression was used to examine the potential of these values in outcome prediction.
Results
ADPKD patients showed significantly higher uDKK3 values compared with the controls (mean 1970 ± 5287 vs 112 ± 134.7 pg/mg creatinine). Furthermore, there was a steady increase in uDKK3 with an increase in the Mayo class (A/B 1262 ± 2315 vs class D/E 3104 ± 7627 pg/mg creatinine), the best-established biomarker of progression in ADPKD. uDKK3 also correlated with estimated glomerular filtration rate (eGFR). Patients with PKD1 mutations show higher uDKK3 levels compared with PKD2 patients (PKD1: 2304 ± 5119; PKD2: 506.6 ± 526.8 pg/mg creatinine). Univariate linear regression showed uDKK3 as a significant predictor of future eGFR slope estimation. In multiple linear regression this effect was not significant in models also containing height-adjusted total kidney volume and/or eGFR. However, adding both copeptin levels and the interaction term between copeptin and uDKK3 to the model resulted in a significant predictive value of all these three variables and the highest R2 of all models examined (∼0.5).
Conclusion
uDKK3 shows a clear correlation with the Mayo classification in patients with ADPKD. uDKK3 levels correlated with kidney function, which could indicate that uDKK3 also predicts a disproportionate loss of renal function in this collective. Interestingly, we found an interaction between copeptin and uDKK3 in our prediction models and the best model containing both variables and their interaction term resulted in a fairly good explanation of variance in eGFR slope compared with previous models. Considering the limited number of patients in these analyses, future studies will be required to confirm the results. Nonetheless, uDKK3 appears to be an attractive candidate to improve outcome prediction of ADPKD in the future.
A new technique is introduced for doping gold nanoclusters by using a metal surface such as Ag, Cu and Cd as a source of heteroatoms. The importance of the thiol ligand in the doping process is ...examined by following the reactions with MALDI-TOF mass spectrometry in the presence and the absence of the thiols on the surface. The doping reactions depend greatly on the type of the cluster and the availability of the ligand which is a crucial element for alloying. The thiol acts as a messenger exchanging the metal atoms between the cluster and the metal surface as revealed by the XPS studies performed on the metal surfaces.
New method to dope gold nanoclusters by using metal surfaces of silver, copper and cadmium as sources of heteroatoms.
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic cause of kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the first drug with proven ...disease-modifying activity. Long-term treatment adherence is crucial, but a considerable fraction of patients discontinue treatment, because of aquaretic side effects.
Twenty-four-hour urine was collected in 75 patients with ADPKD during up-titration of tolvaptan and, in combination with clinical characteristics, examined to identify factors influencing urine volume. Patient-reported outcomes were analyzed using the Short Form-12 (SF-12) and patient-reported outcomes questionnaires reporting micturition frequency and burden of urine volume.
Initiation of therapy led to a large increase in urine volume followed by only minor further increase during up-dosing. Younger patients and patients with better kidney function experienced a larger relative rise. Twenty-four-hour urine osmolality dropped by about 50% after therapy initiation independently of dose, with a considerable proportion of patients achieving adequate suppression. Sodium and potassium intake turned out to be the only significant modifiable factors for urine volume after multivariate linear regression models, whereas age and weight could be identified as non-modifiable factors. No change in quality of life (QoL) was detected in relation to treatment or urine volume using SF-12 questionnaires, a finding that was further supported by the results of the patient-reported outcomes assessment.
This study provides an in-detail analysis of factors associated with the degree of polyuria on tolvaptan and puts them into the context of QoL. These findings will contribute to optimized patient counseling regarding this treatment option in ADPKD.
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Previous research suggests that children with autism have deficits in drawing imaginative content. However, these conclusions are largely based on tasks that require children to draw impossible ...persons, and performance on this task may be limited by social deficits. To determine the generality of the deficit in imagination in children with autism, we asked 25 children with autism (mean age 9;7) and 29 neurotypically developing children (mean age 8;7) to draw an imaginative person and house. Drawings of imaginary houses by children with autism did not differ from those by neurotypically developing controls, but drawings of persons were significantly less imaginative. These findings suggest that the impairment in imagination among children with autism may be specific to social stimuli.
The aim of this consensus statement was to discuss transition of patients with ADHD from child to adult healthcare services, and formulate recommendations to facilitate successful transition. An ...expert workshop was convened in June 2012 by the UK Adult ADHD Network (UKAAN), attended by a multidisciplinary team of mental health professionals, allied professionals and patients. It was concluded that transitions must be planned through joint meetings involving referring/receiving services, patients and their families. Negotiation may be required to balance parental desire for continued involvement in their child's care, and the child's growing autonomy. Clear transition protocols can maintain standards of care, detailing relevant timeframes, responsibilities of agencies and preparing contingencies. Transition should be viewed as a process not an event, and should normally occur by the age of 18, however flexibility is required to accommodate individual needs. Transition is often poorly experienced, and adherence to clear recommendations is necessary to ensure effective transition and prevent drop-out from services.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The RNA world hypothesis describes a stage in the early evolution of life in which catalytic RNAs mediated the replication of RNA world organisms. One challenge to this hypothesis is that most ...existing ribozymes are much longer than what may be expected to originate from prebiotically plausible methods, or from the polymerization by currently existing polymerase ribozymes. We previously developed a 96-nucleotide long ribozyme, which generates a chemically activated 5′-phosphate (a 5′-triphosphate) from a prebiotically plausible molecule, trimetaphosphate, and an RNA 5′-hydroxyl group. Analogous ribozymes may have been important in the RNA world to access an energy source for the earliest life forms. Here we reduce the length of this ribozyme by fragmenting the ribozyme into multiple RNA strands, and by successively removing its longest double strand. The resulting ribozyme is composed of RNA fragments with none longer than 34 nucleotides. The temperature optimum was ∼20 °C, compared to ∼40 °C for the parent ribozyme. This shift in temperature dependence may be a more general phenomenon for fragmented ribozymes, and may have helped RNA world organisms to emerge at low temperature.
The temperature optimum of a triphosphorylation ribozyme shifted to lower temperature, after size reduction and fragmentation.
Four-repeat tauopathies Rösler, Thomas W; Tayaranian Marvian, Amir; Brendel, Matthias ...
Progress in neurobiology,
09/2019, Letnik:
180
Journal Article
Recenzirano
Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton. Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined ...by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease or glial globular tauopathy belong to the group of 4R-tauopathies. The present review provides an introduction in the current concept of 4R-tauopathies, including an overview of the neuropathological and clinical spectrum of these diseases. It describes the genetic and environmental etiological factors, as well as the contemporary knowledge about the pathophysiological mechanisms, including post-translational modifications, aggregation and fragmentation of tau, as well as the role of protein degradation mechanisms. Furthermore, current theories about disease propagation are discussed, involving different extracellular tau species and their cellular release and uptake mechanisms. Finally, molecular diagnostic tools for 4R-tauopathies, including tau-PET and fluid biomarkers, and investigational therapeutic strategies are presented. In summary, we report on 4R-tauopathies as overarching disease concept based on a shared pathophysiological concept, and highlight the challenges and opportunities on the way towards a causal therapy.
ABSTRACT
Background
The identification of new biomarkers in autosomal-dominant polycystic kidney disease (ADPKD) is crucial to improve and simplify prognostic assessment as a basis for patient ...selection for targeted therapies. Post hoc analyses of the TEMPO 3:4 study indicated that copeptin could be one of those biomarkers.
Methods
Copeptin was tested in serum samples from patients of the AD(H)PKD study. Serum copeptin levels were measured using a time-resolved amplified cryptate emission (TRACE)-based assay. In total, we collected 711 values from 389 patients without tolvaptan treatment and a total of 243 values (of which 64 were pre-tolvaptan) from 94 patients on tolvaptan. These were associated with rapid progression and disease-causing gene variants and their predictive capacity tested and compared with the Mayo Classification.
Results
As expected, copeptin levels showed a significant negative correlation with estimated glomerular filtration rate (eGFR). Measurements on tolvaptan showed significantly higher copeptin levels (9.871 pmol/L vs 23.90 pmol/L at 90/30 mg; P < .0001) in all chronic kidney disease stages. Linear regression models (n = 133) show that copeptin is an independent predictor of eGFR slope. A clinical model (including eGFR, age, gender, copeptin) was nearly as good (R2 = 0.1196) as our optimal model (including height-adjusted total kidney volume, eGFR, copeptin, R2 = 0.1256). Adding copeptin to the Mayo model improved future eGFR estimation.
Conclusion
Copeptin levels are associated with kidney function and independently explained future eGFR slopes. As expected, treatment with tolvaptan strongly increases copeptin levels.
Lay Summary
Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic condition that can cause kidney damage. Researchers have been looking for new ways to predict how the disease will progress, so that patients can be offered the best treatment options. Copeptin is a substance that has been identified as a possible new marker for ADPKD. In this study, researchers measured copeptin levels in the blood of tolvaptan-naive ADPKD patients and ADPKD patients taking tolvaptan, a medication that can slow the progression of the disease. They found that copeptin levels were linked to kidney function and could help predict how the disease would progress in the future. The study also showed that tolvaptan increased copeptin levels. This research could help doctors make better treatment decisions for ADPKD patients.
Mutations in PRRT2 cause autosomal dominant paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC).
A previously not recognized intronic PRRT2 mutation (c.880-35G > A; p.S294Lfs*29) ...was found in an 18 month old girl with IC and in her mother with classical presentation of PKD. The mutation results in a novel splice acceptor site in intron 2 of PRRT2. Due to frameshift and a subsequent premature stop-codon the resulting transcript appears to render the PRRT2 protein non/dysfunctional and is the likely cause of disease in this family.
Our findings expand the mutational spectrum of this disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Owing to increased environmental demands to replace petroleum-derived materials with more environmentally friendly materials, research has been directed towards the potential of using wood in the ...automotive industry. This study extensively investigates the compressive strength (
f
c
) of two hardwood species (beech and birch) with different anatomical directions, at various moisture and temperature levels, in an attempt to understand the wood’s behaviour during the forming process. The experimental tests were performed at 20, 100 and 140 °C on specimens with five moisture levels, ranging from completely dry to wet conditions. Overall, irrespective of the investigated direction, the measured compressive strength exhibited a clear exponential trend with increasing moisture content over the whole temperature range. This was capitalised on to present a simple predictive equation to roughly estimate the
f
c
of beech and birch in different moisture and temperature conditions by relating to their dry
f
c
at a reference temperature of 20 °C. The proposed approach was compared with other procedures and trends reported in the literature for the effect of moisture and temperature on the
f
c
of wood. Furthermore, the reduction factors for the effect of temperature on the
f
c
of softwoods, as set out in Eurocode 5 (EN 1995-1-2), were discussed in comparison with the present study findings. It was shown that, although the Eurocode approach is conservative, it may still be applicable for estimating the
f
c
of hardwood species.
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