Quantitative morphology of renal cortical structures during compensatory hypertrophy

The compensatory hypertrophy in different renal cortical structures was studied in rats 10 and 21 days after unilateral nephrectomy (UNX). Quantitative morphological/stereological analysis revealed significant increases in total renal cortical volume - 33% on day 10 and 48% on day 21 - after UNX. These changes were paralleled by significant increments in the volumes of proximal convoluted tubule (PCT, 55%), distal convoluted tubule (DCT, 114%), and cortical collecting duct (CCD, 106%) segments on day 10. The corresponding changes on day 21 were 76, 122, and 212%, respectively. These alterations were accompanied by increases in segment length; 3% PCT, 23% DCT, and 50% CCD on day 10 and 9% PCT, 30% DCT, and 142% CCD on day 21 after UNX. The total luminal and basolateral cell membrane surface areas also exhibited a time-dependent increase after UNX. The increments in both luminal and basolateral membrane domains in PCT and DCT after 10 days were not significant, but reached significance after 21 days (PCT: luminal membrane 21%, basolateral membrane 63%; DCT: luminal membrane 98%, basolateral membrane 63%). In contrast, CCD membrane areas had increased substantially already 10 days after UNX (luminal membrane 92%, basolateral membrane 71%). It declined subsequently by day 21 (luminal membrane 57%, basolateral membrane 32%). The cell rubidium concentration after a 30-second rubidium infusion, an index of Na-K-ATPase activity, as well as sodium concentrations were unaltered in cells of all nephron segments investigated. Altogether the stereological analysis shows that the compensatory increase in organ volume can be attributed primarily to an increase in nephron epithelial volume. The PCT responds with `radial' hypertrophy (thickening of the tubular epithelial wall), while the DCT undergoes `length' hypertrophy (increase of tubular length without thickening of the tubular wall and without an increase in number of cells). This type of hypertrophy is especially prominent on day 21 after UNX for the CCD which doubles in length. Only on day 10 does the CCD seem to respond with hyperplasia. Adaptive changes in response to UNX develop gradually. Only a few of the morphological parameters studied had completed their change by 10 days, the majority required longer

Inhibition of angiotensin-converting enzyme modulates structural and functional adaptation to loop diuretic-induced diuresis

Inhibition of angiotensin-converting enzyme modulates structural and functional adaptation to loop diuretic-induced diuresis. The roles of elevated cell sodium concentrations and the angiotensin-aldosterone system (AAS) in the structural and functional adaptation of the distal tubule and collecting duct system to a chronic increase of sodium delivery were examined using electron microprobe and quantitative morphologic/stereologic analyses. Studies were performed on rats given the loop diuretic torasemide acutely (20 min) or chronically (12 days), either alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor, enalapril. In the sodium-absorbing cells of the distal tubule and cortical collecting duct–that is, in distal convoluted tubule (DCT), connecting tubule (CNT) and principal cells–an acute increase in sodium delivery caused a significant rise in intracellular sodium concentration and rubidium uptake, the latter an index of in vivo Na,K(Rb)-ATPase activity. The elevated cell sodium concentrations returned to, or close to, control values during chronic torasemide treatment. Intracellular rubidium concentrations, measured after a 30-second rubidium exposure, were not different from controls in DCT and CNT cells but were still higher in principal cells. Since, however, the distribution space for rubidium was significantly increased in chronic torasemide animals, rubidium uptake, and hence Na,K-ATPase activity, must have increased in proportion to cell volume in DCT and CNT cells, but more than proportionately in principal cells. When ACE was inhibited during chronic torasemide, the epithelial volume of DCT and cortical collecting duct (CCD) was increased mainly by lengthening and not, as was the case in rats given torasemide alone, by thickening of the tubule wall. Adaptation of the proximal tubule exclusively by lengthening was not affected by inhibition of the ACE. These data indicate that changes in cell ion composition may participate in initiating cell processes leading to adaptation of distal nephron segments to chronically increased salt delivery. Inhibition of the ACE reverses the torasemide-induced increase in apparent Na pump density in principal cells and seems to shift the relationship between hypertrophy and hyperplasia noted in DCT and CCD after chronic torasemide in favor of hyerplasia

Interdigitated aluminium and titanium sensors for assessing epithelial barrier functionality by electric cell-substrate impedance spectroscopy (ECIS)

Electric cell-substrate impedance spectroscopy (ECIS) enables non-invasive and continuous read-out of electrical parameters of living tissue. The aim of the current study was to investigate the performance of interdigitated sensors with 50 μm electrode width and 50 μm inter-electrode distance made of gold, aluminium, and titanium for monitoring the barrier properties of epithelial cells in tissue culture. At first, the measurement performance of the photolithographic fabricated sensors was characterized by defined reference electrolytes. The sensors were used to monitor the electrical properties of two adherent epithelial barrier tissue models: renal proximal tubular LLC-PK1 cells, representing a normal functional transporting epithelium, and human cervical cancer-derived HeLa cells, forming non-transporting cancerous epithelial tissue. Then, the impedance spectra obtained were analysed by numerically fitting the parameters of the two different models to the measured impedance spectrum. Aluminium sensors proved to be as sensitive and consistent in repeated online-recordings for continuous cell growth and differentiation monitoring assensors made of gold, the standard electrode material. Titanium electrodes exhibited an elevated intrinsic ohmic resistance incomparison to gold reflecting its lower electric conductivity. Analysis of impedance spectra through applying models and numerical data fitting enabled the detailed investigation of the development and properties of a functional transporting epithelial tissue using either gold or aluminium sensors. The result of the data obtained, supports the consideration of aluminium and titanium sensor materials as potential alternatives to gold sensors for advanced application of ECIS spectroscopy

Atypical antipsychotic therapy in Parkinson's disease psychosis: A retrospective study.

ObjectiveParkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs.MethodsA retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs.ResultsForty-five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs.LimitationsThis study was limited by its retrospective study design and small sample size and with likely selection bias.ConclusionsThe prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT 2A inverse agonist, pimavanserin, could be a better alternative in the treatment of PDP

Modern air, englacial and permafrost temperatures at high altitude on Mt Ortles (3905 m a.s.l.), in the eastern European Alps

The climatic response of mountain permafrost and glaciers located in high-elevation mountain areas has major implications for the stability of mountain slopes and related geomorphological hazards, water storage and supply, and preservation of palaeoclimatic archives. Despite a good knowledge of physical processes that govern the climatic response of mountain permafrost and glaciers, there is a lack of observational datasets from summit areas. This represents a crucial gap in knowledge and a serious limit for model-based projections of future behaviour of permafrost and glaciers. A new observational dataset is available for the summit area of Mt Ortles, which is the highest summit of South Tyrol, Italy. This paper presents a series of air, englacial, soil surface and rock wall temperatures collected between 2010 and 2016. Details are provided regarding instrument types and characteristics, field methods, and data quality control and assessment. The obtained data series are available through an open data repository (https://doi.org/10.5281/zenodo.8330289, Carturan et al., 2023). In the observed period, the mean annual air temperature at 3830 m a.s.l. was between −7.8 and −8.6 ∘C. The most shallow layers of snow and firn (down to a depth of about 10 m) froze during winter. However, melt water percolation restored isothermal conditions during the ablation season, and the entire firn layer was found at the melting pressure point. Glacier ice is cold, but only from about 30 m depth. Englacial temperature decreases with depth, reaching a minimum of almost −3 ∘C close to the bedrock, at 75 m depth. A small glacier located at 3470 m a.s.l., close to the summit of Mt Ortles, was also found in cold conditions down to a depth of 9.5 m. The mean annual ground surface temperature was negative for all but one monitored sites, indicating cold ground conditions and the existence of permafrost in nearly all debris-mantled slopes of the summit. Similarly, the mean annual rock wall temperature was negative at most monitored sites, except the lowest one at 3030 m a.s.l. This suggests that the rock faces of the summit are affected by permafrost at all exposures.</p

The Ortles ice cores: uncovering an extended climate archive from the Eastern Alps

During the last half century, oxygen and hydrogen stable isotope content of ice cores has been extensively used for air temperature reconstructions. The most suitable glaciers of the Alpine area, most exclusively in the Western Alps, havebeen utilizedfor icecoring formore thanfour decades.The paleoclimatic potential of theEastern Alps isstilllargelyunexploitedandwasscarcelyutilizedinthepastmainlybecauseofthelowerelevation(comparedto Western Alps) and hence the difficulty to find glaciers in cold conditions. The warming temperature trend appears to be particularly pronounced in the Alps, threatening the preservation of the glaciated areas and creating a sense of urgency in retrieving climatic archives before it is too late. In autumn 2011, four deep cores were drilled on Mt Ortles, South Tyrol, Italy, at 3859 m a.s.l. An extensive reconstructed temperature record for the Ortles summit, based on the surrounding meteorological station data, is available for the last 150 years, while an automatic weather station had been operating from 2011 to 2015 in proximity of the drilling site. The new ice core chronology, based on 210Pb, tritium, beta emissions analysis and 14C measurements of the particulate organic carbon, indicates that the bottom ice is 7000 years old, making it the second most extended glaciological archive ever retrieved in the Alps. The three equally long ice cores have been analyzed for oxygen and hydrogen stable isotopes throughout their length, and the goal is to create an Ortles stacked record for d18O and dD and compare the isotopic data to instrumental temperatures and to other Alpine records. Since 2008, several snow pits were dug in proximity of the drilling site during summer, when the temperature can oftenexceedthemeltingpoint.Theisotopicprofilesofthe2015snowpit,dugattheendofanexceptionallywarm summer,showhowtheisotopesignalisnowaffectedbythepost-depositionalprocessesthathaveoccurredduring that summer

Potential of Macrostomum lignano to recover from γ-ray irradiation

Stem cells are the only proliferating cells in flatworms and can be eliminated by irradiation with no damage to differentiated cells. We investigated the effect of fractionated irradiation schemes on Macrostomum lignano, namely, on survival, gene expression, morphology and regeneration. Proliferating cells were almost undetectable during the first week post-treatment. Cell proliferation and gene expression were restored within 1 month in a dose-dependent manner following exposure to up to 150 Gy irradiation. During recovery, stem cells did not cross the midline but were restricted within lateral compartments. An accumulated dose of 210 Gy resulted in a lethal phenotype. Our findings demonstrate that M. lignano represents a suitable model system for elucidating the effect of irradiation on the stem cell system in flatworms and for improving our understanding of the recovery potential of severely damaged stem-cell systems

M4 Safety and tolerability of BN82451B in huntington’s disease

Background BN82451B is a small, orally active molecule with good CNS penetration. Preclinical studies in tgHD R6/2 mice suggested improved motor function and prolonged survival. In addition antidyskinetic activity was observed in other models. The proposed mechanisms of action (MOA) are (1) antiexcytotoxic due to a sodium channel blocking potential, (2) antioxidant, (3) anti-inflammatory due to a cyclooxygenase (COX) inhibitory potential and (4) mitochondrial protective. Aims The primary objective of this phase 2a study (NCT02231580) is to investigate the safety and tolerability of BN82451B bid versus placebo for 28 days in male HD subjects. Secondary objectives include assessment of pharmacokinetics and of pharmacodynamics via the effects on quantitative motor (Q-Motor) measures. UHDRS subscales are implemented as exploratory measures. Methods Subjects: We intend to recruit 30 male HD subjects. 24 receive BN82451B and 6 placebo. The study is conducted in an inpatient setting at a single phase I unit in Germany. Design A sequential design was chosen to enable dose escalation starting with 40 mg bid with a potential maximum dose of 80 mg bid. Three subsequent cohorts of 10 patients each are randomised with different starting doses. Subjects in group one are treated with 40 mg bid for 14 days and may be increased to 60 mg bid the subsequent 14 days. In group 2, subjects may first receive 60 mg bid with possible increase to 80 mg bid. Group 3 subjects may receive 80 mg bid for 28 days. Dose increases in the consecutive groups are subject to approval by a Data Review Committee (DRC). The decision to increase the dose in individual patient will be based on the investigator’s judgement. Results Results of the study are expected for Q4/2016. Conclusions Recruitment in this trial is difficult as in-patient periods of nearly one month are logistically challenging. Safety data will be available soon and pharmacodynamics readouts such as Q-motor measures may help to guide decisions on the further path of development of BN82451B