Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria

Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut0 and mut- subtype respectively) and by defects in the metabolism of its cofactor 5′-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut0 and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut0, 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretio

Cellular senescence predicts treatment outcome in metastasised colorectal cancer

Background: Cellular senescence is a terminal cell-cycle arrest that occurs in response to activated oncogenes and DNA-damaging chemotherapy. Whether cancer cell senescence at diagnosis might be predictive for treatment outcome is unknown. Methods: A senescence index (SI) was developed and used to retrospectively correlate the treatment outcome of 30 UICC stage IV colorectal cancer (CRC) patients with their SI at diagnosis. Results: 5-Fluorouracil/leucovorin-treated CRC patients achieved a significantly longer progression-free survival when presenting with SI-positive tumours before therapy (median 12.0 vs 6.0 months; P=0.044). Conclusion: Cancer cell senescence predicts treatment outcome in metastasised CRC. Prospective analyses of larger patient cohorts are needed

Investigation of amphibian mortality events in wildlife reveals an on-going ranavirus epidemic in the North of the Netherlands

In the four years following the first detection of ranavirus (genus Ranavirus, family Iridoviridae) infection in Dutch wildlife in 2010, amphibian mortality events were investigated nationwide to detect, characterize and map ranaviruses in amphibians over time, and to establish the affected host species and the clinico-pathological presentation of the disease in these hosts. The ultimate goal was to obtain more insight into ranavirus disease emergence and ecological risk. In total 155 dead amphibians from 52 sites were submitted between 2011 and 2014, and examined using histopathology, immunohistochemistry, virus isolation and molecular genetic characterization. Ranavirus-associated amphibian mortality events occurred at 18 sites (35%), initially only in proximity of the 2010 index site. Specimens belonging to approximately half of the native amphibian species were infected, including the threatened Pelobates fuscus (spadefoot toad). Clustered massive outbreaks involving dead adult specimens and ranavirus genomic identity indicated that one common midwife toad virus (CMTV)-like ranavirus strain is emerging in provinces in the north of the Netherlands. Modelling based on the spatiotemporal pattern of spread showed a high probability that this emerging virus will continue to be detected at new sites (the discrete reproductive power of this outbreak is 0.35). Phylogenetically distinct CMTV-like ranaviruses were found in the south of the Netherlands more recently. In addition to showing that CMTV-like ranaviruses threaten wild amphibian populations not only in Spain but also in the Netherlands, the current spread and risk of establishment reiterate that understanding the underlying causes of CMTV-like ranavirus emergence requires international attention

Friesian horses as a possible model for human acquired aortopulmonary fistulation

BACKGROUND: Acquired aortopulmonary fistulation is a rare condition in humans. It usually results as a late complication of a true or pseudoaneurysm of the thoracic aorta. It is most commonly associated with trauma or surgery, less commonly with atherosclerosis, inflammation, hypertension or Marfan's syndrome. Aortopulmonary fistulation is also seen as a rare complication of acute aortic dissection. On rare occasions, acquired aortopulmonary fistulation is reported in aged patients without any of the above mentioned triggering factors. Thus, these cases should be considered as idiopathic aortopulmonary fistulation. Clearly, the pathogenesis of this condition is not yet completely understood. Friesian horses are highly inbred and are affected by several genetic conditions. Rupture of the thoracic aorta has a relatively high prevalence in Friesian horses and is often characterized by the formation of a pseudoaneurysm with subsequent fistulation into the pulmonary artery. Affected animals may survive for several weeks to months. FINDINGS: Here we performed vascular casting in three affected Friesian horses. In all three cases, an aortic rupture at the caudoventral side of the aorta was connected with a rupture of the main pulmonary artery just proximal to its bifurcation. CONCLUSIONS: Affected Friesians show a consistent location and configuration of the aortic rupture site, very similar to the human condition and therefore could act as a spontaneous model to study this disease

Процессы низкотемпературной дипольной релаксации в системах бычий сывороточный альбумин–нанооксид–вода

Методом термостимулированной деполяризации проведены сравнительные исследования процессов низкотемпературной дипольной релаксации в замороженных водных дисперсиях нанооксидов, индивидуальных и в присутствии бычьего сывороточного альбумина (БСА). Для последних систем характерно увеличение вкладов релаксационных процессов при Т > 160–170 К, в то время как для водных дисперсий оксидов бóльшие токи ТСД наблюдаются при Т 160…170 К, в той час як для водних дисперсій оксидів більші струми ТСД спостерігаються при Т 160- 170 К, since for aqueous suspensions of nanooxides, greater TSD currents are observed at Т < 160-170 К. This difference is due to the participation of the BSA molecules (polar bonds, groups, fragments, whole molecules) in the relaxation processes, whose features depend also on the nature of nanooxide and a character of BSA interactions with its surface

Spatiotemporal mortality and demographic trends in a small cetacean: Strandings to inform conservation management

With global increases in anthropogenic pressures on wildlife populations comes a responsibility to manage them effectively. The assessment of marine ecosystem health is challenging and often relies on monitoring indicator species, such as cetaceans. Most cetaceans are however highly mobile and spend the majority of their time hidden from direct view, resulting in uncertainty on even the most basic population metrics. Here, we discuss the value of long-term and internationally combined stranding records as a valuable source of information on the demographic and mortality trends of the harbour porpoise (Phocoena phocoena) in the North Sea. We analysed stranding records (n = 16,181) from 1990 to 2017 and demonstrate a strong heterogeneous seasonal pattern of strandings throughout the North Sea, indicative of season-specific distribution or habitat use, and season-specific mortality. The annual incidence of strandings has increased since 1990, with a notable steeper rise particularly in the southern North Sea since 2005. A high density of neonatal strandings occurred specifically in the eastern North Sea, indicative of areas important for calving, and large numbers of juvenile males stranded in the southern parts, indicative of a population sink or reflecting higher male dispersion. These findings highlight the power of stranding records to detect potentially vulnerable population groups in time and space. This knowledge is vital for managers and can guide, for example, conservation measures such as the establishment of time-area-specific limits to potentially harmful human activities, aiming to reduce the number and intensity of human-wildlife conflicts

Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria

Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut0 and mut- subtype respectively) and by defects in the metabolism of its cofactor 5′-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut0 and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut0, 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretio