The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the ...urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na
-dependent Cl
/HCO
exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl
/HCO
exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.
Background
Enhanced recovery protocols may reduce postoperative complications and length of hospital stay. However, the implementation of these protocols requires time and financial investment. This ...study evaluated the cost‐effectiveness of enhanced recovery implementation.
Methods
The first 50 consecutive patients treated during implementation of an enhanced recovery programme were compared with 50 consecutive patients treated in the year before its introduction. The enhanced recovery protocol principally implemented preoperative counselling, reduced preoperative fasting, preoperative carbohydrate loading, avoidance of premedication, optimized fluid balance, standardized postoperative analgesia, use of a no‐drain policy, as well as early nutrition and mobilization. Length of stay, readmissions and complications within 30 days were compared. A cost‐minimization analysis was performed.
Results
Hospital stay was significantly shorter in the enhanced recovery group: median 7 (interquartile range 5–12) versus 10 (7–18) days (P = 0·003); two patients were readmitted in each group. The rate of severe complications was lower in the enhanced recovery group (12 versus 20 per cent), but there was no difference in overall morbidity. The mean saving per patient in the enhanced recovery group was €1651.
Conclusion
Enhanced recovery is cost‐effective, with savings evident even in the initial implementation period.
Worth the investment
Background
Enhanced recovery after surgery (ERAS) programmes have been shown to decrease complications and hospital stay. The cost‐effectiveness of such programmes has been demonstrated for ...colorectal surgery. This study aimed to assess the economic outcomes of a standard ERAS programme for pancreaticoduodenectomy.
Methods
ERAS for pancreaticoduodenectomy was implemented in October 2012. All consecutive patients who underwent pancreaticoduodenectomy until October 2014 were recorded. This group was compared in terms of costs with a cohort of consecutive patients who underwent pancreaticoduodenectomy between January 2010 and October 2012, before ERAS implementation. Preoperative, intraoperative and postoperative real costs were collected for each patient via the hospital administration. A bootstrap independent t test was used for comparison. ERAS‐specific costs were integrated into the model.
Results
The groups were well matched in terms of demographic and surgical details. The overall complication rate was 68 per cent (50 of 74 patients) and 82 per cent (71 of 87 patients) in the ERAS and pre‐ERAS groups respectively (P = 0·046). Median hospital stay was lower in the ERAS group (15 versus 19 days; P = 0·029). ERAS‐specific costs were €922 per patient. Mean total costs were €56 083 per patient in the ERAS group and €63 821 per patient in the pre‐ERAS group (P = 0·273). The mean intensive care unit (ICU) and intermediate care costs were €9139 and €13 793 per patient for the ERAS and pre‐ERAS groups respectively (P = 0·151).
Conclusion
ERAS implementation for pancreaticoduodenectomy did not increase the costs in this cohort. Savings were noted in anaesthesia/operating room, medication and laboratory costs. Fewer patients in the ERAS group required an ICU stay.
Some savings
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•A. brasilense is able to efficiently reduce toxic selenite to Se0S0-nanoparticles.•Reduction was also possible in environmental waters supplemented with selenite.•Biogenic ...nanoparticles are Se8-nSn structured spheres, most likely Se6S2.•Se0S0- nanoparticles occur extracellularly with an average size of 400nm.•Se0S0-nanoparticles form a (destabilized) colloidal suspension (ζ-potential −18mV).
This study combines the interaction between the toxic oxyanions selenite and selenate and the plant growth promoting bacterium Azospirillum brasilense with a comprehensive characterization of the formed selenium particles. As selenium is an essential trace element, but also toxic in high concentrations, its state of occurrence in nature is of major concern. Growth of the bacterium was affected by selenite (1–5mM) only, observable as a prolonged growth lag-phase of 3days. Subsequently, selenite reduction occurred under aerobic conditions resulting in extracellularly formed insoluble Se0 particles. Complementary studies by microscopic and spectroscopic techniques revealed the particles to be homogeneous and stable Se8-nSn structured spheres with an average size of 400nm and highly negative surface charge of −18mV in the neutral pH range. As this is the first study showing Azospirillum brasilense being able to biotransform selenite to selenium particles containing a certain amount of sulfur, even if environmental waters supplemented with selenite were used, they may significantly contribute to the biogeochemical cycling of both elements in soil as well as to their soil-plant transfer. Therefore, microbial biotransformation of selenite under certain circumstances may be used for various bio-remediation and bio-technological applications.
Cardio‐facio‐cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of ...the RAS–RAF–MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC‐affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty‐four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC‐affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty‐eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1‐ and MAP2K2‐mutation positive individuals, suggesting possible genotype–phenotype correlations.
Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we ...reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy.
Mutations in CRLF1 cause familial achalasia Busch, A.; Žarković, M.; Lowe, C. ...
Clinical genetics,
July 2017, 2017-Jul, 2017-07-00, 20170701, Letnik:
92, Številka:
1
Journal Article
Recenzirano
We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease‐associated genes by a next‐generation sequencing ...(NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor‐like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold‐induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor‐like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1‐related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.
Based on small scale studies or on little sensitive serological tests, bovines in the south of the state of Rio Grande do Sul, Brazil, are known to be infected with either
bovine herpesvirus 1 ...(BoHV-1) or 5 (BoHV-5). However, whether the prevalence of each of these viruses is high or low is currently still unknown. In order to determine the extent of BoHV (-1 and/or -5) infections in bovines in this region of Brazil, 200 bovines were studied for the presence of BoHV DNA. To this end, first a quantitative PCR was developed that amplified BoHV-1 DNA as well as BoHV-5 DNA. Using this PCR the number of BoHV genomes normally present in latently infected ganglia of naturally infected bovines was estimated. The new PCR was sensitive enough to detect most BoHV DNA in infected ganglia. The results of this first PCR showed that at least 87% of the bovines in the south of Rio Grande do Sul were (latently) infected with either BoHV-1 or BoHV-5. To determine the prevalence of BoHV-1 and BoHV-5 separately, two type-specific PCRs – one for each virus – were developed that used the products of the first PCR as a template. The results of these type-specific PCRs showed that 82.8% of the BoHV positive population was (latently) infected with BoHV-1, 93.1% with BoHV-5 and 75.9% with both BoHV-1 and BoHV-5. This is the first time that such a high frequency of co-infection of BoHV-1 and BoHV-5 in bovines has been demonstrated.
Synaptic inhibition by GABAA and glycine receptors, which are ligand-gated anion channels, depends on the electrochemical potential for chloride. Several potassium-chloride cotransporters can lower ...the intracellular chloride concentration Cl−i, including the neuronal isoform KCC2. We show that KCC2 knockout mice died immediately after birth due to severe motor deficits that also abolished respiration. Sciatic nerve recordings revealed abnormal spontaneous electrical activity and altered spinal cord responses to peripheral electrical stimuli. In the spinal cord of wild-type animals, the KCC2 protein was found at inhibitory synapses. Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition.
The question of how RNA, as the principal carrier of genetic information evolved is fundamentally important for our understanding of the origin of life. The RNA molecule is far too complex to have ...formed in one evolutionary step, suggesting that ancestral proto‐RNAs (first ancestor of RNA) may have existed, which evolved over time into the RNA of today. Here we show that isoxazole nucleosides, which are quickly formed from hydroxylamine, cyanoacetylene, urea and ribose, are plausible precursors for RNA. The isoxazole nucleoside can rearrange within an RNA‐strand to give cytidine, which leads to an increase of pairing stability. If the proto‐RNA contains a canonical seed‐nucleoside with defined stereochemistry, the seed‐nucleoside can control the configuration of the anomeric center that forms during the in‐RNA transformation. The results demonstrate that RNA could have emerged from evolutionarily primitive precursor isoxazole ribosides after strand formation.
Prebiotically plausible isoxazole nucleosides are shown to be excellent candidates for proto‐nucleosides and proto‐RNAs. The proto‐nucleoside forms 2 instructive H‐bonds with guanosine and can directly rearrange in RNA to give cytidine. The stereochemical outcome of the reaction is controlled by already present canonical seed‐nucleosides.
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