Notes

Peri-implant bone tissue augmentation from the sub-periosteal peri-implant enhanced layer technique as well as a bovine-derived navicular bone prevent: In a situation statement.
Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system.Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1(c.1276_1298del) mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1(c.1276_1298del) zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of age-related macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.CD103(+) dendritic cells (DCs) in nonlymphoid organs exhibit two main functions maintaining tolerance by induction of regulatory T cells and protecting against tissue infection through cross-presentation of foreign antigens to CD8(+) T cells. However, the role of CD103(+) DCs in kidney disease is unknown. In this study, we show that CD103(+) DCs are one of four subpopulations of renal mononuclear phagocytes in normal kidneys. CD103(+) DCs expressed DC-specific surface markers, transcription factors, and growth factor receptors and were found in the kidney cortex but not in the medulla. The number of kidney CD103(+) DCs was significantly higher in mice with adriamycin nephropathy (AN) than in normal mice, and depletion of CD103(+) DCs attenuated kidney injury in AN mice. In vitro, kidney CD103(+) DCs preferentially primed CD8(+) T cells and did not directly induce tubular epithelial cell apoptosis. Adoptive transfer of CD8(+) T cells significantly exacerbated kidney injury in AN SCID mice, whereas depletion of CD103(+) DCs in these mice impaired activation and proliferation of transfused CD8(+) T cells and prevented the exacerbation of kidney injury associated with this transfusion. In conclusion, kidney CD103(+) DCs display a pathogenic role in murine CKD via activation of CD8(+) T cells.A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. see more Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.Blue whiting Micromesistius poutassou mean total length at age in the north-east Atlantic Ocean was found to vary by around ±6% during the period 2004-2011 and mean mass at age by ±22% during the years 1981-2013. Linear modelling provided strong evidence that these phenotypic growth variations can be explained by trophic conditions, mainly negative density dependence and also food availability, and a negative long-term temperature effect on asymptotic size.Due to a typesetting error, the labelling was changed and the figures in this article [1] were presented in the order 2, 4, 10, 6, 1, 3, 5, 7, 8, 9, 11, 12, 13, 14 and the supplementary figure links were inverted. The revised version has the figures in the correct order.
Cuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16weeks in male rats, changes in sensory and autonomic innervation of the skin were described after cuff and SNI using immunohistochemistry to label myelinated (neurofilament 200 positive-NF200+) and peptidergic (calcitonin gene-related peptide positive-CGRP+) primary afferents and sympathetic fibres (dopamine β-hydroxylase positive-DBH+)

Cuff and SNI caused an early loss and later reinnervation of NF200 and CGRP fibres in the plantar hind paw skin. In both models, DBH+ fibres sprouted into the upper dermis of the plantar skin 4 and 6weeks after injury. Despite these similarities, behavioural pain measures were significantly different in each model. Sympathectomy using guanethidine significantly alleviated mechanical allodynia 6weeks after cuff, when peak sympathetic sprouting was observed, having no effect at 2weeks, when fibres were absent. In SNI animals, mechanical allodynia in the lateral paw was significantly improved by guanethidine at 2 and 6weeks, and the development of cold hyperalgesia, which roughly paralleled the appearance of ectopic sympathetic fibres, was alleviated by guanethidine at 6weeks. Sympathetic fibres did not sprout into the dorsal root ganglia at 2 or 6weeks, indicating their unimportance to pain behaviour in these two models.

Alterations in sympathetic innervation in the skin represents an important mechanism that contributes to pain in cuff and SNI models of neuropathic pain.
Alterations in sympathetic innervation in the skin represents an important mechanism that contributes to pain in cuff and SNI models of neuropathic pain.
Recent advances in wheeled mobility technology are multiplying opportunities for community integration and improved quality of life. The mobility needs of older wheelchair users are particularly complex due to a constellation of chronic conditions and comorbidities that may compromise optimal use of the device. The purpose of the Mobility Outcomes via Information Technologies (MOvIT) project is to examine the feasibility of automated calls for the systematic monitoring for adverse outcomes associated with wheelchair use.

A two-phase mixed methods approach was used. Phase I involved user-centered development and face validation of a monitoring questionnaire with end-users (seven wheelchair users and five healthcare providers). Phase II tested the feasibility of monitoring outcomes using automated calls to administer the MOvIT questionnaire 1 and 3 months after wheelchair delivery with a prospective cohort of older adults (50-84 years of age). When problems were identified, the computer monitoring system notified a clinical coordinator who followed up with respondents requiring interventions.
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