Neural stem cells from protein tyrosine phosphatase sigma knockout mice generate an altered neuronal phenotype in culture

BACKGROUND: The LAR family Protein Tyrosine Phosphatase sigma (PTPσ) has been implicated in neuroendocrine and neuronal development, and shows strong expression in specific regions within the CNS, including the subventricular zone (SVZ). We established neural stem cell cultures, grown as neurospheres, from the SVZ of PTPσ knockout mice and sibling controls to determine if PTPσ influences the generation and the phenotype of the neuronal, astrocyte and oligodendrocyte cell lineages. RESULTS: The neurospheres from the knockout mice acquired heterogeneous developmental characteristics and they showed similar morphological characteristics to the age matched siblings. Although Ptprs expression decreases as a function of developmental age in vivo, it remains high with the continual renewal and passage of the neurospheres. Stem cells, progenitors and differentiated neurons, astrocytes and oligodendrocytes all express the gene. While no apparent differences were observed in developing neurospheres or in the astrocytes and oligodendrocytes from the PTPσ knockout mice, the neuronal migration patterns and neurites were altered when studied in culture. In particular, neurons migrated farther from the neurosphere centers and the neurite outgrowth exceeded the length of the neuronal processes from age matched sibling controls. CONCLUSION: Our results imply a specific role for PTPσ in the neuronal lineage, particularly in the form of inhibitory influences on neurite outgrowth, and demonstrate a role for tyrosine phosphatases in neuronal stem cell differentiation

Rapid review on safeguarding to inform the Healthy Child Programme 5 to 19

This is the final version of the article. Available from PHE Publications via the DOI in this recordSummary of key points 1. The purpose of this rapid review is to update the evidence in relation to safeguarding guidance in the Healthy Child Programme for 5 to 19 year-olds. 2. It synthesises evidence about ‘what works’ in prevention and early intervention as regards child abuse and neglect, child sexual abuse and exploitation, intimate partner violence (IPV), female genital mutilation (FGM) and gang violence. 3. Focusing on the period 2006 to 2015, a total of 27 systematic reviews and 9 additional randomised controlled trials (RCTs) are included. 4. Key messages on identifying families in need of additional support, the effective implementation of interventions, and workforce skills and training are also included, as is evidence on the economic aspects of safeguarding

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Holocene glacier and ice cap fluctuations in southwest Greenland inferred from two lake records

Glaciers and ice caps (GICs) respond rapidly to changes in temperature and precipitation. Thus, records of their past fluctuations yield valuable information on past climate. However, relatively little is known about the long-term, Holocene history of Greenland’s local GICs, peripheral to the Greenland Ice Sheet. Here we report sediment records of Holocene glacier activity from two distally fed glacial lakes near Buksefjord, southwest Greenland. The two lakes’ watersheds host modern GICs of contrasting size. The Pers Lake (informal name) watershed drains part (3 km2) of a single small ice cap. In contrast, nearby Lake T3’s (informal name) watershed drains numerous GICs totaling 100 km2. At the time it emerged from the sea ∼8.6 ka BP, Pers Lake was receiving no glacial meltwater input. Sediment physical and geochemical properties indicate persistent meltwater input and regrowth of the ice cap within the Pers Lake catchment beginning at ∼1.4 ka BP, after almost 3000 years of sporadic meltwater input beginning ∼4.3 ka BP. The ice cap above Pers Lake reached a maximum late Holocene extent during the final phase of the Little Ice Age (LIA), ∼0.1 ka BP. The complementary Lake T3 sediment record suggests continued meltwater input from the larger suite of upstream GICs from the time of the lake’s isolation from the sea ∼8.4–7.5 ka BP through to the present. This indicates that some GICs here probably survived the Holocene Thermal Maximum (HTM), although were significantly reduced in size for an extended period (of unknown age and duration). Combined with evidence from Pers Lake and prior studies that show GICs at low and intermediate elevations in this region melted away completely during the HTM, and evidence for GIC presence at Lake T3, we provide lower and upper bounds on regional HTM equilibrium-line altitudes (ELAs). We estimate that regional ELAs were between ∼1370 and 1470 m above sea level in the early-to-middle Holocene. From the middle to late Holocene, our results, along with other regional GIC studies, indicate progressive lowering of regional glacier ELAs in response to Neoglacial summer cooling of ∼2.7 °C, assuming no change in precipitation

Neural stem cells from protein tyrosine phosphatase sigma knockout mice generate an altered neuronal phenotype in culture

Abstract Background The LAR family Protein Tyrosine Phosphatase sigma (PTPσ) has been implicated in neuroendocrine and neuronal development, and shows strong expression in specific regions within the CNS, including the subventricular zone (SVZ). We established neural stem cell cultures, grown as neurospheres, from the SVZ of PTPσ knockout mice and sibling controls to determine if PTPσ influences the generation and the phenotype of the neuronal, astrocyte and oligodendrocyte cell lineages. Results The neurospheres from the knockout mice acquired heterogeneous developmental characteristics and they showed similar morphological characteristics to the age matched siblings. Although Ptprs expression decreases as a function of developmental age in vivo, it remains high with the continual renewal and passage of the neurospheres. Stem cells, progenitors and differentiated neurons, astrocytes and oligodendrocytes all express the gene. While no apparent differences were observed in developing neurospheres or in the astrocytes and oligodendrocytes from the PTPσ knockout mice, the neuronal migration patterns and neurites were altered when studied in culture. In particular, neurons migrated farther from the neurosphere centers and the neurite outgrowth exceeded the length of the neuronal processes from age matched sibling controls. Conclusion Our results imply a specific role for PTPσ in the neuronal lineage, particularly in the form of inhibitory influences on neurite outgrowth, and demonstrate a role for tyrosine phosphatases in neuronal stem cell differentiation

Neural stem cells from protein tyrosine phosphatase sigma knockout mice generate an altered neuronal phenotype in culture

Abstract Background The LAR family Protein Tyrosine Phosphatase sigma (PTPσ) has been implicated in neuroendocrine and neuronal development, and shows strong expression in specific regions within the CNS, including the subventricular zone (SVZ). We established neural stem cell cultures, grown as neurospheres, from the SVZ of PTPσ knockout mice and sibling controls to determine if PTPσ influences the generation and the phenotype of the neuronal, astrocyte and oligodendrocyte cell lineages. Results The neurospheres from the knockout mice acquired heterogeneous developmental characteristics and they showed similar morphological characteristics to the age matched siblings. Although Ptprs expression decreases as a function of developmental age in vivo, it remains high with the continual renewal and passage of the neurospheres. Stem cells, progenitors and differentiated neurons, astrocytes and oligodendrocytes all express the gene. While no apparent differences were observed in developing neurospheres or in the astrocytes and oligodendrocytes from the PTPσ knockout mice, the neuronal migration patterns and neurites were altered when studied in culture. In particular, neurons migrated farther from the neurosphere centers and the neurite outgrowth exceeded the length of the neuronal processes from age matched sibling controls. Conclusion Our results imply a specific role for PTPσ in the neuronal lineage, particularly in the form of inhibitory influences on neurite outgrowth, and demonstrate a role for tyrosine phosphatases in neuronal stem cell differentiation.</p

Timing and magnitude of early to middle Holocene warming in East Greenland inferred from chironomids

Much of Greenland experienced summers warmer than present during parts of the early to middle Holocene, during a precession-driven positive anomaly in summer insolation. However, the magnitude of that warmth remains poorly known, and its timing and spatial pattern are uncertain. Here we describe the first quantitative Holocene palaeotemperature reconstruction from central East Greenland based upon insect (chironomid) assemblages preserved in lake sediments. We postulate that landscapes like our study site, characterized by minimal soil and vegetation development through the Holocene and thus less influenced by some important secondary gradients, are especially well-suited to the use of chironomids to reconstruct Holocene temperatures. The inferred timing of warmth at our study site near Scoresby Sund agrees well with other nearby evidence, including glacial geological reconstructions and temperatures inferred from precipitation isotopes at Renland ice cap, supporting the use of chironomids to reconstruct temperatures at this site. We infer highest temperatures from ~10 to 5.5 ka, followed by gradual cooling after 5.5 ka and progressively colder and less productive conditions after 3.5 ka. Models based upon two independent training sets yield similar inferred temperature trends, and suggest an average summer temperature anomaly from ~10 to 5.5 ka of 3 to 4 °C relative to the preindustrial last millennium. The estimated overall rate of Neoglacial cooling averaged over the period from 5.5 to 0.5 ka was 0.6 to 0.8 °C per thousand years, more than twice the rate previously estimated for the Arctic as a whole. Given strong apparent spatial variability in Holocene climate around the Arctic, and the utility of palaeoclimate data for improving climate and ice sheet models, it should be a priority to further quantify past temperature changes around the margins of the Greenland Ice Sheet, where few quantitative reconstructions exist and future warming will affect global sea level.<br/