Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Titanium based cranial reconstruction using incremental sheet forming

In this paper, we report recent work in cranial plate manufacturing using incremental sheet forming (ISF) process. With a typical cranial shape, the ISF process was used to manufacture the titanium cranial shape by using different ISF tooling solutions with and without backing plates. Detailed evaluation of the ISF process including material deformation and thinning, geometric accuracy and surface finish was conducted by using a combination of experimental testing and Finite Element (FE) simulation. The results show that satisfactory cranial shape can be achieved with sufficient accuracy and surface finish by using a feature based tool path generation method and new ISF tooling design. The results also demonstrate that the ISF based cranial reconstruction has the potential to achieve considerable lead time reduction as compared to conventional methods for cranial plate manufacturing. This outcome indicates that there is a potential for the ISF process to achieve technological advances and economic benefits as well as improvement to quality of life

Birth characteristics and the risk of childhood leukaemias and lymphomas in New Zealand: a case-control study

BACKGROUND: Some studies have found that lower parity and higher or lower social class (depending on the study) are associated with increased risks of childhood acute lymphoblastic leukaemia (ALL). Such findings have led to suggestions that infection could play a role in the causation of this disease. An earlier New Zealand study found a protective effect of parental marriage on the risk of childhood ALL, and studies elsewhere have reported increased risks in relation to older parental ages. This study aimed to assess whether lower parity, lower social class, unmarried status and older parental ages increase the risk of childhood ALL (primarily). These variables were also assessed in relation to the risks of childhood acute non-lymphoblastic leukaemia, non-Hodgkin's lymphomas and Hodgkin's disease. METHODS: A case control study was conducted. The cases were 585 children diagnosed with leukaemias or lymphomas throughout New Zealand over a 12 year period. The 585 age and sex matched controls were selected at random from birth records. Birth records from cases (via cancer registration record linkage) and from controls provided accurate data on maternal parity, social class derived from paternal occupation, maternal marital status, ages of both parents, and urban status based on the address on the birth certificate. Analysis was by conditional logistic regression. RESULTS: There were no statistically significant associations overall between childhood ALL and parity of the mother, social class, unmarried maternal status, increasing parental ages (continuous analysis), or urban status. We also found no statistically significant associations between the risks of childhood acute non-lymphoblastic leukaemia, non-Hodgkin lymphomas, or Hodgkin's disease and the variables studied. CONCLUSION: This study showed no positive results though of reasonable size, and its record linkage design minimised bias. Descriptive studies (eg of time trends of ALL) show that environmental factors must be important for some diagnoses. Work has been done on the risk of ALL in relation to chemicals (eg pesticides) and drugs, dietary factors (eg vitamins), electromagnetic fields and infectious hypotheses (to name some); but whether these or other unknown factors are truly important remains to be seen

An Urban Neo-Poverty Population-Based Quality of Life and Related Social Characteristics Investigation from Northeast China

OBJECTIVE: To investigate quality of life (QOL) and related characteristics among an urban neo-poverty population in northeast China, and to compare this population with a traditional poverty cohort. DESIGN: The research was a cross-sectional survey executed from June 2005 to October 2007, with a sample of 2940 individuals ages 36 to 55 in three different industrial cities of northeast China. Data were collected on QOL status and sociodemographic characteristics. QOL was assessed using the 36-item Short Form Health Survey (Chinese version). Multiple regression analysis was employed to analyze association between sociodemographic variables and QOL. RESULTS: The scores for QOL in the neo-poverty group were higher than those in the traditional poverty group, but lower than those in the general population. When the neo-poverty population was divided into two subgroups by age, 36-45 years and 46-55 years, the differences in QOL scores were not significant. However, there were significant differences in several dimensions between two subgroups according to unemployment time (<5 years and >5 years). Additionally, stepwise regression analysis indicated that disease burden, including disease and medical expenditures, was a common risk factor for declining QOL in the neo-poverty group. CONCLUSIONS: Despite some limitations, this study provides initial evidence that the QOL of the urban neo-poverty population lies between that of the general population and traditional poverty. QOL of the neo-poverty group approached QOL of the traditional poverty group with increased unemployment years. In addition to decreased income, disease burden is the most important factor influencing QOL status in urban neo-poverty

Peroxisomal Alanine: Glyoxylate Aminotransferase AGT1 Is Indispensable for Appressorium Function of the Rice Blast Pathogen, Magnaporthe oryzae

The role of β-oxidation and the glyoxylate cycle in fungal pathogenesis is well documented. However, an ambiguity still remains over their interaction in peroxisomes to facilitate fungal pathogenicity and virulence. In this report, we characterize a gene encoding an alanine, glyoxylate aminotransferase 1 (AGT1) in Magnaporthe oryzae, the causative agent of rice blast disease, and demonstrate that AGT1 is required for pathogenicity of M. oryzae. Targeted deletion of AGT1 resulted in the failure of penetration via appressoria; therefore, mutants lacking the gene were unable to induce blast symptoms on the hosts rice and barley. This penetration failure may be associated with a disruption in lipid mobilization during conidial germination as turgor generation in the appressorium requires mobilization of lipid reserves from the conidium. Analysis of enhanced green fluorescent protein expression using the transcriptional and translational fusion with the AGT1 promoter and open reading frame, respectively, revealed that AGT1 expressed constitutively in all in vitro grown cell types and during in planta colonization, and localized in peroxisomes. Peroxisomal localization was further confirmed by colocalization with red fluorescent protein fused with the peroxisomal targeting signal 1. Surprisingly, conidia produced by the Δagt1 mutant were unable to form appressoria on artificial inductive surfaces, even after prolonged incubation. When supplemented with nicotinamide adenine dinucleotide (NAD+)+pyruvate, appressorium formation was restored on an artificial inductive surface. Taken together, our data indicate that AGT1-dependent pyruvate formation by transferring an amino group of alanine to glyoxylate, an intermediate of the glyoxylate cycle is required for lipid mobilization and utilization. This pyruvate can be converted to non-fermentable carbon sources, which may require reoxidation of NADH generated by the β-oxidation of fatty acids to NAD+ in peroxisomes. Therefore, it may provide a means to maintain redox homeostasis in appressoria

Adaptation of a Mindfulness-Based Intervention for Incarcerated Young Men: a Feasibility Study

Objectives: Incarcerated young men commonly experience problems with impulsivity and emotional dysregulation. Mindfulness training could help but the evidence is limited. This study developed and piloted an adapted mindfulness-based intervention for this group (n = 48). Methods: Feasibility of recruitment, retention, and data collection were assessed, and the effectiveness of mindfulness training measured using validated questionnaires. Twenty-five qualitative interviews were conducted to explore experiences of the course, and barriers and facilitators to taking part. Results: The findings indicated that recruitment and retention to mindfulness training groups was a challenge despite trying various adaptive strategies to improve interest, relevance, and acceptability. Quantitative data collection was feasible at baseline and post-course. There were significant improvements following training in impulsivity (effect size [ES] 0.72, 95% CI 0.32–1.11, p = 0.001), mental wellbeing (ES 0.50; 95% CI 0.18–0.80; p = 0.003), inner resilience (comprehensibility ES 0.35; 95% CI − 0.02–0.68; p = 0.03), and mindfulness (ES 0.32; 95% CI 0.03–0.60; p = 0.03). The majority (70%) of participants reported finding the course uncomfortable or disconcerting at first but if they chose to remain, this changed as they began to experience benefit. The body scan and breathing techniques were reported as being most helpful. Positive experiences included better sleep, less stress, feeling more in control, and improved relationships. Conclusions: Developing and delivering mindfulness training for incarcerated young men is feasible and may be beneficial, but recruitment and retention may limit reach. Further studies are required that include a control group

Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival.

TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours

Hyperphosphorylation as a Defense Mechanism to Reduce TDP-43 Aggregation

Several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are characterized by inclusion bodies formed by TDP-43 (TDP). We established cell and transgenic Drosophila models expressing TDP carboxyl terminal fragment (ND251 and ND207), which developed aggregates recapitulating important features of TDP inclusions in ALS/FTLD-U, including hyperphosphorylation at previously reported serine403,404,409,410 residues, polyubiquitination and colocalization with optineurin. These models were used to address the pathogenic role of hyperphosphorylation in ALS/FTLD-U. We demonstrated that hyperphosphorylation and ubiquitination occurred temporally later than aggregation in cells. Expression of CK2α which phosphorylated TDP decreased the aggregation propensity of ND251 or ND207; this effect could be blocked by CK2 inhibitor DMAT. Mutation of serines379,403,404,409,410 to alanines (S5A) to eliminate phosphorylation increased the aggregation propensity and number of aggregates of TDP, but mutation to aspartic acids (S5D) or glutamic acids (S5E) to simulate hyperphosphorylation had the opposite effect. Functionally, ND251 or ND207 aggregates decreased the number of neurites of Neuro2a cells induced by retinoic acid or number of cells by MTT assay. S5A mutation aggravated, but S5E mutation alleviated these cytotoxic effects of aggregates. Finally, ND251 or ND251S5A developed aggregates in neurons, and salivary gland of transgenic Drosophila, but ND251S5E did not. Taken together, our data indicate that hyperphosphorylation may represent a compensatory defense mechanism to stop or prevent pathogenic TDP from aggregation. Therefore, enhancement of phosphorylation may serve as an effective therapeutic strategy against ALS/FTLD-U