Macrobiota — helminths as active participants and partners of the microbiota in host intestinal homeostasis

Homeostatic interactions between helminths, commensals and the host immune system; red arrows denote pro-inflammatory pathways, blue arrow counter-inflammatory. Direct tissue damage provokes release of alarmins (IL-33, also TSLP and IL-25) and can allow bacterial translocation with consequent TLR stimulation of host cells. Helminth secreted products (ES) are known to inhibit expression of the IL-33R (ST2) and host responses to TLR ligation. In addition, both helminths and commensals maintain host immunoregulatory networks through ES products and the production of short chain fatty acids (SCFAs).

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Cancer mortality in a population-based cohort of American Indians – The strong heart study

BackgroundCancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.MethodsCancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45–74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.ResultsAfter a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67–7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46–10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87–6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32−0.71).ConclusionsRegional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.     

Improved survival in both men and women with diabetes between 1980 and 2004 – a cohort study in Sweden

Background

In Sweden, diabetes prevalence is increasing in spite of unchanged incidence, indicating improved survival. In recent US studies mortality in diabetic subjects has decreased over three decades, but only in men. Our aim was to study mortality over time in diabetic subjects.

Methods

The annual Swedish Living Conditions Survey from 1980 to 2004 has been record-linked to the Cause of Death Register in order to study trends in mortality risk for those reporting diabetes as a chronic illness. Survival and the relative mortality risk within 5 years of follow-up have been calculated for a random sample of men and women aged 40–84 years with (n = 3,589) and without diabetes (n = 85,685) for the period 1980 to 2004. Poisson regression models were used.

Results

The age-adjusted mortality risk relative to non-diabetics within 5 years of follow-up for men was doubled during all periods. The relative risk for women was initially about 2.5, with a substantial drop in mortality in 1995–1999 to 1.45 although it increased to 1.90 in the last period. Using models that took into consideration the presence of heart disease, hypertension, daily smoking, and socio-economic status at the initial interview did not change the relative mortality risk. The age-adjusted 10-year observed survival rate for men with diabetes increased from 41.4% 1980–1984 to 51.5% in 1995–1999. The observed survival for women increased from 43.7% to 61.0%.

Conclusion

Survival rates have improved in subjects with diabetes since the early 1980s, more so in women than in men, thereby decreasing the gap to non-diabetic women.

     

School start time influences melatonin and cortisol levels in children and adolescents – a community-based study

School start time influences sleep parameters. Differences between circadian sleep parameters on weekends and weekdays have been associated with obesity, sleep, and psychiatric disorders. Moreover, circadian rhythm dysregulation affects the secretion of some hormones, such as melatonin and cortisol. In the current study, we investigate the effect of school start time on cortisol and melatonin levels in a community sample of Brazilian children and adolescents. This was a cross-sectional study of 454 students (mean age, 12.81 ± 2.56 years; 58.6% female). From this sample, 80 participants were randomly selected for saliva collection to measure melatonin and cortisol levels. Circadian sleep parameters were assessed by self-reported sleep and wake up schedules and the Morningness–Eveningness Questionnaire. The outcomes, salivary melatonin and cortisol levels, were measured in morning, afternoon and night saliva samples, and behavior problems were assessed using the Child Behavior Checklist (CBCL). The main results revealed that morning school start time decreased the secretion of melatonin. Morning melatonin levels were significantly positively correlated with the sleep midpoint on weekdays and on weekends. Afternoon melatonin levels were positively correlated with the sleep midpoint on weekends in the morning school students. Conversely, in the afternoon school students, night melatonin levels were negatively correlated with the sleep midpoint on weekdays. Cortisol secretion did not correlate with circadian sleep parameters in any of the school time groups. In conclusion, school start time influences melatonin secretion, which correlated with circadian sleep parameters. This correlation depends on the presence of psychiatric symptoms. Our findings emphasize the importance of drawing attention to the influence of school start time on the circadian rhythm of children and adolescents.     

A segmental radiological study of the spine and rib – cage in children with progressive Infantile Idiopathic Scoliosis

Background

The role of rib cage in the development of progressive infantile idiopathic scoliosis (IIS) has not been studied previously. No report was found for rib growth in children with IIS. These findings caused us to undertake a segmental radiological study of the spine and rib-cage in children with progressive IIS. The aim of the present study is to present a new method for assessing the thoracic shape in scoliotics and in control subjects and to compare the findings between the two groups.

Materials and methods

In the posteroanterior (PA) spinal radiographs of 24 patients with progressive IIS, with a mean age of 4.1 years old, the Thoracic Ratios (TRs) (segmental convex and concave TRs), the Cobb angle, the segmental vertebral rotation and vertebral tilt were measured. In 233 subjects, with a mean age of 5.1 years old, who were used as a control group, the segmental left and right TRs and the total width of the chest (left plus right TRs) were measured in PA chest radiographs. Statistical analysis included Mann-Whitney, Spearman correlation coefficient, multiple linear regression analysis and ANOVA.

Results

The comparison shows that the scoliotic thorax is significantly narrower than that of the controls at all spinal levels. The upper chest in IIS is funnel-shaped and the vertebral rotation at T4 early in management correlates significantly with the apical vertebral rotation at follow up.

Conclusion

The IIS thorax is narrower than that of the controls, the upper chest is funnel-shaped and there is a predictive value of vertebral rotation at the upper limit of the thoracic curve of IIS, which reflects, impaired rib control of spinal rotation possibly due to neuromuscular factors, which contribute also to the funnel-shaped chest.     

Effect of salinity on the distribution of Ponto-Caspian gammarids in a non-native area – environmental and experimental study

The native area of gammarids from the so-called ‘Caspian complex’, Pontogammarus robustoides (G.O. Sars, 1894), Obesogammarus crassus (G.O. Sars, 1894), Dikerogammarus haemobaphes (Eichwald, 1841) and D. villosus (Sowinsky, 1894), is associated with brackish waters. Over the last several decades they have colonized the European inland waters and part of the brackish Baltic Sea. It is believed that anthropogenic increase in the salinity of inland waters facilitated their expansion. However, the influence of salinity on the dispersal of gammarid species outside their native area is not fully understood. We tested the hypothesis that salinity was a major factor in determining distribution, based on the abundance of Gammaridae in three coastal areas of low salinity (brackish Baltic), i.e. 0.3, 3.4 and 7.3 PSU, successfully inhabited by them. Additionally, for the first time, the effect of water salinity on the osmoregulatory capacity of O. crassus was examined under laboratory conditions, for the salinities given above. The experiments showed that similarly as in the case of other Caspian complex species, salinity values of about 7 PSU create better conditions for osmoregulation in O. crassus than lower salinities (i.e. 0.3 and 3.4 PSU). In the environmental part of the study, we observed that only D. villosus achieved a significantly higher abundance in the area of 7.3 PSU. Thus, we concluded that in the range of 0.3–7.3 PSU, salinity is not a key factor governing the distribution of Ponto-Caspian gammarids.     

Cancer risks in children with congenital malformations in the nervous and circulatory system—A population based cohort study

AimWe estimated the age and organ-specific cancer risk for children with a congenital malformation (CM) in the nervous or in the circulatory system.MethodsWe identified 1,709,456 live born singletons in Denmark between 1 January 1977 and 31 December 2007 and excluded children with chromosomal birth defects. Information on CMs was obtained from the Danish National Hospital Register. Information on cancer occurrence was obtained from the Danish Cancer Registry. We applied Cox proportional hazards regression model to estimate hazard ratios (HR) for cancer. Children entered into the CM cohort on the day of birth regardless of when the CM was diagnosed or on the day of CM diagnosis in an alternative analysis.ResultsOverall, 4484 (0.26%) and 24,643 (1.44%) children were diagnosed with a CM in the nervous and in the circulatory system, respectively. Compared with children without any CM, children with a CM in the nervous system had a 5.97 fold (95%CI [confidence interval]: 4.66–7.64) higher risk of cancer, including cancer in the central nervous system (HR = 18.84, 95%CI: 12.67–28.01), in the mesothelial and soft tissue (HR = 15.64, 95%CI: 7.99–30.60), in the skin (HR = 4.91, 95%CI: 2.19–11.0). The associations were stronger early in life. Children with a CM in the circulatory system had a 2.64 fold (95%CI: 2.21–3.16) higher risk of cancer, including cancer in the lymphatic and haematopoietic tissues (HR = 3.22, 95%CI: 2.43–4.27) and cancer in the CNS (HR = 2.40, 95%CI: 1.43–4.02). Some of these associations were weaker in the alternative analysis. Children with subtypes of CM in the two systems showed a higher cancer risk.ConclusionsChildren who were diagnosed with a CM in the nervous system had a substantially higher cancer risk especially early in life. Children diagnosed with a CM in the circulatory system had a moderately higher cancer risk.     

Trace element imbalances in patients undergoing chronic hemodialysis therapy – Report of an observational study in a cohort of Portuguese patients

IntroductionPatients with end-stage renal disease undergoing hemodialysis therapy are at risk of developing deficiencies of essential trace elements and/or overload of toxic trace elements, both of which may significantly affect their clinical status of. Those imbalances may result from the disease itself but also from the quality of the therapeutic process, namely the hemodialysis process, which has greatly evolved in the last decades. Thus, old observations that have been assumed as very well-proven have been recently questioned. In this case-control study we evaluate the current trace elements status in a group of Portuguese patients under hemodialysis therapy.Material and methodsSerum samples from patients (n = 93), collected for the routine periodic control of Al levels, were analyzed for a wide panel of trace elements (Li, Al, Mn, Co, Ni, Cu, Zn, Se, Rb, Sr, Mo, Cd, Ba, Pb) using inductively coupled plasma mass spectrometry technique (hemodialysis patients’ group). For comparison purposes, samples of individuals with no evidence of renal disease according to standard laboratory analytical criteria (n = 50) were also analyzed (control group).ResultsThe results showed significant differences between the two groups, with higher values in hemodialysis patients group for Al (14.6 vs. 9.5 μg/L), Co, Ni, Sr, Mo (4.5 vs. 1.4 μg/L), Cd (0.058 vs. 0.025 μg/L) and Pb (0.55 vs. 0.30 μg/L); and lower values in hemodialysis patients group for Li (4.0 vs. 75.8 μg/L), Mn, Cu (943.5 vs. 1038.5 μg/L), Zn (943.5 vs. 1038.5 μg/L), Se (71.5 vs. 103.8 μg/L), Rb (202.4 vs. 300.3 μg/L) and Ba (0.65 vs. 8.7 μg/L).ConclusionThis study confirms that hemodialysis patients tend to present significant trace elements imbalances, which may be related to the higher morbidity and mortality observed in this specific patients’ group.     

Measuring the postfire resilience of a bird–vegetation system: a 28-year study in a Mediterranean oak woodland

Despite numerous studies on the response of Mediterranean ecosystems to fire, few have measured the respective resilience of vegetation and fauna compartments. For 28 years, we conducted an annual monitoring of avifauna composition and vegetation structure (cover profile) following a severe wildfire in a holm oak (Quercus ilex) stand in southern France. Our aim was to estimate the time necessary for this bird–vegetation system to return to a state analogous to its pre-fire state. In the burned plots, low herbaceous and shrub layers were gradually replaced by higher, woody layers of vegetation. Neither bird species richness nor inter-annual bird species turnover showed significant differences from one year to the next over the study period. In contrast, bird species composition did change steadily, leading to an almost complete replacement of early-successional species by late-successional ones. Using the first axes of multivariate analyses as ‘proxy variables’ of vegetation or avifauna recoveries, we estimated by extrapolation the recovery times of these two ecosystem components at ca. 50 and 35 years, respectively. Towards the end of the study period, the rate of change in avifauna composition decreased comparatively to that of vegetation structure. Our results show that holm oak woodlands are highly resilient and seem to tolerate a ~50-year fire interval, even if it remains to be assessed how resilient they would be in the case of increased fire frequency. More generally, our multivariate approach, which allows comparative estimations of resilience in different components of an ecosystem using qualitative as well as quantitative criteria, could be applied to various case studies in disturbance and restoration ecology.     

Raman–deuterium isotope probing to study metabolic activities of single bacterial cells in human intestinal microbiota

Human intestinal microbiota is important to host health and is associated with various diseases. It is a challenge to identify the functions and metabolic activity of microorganisms at the single-cell level in gut microbial community. In this study, we applied Raman microspectroscopy and deuterium isotope probing (Raman–DIP) to quantitatively measure the metabolic activities of intestinal bacteria from two individuals and analysed lipids and phenylalanine metabolic pathways of functional microorganisms in situ. After anaerobically incubating the human faeces with heavy water (D₂O), D₂O with specific substrates (glucose, tyrosine, tryptophan and oleic acid) and deuterated glucose, the C–D band in single-cell Raman spectra appeared in some bacteria in faeces, due to the Raman shift from the C–H band. Such Raman shift was used to indicate the general metabolic activity and the activities in response to the specific substrates. In the two individuals' intestinal microbiota, the structures of the microbial communities were different and the general metabolic activities were 76 ± 1.0% and 30 ± 2.0%. We found that glucose, but not tyrosine, tryptophan and oleic acid, significantly stimulated metabolic activity of the intestinal bacteria. We also demonstrated that the bacteria within microbiota preferably used glucose to synthesize fatty acids in faeces environment, whilst they used glucose to synthesize phenylalanine in laboratory growth environment (e.g. LB medium). Our work provides a useful approach for investigating the metabolic activity in situ and revealing different pathways of human intestinal microbiota at the single-cell level.     

Outcome predictors of intra-articular glucocorticoid treatment for knee synovitis in patients with rheumatoid arthritis – a prospective cohort study

Introduction

Intra-articular glucocorticoid treatment (IAGC) is widely used for symptom relief in arthritis. However, knowledge of factors predicting treatment outcome is limited. The aim of the present study was to identify response predictors of IAGC for knee synovitis in patients with rheumatoid arthritis (RA).

Methods

In this study 121 RA patients with synovitis of the knee were treated with intra-articular injections of 20 mg triamcinolone hexacetonide. They were followed for six months and the rate of clinical relapse was studied. Non-responders (relapse within 6 months) and responders were compared regarding patient characteristics and knee joint damage as determined by the Larsen-Dale index. In addition, matched samples of serum and synovial fluid were analysed for factors reflecting the inflammatory process (C-reactive protein, interleukin 6, tumour necrosis factor alpha, vascular endothelial growth factor), joint tissue turnover (cartilage oligomeric matrix protein, metalloproteinase 3), and autoimmunity (antinuclear antibodies, antibodies against citrullinated peptides, rheumatoid factor).

Results

During the observation period, 48 knees relapsed (40%). Non-responders had more radiographic joint damage than responders (P = 0.002) and the pre-treatment vascular endothelial growth factor (VEGF) level in synovial fluid was significantly higher in non-responders (P = 0.002).

Conclusions

Joint destruction is associated with poor outcome of IAGC for knee synovitis in RA. In addition, higher levels of VEGF in synovial fluid are found in non-responders, suggesting that locally produced VEGF is a biomarker for recurrence of synovial hyperplasia and the risk for arthritis relapse.     

The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer?

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and, even though 5-15% of the total CRC cases can be attributed to individual genetic predisposition, environmental factors could be considered major factors in susceptibility to CRC. Lifestyle factors increasing the risks of CRC include elevated body mass index, obesity, and reduced physical activity. Additionally, a number of dietary elements have been associated with higher or lower incidence of CRC. In this context, it has been suggested that diets high in fruit and low in meat might have a protective effect, reducing the incidence of colorectal adenomas by modulating the composition of the normal nonpathogenic commensal microbiota. In addition, it has been demonstrated that changes in abundance of taxonomic groups have a profound impact on the gastrointestinal physiology, and an increasing number of studies are proposing that the microbiota mediates the generation of dietary factors triggering colon cancer. High-throughput sequencing and molecular taxonomic technologies are rapidly filling the knowledge gaps left by conventional microbiology techniques to obtain a comprehensive catalog of the human intestinal microbiota and their associated metabolic repertoire. The information provided by these studies will be essential to identify agents capable of modulating the massive amount of gut bacteria in safe noninvasive manners to prevent CRC. Probiotics, defined as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" (219), are capable of transient modulation of the microbiota, and their beneficial effects include reinforcement of the natural defense mechanisms and protection against gastrointestinal disorders. Probiotics have been successfully used to manage infant diarrhea, food allergies, and inflammatory bowel disease; hence, the purpose of this review was to examine probiotic metabolic activities that may have an effect on the prevention of CRC by scavenging toxic compounds or preventing their generation in situ. Additionally, a brief consideration is given to safety evaluation and production methods in the context of probiotics efficacy.     

Impact of land use on plant biodiversity and measures for biodiversity conservation in the Loess Plateau in China – a case study in a hilly-gully region of the Northern Loess Plateau

The Loess Plateau is a special natural–cultural unit in northern China. Intensive land use in the past has had, and forestation and grass planting at present will have inevitable impacts on plant biodiversity in the Loess Plateau. Based on the analysis of floristic features within three sampling sites with different land use practices and analysis of species richness among different land use types, we discuss impacts of land use on species richness and floristic features in the Northern Loess Plateau. The results drawn from this case study are as follows: (1) It appears that forestation and grass planting have had a positive influence on the local species diversity, but they have contributed little to the native vegetation in terms of conserving its floristic features. (2) Caragana intermedia shrubland, Pinus tabulaeformis forestland, and natural grassland have made important contributions to supporting indigenous species and maintaining local plant biodiversity. (3) There is a significant positive correlation between land use diversity and species richness. These results imply that practicing biodiversity conservation in situ is feasible and the suitable choice for the Loess Plateau. Concrete measures for biodiversity conservation in the area can include setting up small nature reserves and diversifying land use patterns to maintain as much habitat as possible for native vegetation. The artificial Hippophae rhamnoides shrubland should not be further promoted, considering its negative influence on biodiversity conservation.     

Fast and slow photoreceptors — a comparative study of the functional diversity of coding and conductances in the Diptera

1. From a comparison of the photoresponses and membrane properties of photoreceptors from 20 species of Diptera, we conclude that coding in the time domain is matched to the dictates of visual ecology. This matching involves the dynamics of phototransduction and the use of an appropriate mix of potassium conductances to tune the photoreceptor membrane.
2. Rapidly flying, manoeuvrable diurnal Diptera from several families have fast photoreceptors, with corner frequencies (the frequency at which signal power falls by a half) of between 50 and 107 Hz. The ponderous and predominantly nocturnal tipulids have slow photoreceptors with fully light adapted corner frequencies of 16 to 19 Hz.
3. Dark adapted fast photoreceptors have a lower gain (as indicated by lower noise levels), a lower sensitivity, and light adapt more rapidly than dark adapted slow photoreceptors. Fast cells also have much lower input resistances and shorter time constants.
4. Fast photoreceptors rectify more strongly in the steady state because of a weakly inactivating delayed rectifier potassium conductance with fast and slow components of activation. Slow photoreceptors rectify less strongly in the steady state because their membrane properties are dominated by strongly inactivating outward currents with reversal potentials in the range — 80 to -90 mV.
5. The differences between potassium conductances match the differing functional requirements of fast and slow photoreceptors. The non-inactivating delayed rectifier promotes the rapid response of fast cells by reducing the membrane time constant. This is an expensive strategy, involving large conductances and currents. Slowly flying nocturnal insects do not require a high speed of response. The potassium conductances in their slow photoreceptors inactivate to avoid costly and unnecessary ion fluxes.
6. Both the dynamics of the photoresponse and photoreceptor membrane properties exhibit sexual dimorphism. Light adapted photoreceptors in the enlarged male dorsal eye of Bibio markii have a corner frequency of 42 Hz, compared with 27 Hz for cells in the smaller female eye. This difference in frequency response correlates with the male's higher spatial acuity and is accompanied by consistent differences in potassium conductance activation rate. We conclude that the divison between fast and slow cells is the product of cellular constraints, metabolic costs and the requirements of coding efficiency at different light levels and retinal image velocities.

     

Antioxidant mechanisms of Quercetin and Myricetin in the gas phase and in solution – a comparison and validation of semi-empirical methods

Flavonoids have long been recognized for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work we have studied the properties of two flavonols, quercetin and myricetin, using semi-empirical methods in order to validate the application of the recent Parametric Model 6 and to understand the fundamental difference between the two molecules. Their geometries have been optimized and important molecular properties have been calculated. The energetic of the possible antioxidant mechanisms have also been analyzed. The two studied flavonols do not differ significantly in their molecular properties, but the antioxidant mechanisms by which they may act in solution can be rather different. Moreover, we also show that the Parametric Model 6 can produce reliable information for this type of compounds.     

NT-proBNP independently predicts long term mortality after acute exacerbation of COPD – a prospective cohort study

Background

Cardiovascular disease is prevalent and frequently unrecognized in patients with chronic obstructive pulmonary disease (COPD). NT-proBNP is an established risk factor in patients with heart failure. NT-proBNP may also be released from the right ventricle. Thus serum NT-proBNP may be elevated during acute exacerbations of COPD (AECOPD). The prognostic value of NT-proBNP in patients hospitalized with AECOPD is sparsely studied. Our objective was to test the hypothesis that NT-proBNP independently predicts long term mortality following AECOPD.

Methods

A prospective cohort study of 99 patients with 217 admissions with AECOPD. Clinical, electrocardiographic, radiological and biochemical data were collected at index and repeat admissions and analyzed in an extended survival analysis with time-dependent covariables.

Results

Median follow-up time was 1.9 years, and 57 patients died during follow-up. NT-proBNP tertile limits were 264.4 and 909 pg/mL, and NT-proBNP in tertiles 1 through 3 was associated with mortality rates of 8.6, 35 and 62 per 100 patient-years, respectively (age-adjusted log-rank p<0.0001). After adjustment for age, gender, peripheral edema, cephalization and cTnT in a multivariable survival model, the corresponding hazard ratios for dying were 2.4 (0.95-6.0) and 3.2 (1.3-8.1) (with 95% confidence intervals in parentheses, p-value for trend 0.013).

Conclusions

NT-proBNP is a strong and independent determinant of mortality after AECOPD.     

The root microbiota—a fingerprint in the soil?

Background

The root system of a plant is known to host a wide diversity of microbes that can be essential or detrimental to the plant. Microbial ecologists have long struggled to understand what factors structure the composition of these communities. An overlooked part of the microbial community succession in root systems has been the potential for individual variation among plants shaped by early colonisation events such as microbial exposure of the seed inside the parent plant and during dispersal.

Scope

In this review we outline life events of the plant that can affect the composition of its root microbiota and relate ecological theory of community assembly to the formation of the root microbiota.

Conclusion

All plants are exposed to environmental conditions and events throughout their lifetime that shape their phenotype. The microbial community associated with the plant is ultimately an extension of this phenotype. Therefore, only by following a plant from its origin inside the flower to senescence, can we fully understand how the associated microbial community was assembled and what determined its composition.     

MR microscopy of the human fetal upper extremity – a proof-of-principle study

Background

Bone morphogenetic proteins regulate multiple processes in embryonic development, including early dorso-ventral patterning and neural crest development. BMPs activate heteromeric receptor complexes consisting of type I and type II receptor-serine/threonine kinases. BMP receptors Ia and Ib, also known as ALK3 and ALK6 respectively, are the most common type I receptors that likely mediate most BMP signaling events. Since early expression patterns and functions in Xenopus laevis development have not been described, we have addressed these questions in the present study.

Results

Here we have analyzed the temporal and spatial expression patterns of ALK3 and ALK6; we have also carried out loss-of-function studies to define the function of these receptors in early Xenopus development. We detected both redundant and non-redundant roles of ALK3 and ALK6 in dorso-ventral patterning. From late gastrula stages onwards, their expression patterns diverged, which correlated with a specific, non-redundant requirement of ALK6 in post-gastrula neural crest cells. ALK6 was essential for induction of neural crest cell fate and further development of the neural crest and its derivatives.

Conclusions

ALK3 and ALK6 both contribute to the gene regulatory network that regulates dorso-ventral patterning; they play partially overlapping and partially non-redundant roles in this process. ALK3 and ALK6 are independently required for the spatially restricted activation of BMP signaling and msx2 upregulation at the neural plate border, whereas in post-gastrula development ALK6 exerts a highly specific, conserved function in neural crest development.

     

Low hepatic manganese concentrations in patients with hepatic steatosis – A cohort study of copper,iron and manganese in liver biopsies

Background and aimsHepatic steatosis is the most common histopathological finding on liver biopsy, with the most prevalent etiology being NAFLD. The pathogenesis of hepatic steatosis and NAFLD is multifactorial, however, studies on the importance of manganese in NAFLD are limited. We aimed to study hepatic manganese content, and other trace elements, in relation to hepatic steatosis in patients with chronic liver diseases of different etiology, mainly NAFLD.MethodsPatients with chronically elevated liver function tests underwent a diagnostic work-up, including routine blood tests and two liver biopsies. One of the biopsies was sent for histopathological evaluation, and the other for ultra-trace elemental determinations. Steatosis was graded using conventional histopathological methodology, and fat content was also quantitated in biopsy samples by measuring the steatotic area of the section using stereological point counting (SPC). Ultra-trace elemental analysis was utilized for determining manganese, iron, and copper using inductively coupled plasma sector field mass spectrometry (ICP-SFMS).Results76 patients were included in the study. Hepatic manganese concentrations in patients with steatosis were lower than in patients without hepatic steatosis (3.8 ± 1.1 vs. 6.4 ± 1.8, P < 0.001). Similar results were seen for blood manganese levels and hepatic steatosis. We found a strong inverse correlation between steatosis grade and hepatic manganese content (ρ=-0.743, P < 0.001). Also, low levels of manganese independently predicted the presence of steatosis (aOR 0.07 [95%CI: 0.01−0.63]).ConclusionPatients with NAFLD, or other CLD and concomitant hepatic steatosis, showed lower levels of hepatic manganese content with increasing grade of steatosis.     

Diagnostic and economic evaluation of new biomarkersfor Alzheimer¿s disease: the research protocol of a prospective cohort study

ABSTRACT: BACKGROUND: New research criteria for the diagnosis of Alzheimer's disease (AD) have recently been developed to enable an early diagnosis of AD pathophysiologyby relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1) assess the diagnostic test accuracy of current clinical diagnostic work-up and emerging biomarkers in MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model.Methods/designIn a cohort design 223 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life, costs and emerging biomarkers are gathered.Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to the reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers). The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period.A decision analytic model is built combining available evidence from different resources among which (accuracy) results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers. DISCUSSION: Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results are generalizable to a population of patients who are referred to a memory clinic due to their memory problems.Trial registrationNCT01450891.