Biomarkers of systemic inflammation and growth in early infancy are associated with stunting in young Tanzanian children

Stunting can afflict up to one-third of children in resource-constrained countries. We hypothesized that low-grade systemic inflammation (defined as elevations in serum C-reactive protein or alpha-1-acid glycoprotein) in infancy suppresses the growth hormone–insulin-like growth factor (IGF) axis and is associated with subsequent stunting. Blood samples of 590 children from periurban Dar es Salaam, Tanzania, were obtained at 6 weeks and 6 months of age as part of a randomized controlled trial. Primary outcomes were stunting, underweight, and wasting (defined as length-for-age, weight-for-age and weight-for-length z-scores < −2) between randomization and endline (18 months after randomization). Cox proportional hazards models were constructed to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of time to first stunting, underweight, and wasting as outcomes, with measures of systemic inflammation, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) as exposures, adjusting for numerous demographic and clinical variables. The incidences of subsequent stunting, underweight, and wasting were 26%, 20%, and 18%, respectively. In multivariate analyses, systemic inflammation at 6 weeks of age was significantly associated with stunting (HR: 2.14, 95% CI: 1.23, 3.72; p = 0.002). Children with higher levels of IGF-1 at 6 weeks were less likely to become stunted (HR: 0.58, 95% CI: 0.37, 0.93; p for trend = 0.019); a similar trend was noted in children with higher levels of IGF-1 at 6 months of age (HR: 0.50, 95% CI: 0.22, 1.12; p for trend = 0.07). Systemic inflammation occurs as early as 6 weeks of age and is associated with the risk of future stunting among Tanzanian children.This research was funded by the National Institutes of Health (R01 HD048969, 2P30 DK040561, K24 DK104676-Dr. Duggan) and the Bill and Melinda Gates Foundation (OPP1066203-Dr. Duggan). (R01 HD048969 - National Institutes of Health; 2P30 DK040561 - National Institutes of Health; K24 DK104676 - National Institutes of Health; OPP1066203 - Bill and Melinda Gates Foundation)Accepted manuscrip

Patient and researcher perspectives on facilitating patient and public involvement in rheumatology research

No abstract available

ALMA Imaging of Gas and Dust in a Galaxy Protocluster at Redshift 5.3: [CII] Emission in "Typical" Galaxies and Dusty Starbursts ~1 Billion Years after the Big Bang

We report interferometric imaging of [CII] and OH emission toward the center of the galaxy protocluster associated with the z=5.3 submillimeter galaxy (SMG) AzTEC-3, using the Atacama Large (sub)Millimeter Array (ALMA). We detect strong [CII], OH, and rest-frame 157.7 um continuum emission toward the SMG. The [CII] emission is distributed over a scale of 3.9 kpc, implying a dynamical mass of 9.7 x 10^10 Msun, and a star formation rate (SFR) surface density of Sigma_SFR = 530 Msun/yr/kpc2. This suggests that AzTEC-3 forms stars at Sigma_SFR approaching the Eddington limit for radiation pressure supported disks. We find that the OH emission is slightly blueshifted relative to the [CII] line, which may indicate a molecular outflow associated with the peak phase of the starburst. We also detect and dynamically resolve [CII] emission over a scale of 7.5 kpc toward a triplet of Lyman-break galaxies with moderate UV-based SFRs in the protocluster at ~95kpc projected distance from the SMG. These galaxies are not detected in the continuum, suggesting far-infrared SFRs of <18-54 Msun/yr, consistent with a UV-based estimate of 22 Msun/yr. The spectral energy distribution of these galaxies is inconsistent with nearby spiral and starburst galaxies, but resembles those of dwarf galaxies. This is consistent with expectations for young starbursts without significant older stellar populations. This suggests that these galaxies are significantly metal-enriched, but not heavily dust-obscured, "normal" star-forming galaxies at z>5, showing that ALMA can detect the interstellar medium in "typical" galaxies in the very early universe.Comment: 15 pages, 12 figures, 4 tables, to appear in ApJ (accepted October 15, 2014

Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis

DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development

Prompting arm activity after stroke: a clinical proof of concept study of wrist-worn accelerometers with a vibrating alert function

Background: Frequent practice of functional movements after stroke may optimise motor recovery; however, it is challenging for patients to remember to integrate an impaired limb into daily activities. We report the activity responses of stroke patients receiving a vibrating alert delivered by a tri-axial accelerometer wristband to prompt movement of the impaired arm if hourly activity levels fell. Methods: Adults with upper limb impairment &lt;= 28 days post-stroke wore the device for four weeks. Therapists and patients reviewed movement activity data twice weekly to agree ongoing rehabilitation activities and programme the wristband with a personalised prompt threshold (median baseline activity + 5%, 25% or 50%). Results: Seven patients completed the programme (five males; meanstandard deviation (age) 64 +/- 5 years; days post-stroke 13 +/- 7; baseline/four-week Action Research Arm Test median (Interquartile range (IQR)) 39 (8, 44)/56 (11, 57)). Wristbands were worn for 89% of programme duration. A total of 1,288 prompts were delivered, with a median of four (IQR 3,7) prompts per patient per day. Mean activity increases following a prompt ranged from 11% to 29%. Conclusions: Feedback delivered by a programmable accelerometer increased impaired arm activity. Improvements are required in device reliability before conducting a pragmatic clinical trial to examine the impact upon recovery.</p

KINEROS2 application for land use/cover change impact analysis at the Hulu Langat Basin, Malaysia

The impacts of land use/cover changes (LUCC) on a developed basin in Malaysia were evaluated. Three storm events in different intensities and durations were required for KINEROS2 (K2) calibration and LUCC impact analysis. K2 validation was performed using three other rainfall events. Calibration results showed excellent and very good fittings for runoff and sediment simulations based on the aggregated measure. Validation results demonstrated that the K2 is reliable for runoff modelling, while K2 application for sediment simulation was only valid for the period 1984-1997. LUCC impacts analysis revealed that direct runoff and sediment discharge increased with the progress of urban development and unmanaged agricultural activities. These observations were supported by the NDVI, landscape and hydrological trend analyses

Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma

Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies

Multivitamin Supplementation Improves Haematologic Status in Children Born to HIV-positive women in Tanzania.

Anaemia is prevalent among children born to HIV-positive women, and it is associated with adverse effects on cognitive and motor development, growth, and increased risks of morbidity and mortality. To examine the effect of daily multivitamin supplementation on haematologic status and mother-to-child transmission (MTCT) of HIV through breastfeeding. A total of 2387 infants born to HIV-positive women from Dar es Salaam, Tanzania were enrolled in a randomized, double-blind, placebo-controlled trial, and provided a daily oral supplement of multivitamins (vitamin B complex, C and E) or placebo at age 6 weeks for 24 months. Among them, 2008 infants provided blood samples and had haemoglobin concentrations measured at baseline and during a follow-up period. Anaemia was defined as haemoglobin concentrations <11 g/dL and severe anaemia <8.5 g/dL. Haemoglobin concentrations among children in the treatment group were significantly higher than those in the placebo group at 12 (9.77 vs. 9.64 g/dL, p=0.03), 18 (9.76 vs. 9.57 g/dL, p=0.004), and 24 months (9.93 vs. 9.75 g/dL, p=0.02) of follow-up. Compared to those in the placebo group, children in the treatment group had a 12% lower risk of anaemia (hazard ratio (HR): 0.88; 95% CI: 0.79-0.99; p=0.03). The treatment was associated with a 28% reduced risk of severe anaemia among children born to women without anaemia (HR: 0.72; 95% CI: 0.56-0.92; p=0.008), but not among those born to women with anaemia (HR: 1.10; 95% CI: 0.79-1.54; p=0.57; p for interaction=0.007). One thousand seven hundred fifty three infants who tested HIV-negative at baseline and had HIV testing during follow-up were included in the analysis for MTCT of HIV. No association was found between multivitamin supplements and MTCT of HIV. Multivitamin supplements improve haematologic status among children born to HIV-positive women. Further trials focusing on anaemia among HIV-exposed children are warranted in the context of antiretroviral therapy

Diving into the collections: Analysing two excavated Sotho-Tswana compounds in the Suikerbosrand, Gauteng Province

In this article, we set out to publish the results of extensive excavations conducted in the late 1980s and early 1990s by staff and students of the Archaeology Department, University of the Witwatersrand, at two Late Iron Age stone-walled compounds in the western foothills of the Suikerbosrand massif, near Johannesburg. While these two compounds, Sun Shadow and Boschoek, have been extensively cited in the literature, their data have never been published. Here, we analyse the distribution of their collected artefacts, in conjunction with their field maps, to better understand the spatial organisation of these two Molokwane-style stone-walled compounds. We were also interested to assess the merits of revisiting under-analysed archaeological materials housed in the University of the Witwatersrand’s collections. The results revealed frustrating gaps and shortcomings in the collections, but also shed new light on the social organisation of these settlements. Overall, we feel that the exercise was worthwhile and we encourage similar such studies in the future, allowing researchers to explore the scientific potential of the masses of buried treasure within the university’s collections