Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition.

Collagen assembly during development is essential for successful matrix mineralisation, which determines bone quality and mechanocompetence. However, the biochemical and structural perturbations that drive pathological skeletal collagen configuration remain unclear. Deletion of vascular endothelial growth factor (VEGF) in bone forming osteoblasts (OBs) induces sex-specific alterations in extracellular matrix (ECM) conformation and mineralisation coupled to vascular changes, which are augmented in males. Whether this phenotypic dimorphism arises as a result of the divergent control of ECM composition and its subsequent arrangement is unknown and is the focus of this study. Herein, we have used a murine osteocalcin-specific Vegf knockout (OcnVEGFKO) and performed ex vivo multiscale analysis at the tibiofibular junction of both sexes. Furthermore, we also deleted Vegf in vitro in OBs extracted from male and female mice in an attempt to link sex-specific matrix signatures to deviations in gene expression. Label-free and non-destructive polarisation-resolved second harmonic generation microscopy (p-SHG) revealed a reduction in collagen fibre number in males following the loss of VEGF, complemented by observable defects in matrix organisation by backscattered electron scanning electron microscopy. This was accompanied only in males by localised divergence in collagen orientation, determined by p-SHG anisotropy measurements, as a result of OcnVEGFKO. Raman spectroscopy confirmed the effect on collagen was linked to molecular dimorphic VEGF effects on collagen-specific proline and hydroxyproline, and collagen intra-stand stability, in addition to matrix carbonation and mineralisation. Vegf deletion in male and female murine OB cultures in vitro further highlighted divergence in genes regulating local ECM structure including Adamts2, Spp1, Mmp9 and Lama1 The current results demonstrate the utility of macromolecular imaging and spectroscopic modalities for the detection of collagen arrangement and ECM composition in pathological bone. Linking the sex-specific genetic regulators to matrix signatures could be important for treatment of dimorphic bone disorders which clinically manifest in both pathological nano and macro-level disorganisation

Sjeldne fugler i Norge i 2004 - Rapport fra Norsk sjeldenhetskomité for fugl (NSKF)

This is the 29th annual report and the 30th announcement from the Norwegian Rarities Committee (NSKF). The majority of records treated here are from 2004, but some older records are also included. Norway follows taxonomic advises given by the Taxonomic Advisory Committee (TAC) in the Association of European Rarity Committees (AERC). The systematic list of accepted records is set out in the following system: (1) The birds Norwegian name, (2) scientific name, (3) the numbers in brackets, e.g. (30/32 - 1), refers respectively to the total number of records/total number of individuals up to and including 2003, and in 2004, (4) any limitations given of (3), (5) any breeding, (6) year, (7) county, (8) number of individuals, age (1K = first calendar year etc.), sex (if known) and sometimes circumstances («rm» means that the bird was ringed), (9) site and municipality, (10) date, (11) * indicates if the record was complemented by positive evidence, and type of the evidence (F = photo, V = video-recorded, L = tape-recorded, D = found dead), (12) observers names in brackets, main observer is specified first and emphasized with *, (13) roughly gives the species distribution and (14) comments concerning the records.General trends:2004 was one of the best years in the history of NSKF, With 223 accepted records. 76 accepted records from previous years help to complete the Norwegian Bird list. There are 22 records presented that have been shelved. Half of these are concerning first year «Eastern Yellow Wagtails». This is due to the lack of identification knowledge in the literature for such birds. Also presented are 47 records that for some reason have not been accepted. The records from 2004 shows few extraordinary trends, maybe except for a smaller influx of Sabine’s Gulls (16 records). It was the second best year for Green-winged Teal Anas carolinensis (10 records) and the best year for Bee-eater Merops apiaster (7 records) and Caspian Gull Larus cachinnans (4 records). Other records of interest are Norway’s fourth Short-toed Eagle Circaetus gallicus, sixth Gull-billed Tern Sterna niloctia, fifth Pallid Swift Apus pallidus, second White-winged Lark Melanocorypha leucoptera and second Eastern Bonelli’s Warbler Phylloscopus orientalis. Five records of White-winged Black Tern Chlidonias leucopterus and two records of Whites Thrush Zootera dauma are also more than normal.New species to the Norwegian list:There are a total of five new species to the Norwegian category A list presented in this report, all from 2004. This brings the official Norwegian Bird list to 471 species. Included in this list are accepted records in category A-C. The new species are Baird’s Sandpiper Calidris bairdii, Bridled Tern Sterna anaetheus, Thick-billed Warbler Acrocephalus aedon, Eastern Olivaceous Warbler Hippolais pallida and Eastern Orphean Warbler Sylvia crassirostris

Evaluation of test statistics in split-mouth clinical trials

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65787/1/j.1600-0765.1988.tb01616.x.pd

Mechanisms Promoting the Long-Term Persistence of a Wolbachia Infection in a Laboratory-Adapted Population of Drosophila melanogaster

Intracellular bacteria of the genus Wolbachia are widespread endosymbionts across diverse insect taxa. Despite this prevalence, our understanding of how Wolbachia persists within populations is not well understood. Cytoplasmic incompatibility (CI) appears to be an important phenotype maintaining Wolbachia in many insects, but it is believed to be too weak to maintain Wolbachia in Drosophila melanogaster, suggesting that Wolbachia must also have other effects on this species. Here we estimate the net selective effect of Wolbachia on its host in a laboratory-adapted population of D. melanogaster, to determine the mechanisms leading to its persistence in the laboratory environment. We found i) no significant effects of Wolbachia infection on female egg-to-adult survival or adult fitness, ii) no reduced juvenile survival in males, iii) substantial levels of CI, and iv) a vertical transmission rate of Wolbachia higher than 99%. The fitness of cured females was, however, severely reduced (a decline of 37%) due to CI in offspring. Taken together these findings indicate that Wolbachia is maintained in our laboratory environment due to a combination of a nearly perfect transmission rate and substantial CI. Our results show that there would be strong selection against females losing their infection and producing progeny free from Wolbachia

Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer

Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

High maternal mortality estimated by the sisterhood method in a rural area of Mali

<p>Abstract</p> <p>Background</p> <p>Maternal mortality is high in Mali. Nevertheless, there are few studies on this topic from rural areas, and current estimates are mostly based on studies from urban settings. Our objective was to estimate the maternal mortality ratio in Kita, rural Mali.</p> <p>Methods</p> <p>Using the "sisterhood method", we interviewed participants aged 15-50 years from 20 villages in Kita, Mali, and thereby created a retrospective cohort of their sisters in reproductive age. Based on population and fertility estimates, we calculated the lifetime risk of maternal death, and from that the estimated approximate maternal mortality ratio.</p> <p>Results</p> <p>The 2,039 respondents reported 4,628 sisters who had reached reproductive age. Of these 4,628 sisters, almost a third (1,233; 27%) had died, and 429 (9%) had died during pregnancy or childbirth. This corresponded to a lifetime risk of maternal death of 20% and a maternal mortality ratio of 3,131 per 100,000 live births (95% confidence interval 2,967-3,296), with a time reference around 1999.</p> <p>Conclusions</p> <p>We found a very high maternal mortality in rural Mali and this highlights the urgent need for obstetric services in the remote rural areas.</p

Comparison of outcomes following a cytological or histological diagnosis of malignant mesothelioma

Background: Survival with the epithelioid subtype of malignant mesothelioma (MM) is longer than the biphasic or sarcomatoid subtypes. There is concern that cytology-diagnosed epithelioid MM may underdiagnose the biphasic subtype. This study examines survival differences between patients with epithelioid MM diagnosed by cytology only and other subtypes diagnosed by histology. Methods: Demographics, diagnosis method, MM subtype and survival were extracted from the Western Australia (WA) Mesothelioma Registry, which records details of all MM cases occurring in WA. Results: A total of 2024 MM cases were identified over 42 years. One thousand seven hundred forty-four (86.2%) were male, median (IQR) age was 68.6 (60.4–77.0) years. A total of 1212 (59.9%) cases were identified as epithelioid subtype of which 499 (41.2%) were diagnosed using fluid cytology only. Those with a cytology-only diagnosis were older than the histology group (median 70.2 vs 67.6 years, P<0.001), but median survival was similar (cytology 10.6 (5.5–19.2) vs histology 11.1 (4.8–19.8) months, P=0.727) and Cox regression modelling adjusting for age, sex, site and time since first exposure showed no difference in survival between the different diagnostic approaches. Conclusions: Survival of cytologically and histologically diagnosed epithelioid MM cases does not differ. A diagnostic tap should be considered adequate to diagnose epithelioid MM without need for further invasive testing

Maternal Near Miss and Mortality in a Rural Referral Hospital in Northern Tanzania: A Cross-Sectional Study.

Maternal morbidity and mortality in sub-Saharan Africa remains high despite global efforts to reduce it. In order to lower maternal morbidity and mortality in the immediate term, reduction of delay in the provision of quality obstetric care is of prime importance. The aim of this study is to assess the occurrence of severe maternal morbidity and mortality in a rural referral hospital in Tanzania as proposed by the WHO near miss approach and to assess implementation levels of key evidence-based interventions in women experiencing severe maternal morbidity and mortality. A prospective cross-sectional study was performed from November 2009 until November 2011 in a rural referral hospital in Tanzania. All maternal near misses and maternal deaths were included. As not all WHO near miss criteria were applicable, a modification was used to identify cases. Data were collected from medical records using a structured data abstraction form. Descriptive frequencies were calculated for demographic and clinical variables, outcome indicators, underlying causes, and process indicators. In the two-year period there were 216 maternal near misses and 32 maternal deaths. The hospital-based maternal mortality ratio was 350 maternal deaths per 100,000 live births (95% CI 243-488). The maternal near miss incidence ratio was 23.6 per 1,000 live births, with an overall case fatality rate of 12.9%. Oxytocin for prevention of postpartum haemorrhage was used in 96 of 201 women and oxytocin for treatment of postpartum haemorrhage was used in 38 of 66 women. Furthermore, eclampsia was treated with magnesium sulphate in 87% of all cases. Seventy-four women underwent caesarean section, of which 25 women did not receive prophylactic antibiotics. Twenty-eight of 30 women who were admitted with sepsis received parenteral antibiotics. The majority of the cases with uterine rupture (62%) occurred in the hospital. Maternal morbidity and mortality remain challenging problems in a rural referral hospital in Tanzania. Key evidence-based interventions are not implemented in women with severe maternal morbidity and mortality. Progress can be made through up scaling the use of evidence-based interventions, such as the use of oxytocin for prevention and treatment of postpartum haemorrhage