The effect of natural and induced calving of beef heifers on stress-related gene expression and maternal health and immunity.

The peri-partum processes can exert stress on a cow on many levels. There is little evidence about acute stress around the calving event and subsequent potential effects for the cows' immunological status or subsequent reproductive health. To investigate this, 55 crossbred recipient beef heifers carrying purebred Simmental embryos were assigned to one of three groups on day 285 of gestation: (i) control (no parturition induction treatment; n = 19); (ii) induction of parturition with corticosteroid (n = 20) and (iii) induction of parturition with corticosteroid plus prostaglandin (n = 16). Interval from induction of parturition to calving and calving ease was recorded. Reproductive tract examinations were conducted on Day 21 (D21) and Day 42, and a sample was obtained for the determination of uterine cytology on D21. Blood samples were taken from the dams two weeks before parturition, one day after parturition (D1) and two weeks after parturition (D14) for gene expression and cortisol and calcium concentration determination. Calves were weighed at birth and subsequently every week until they were 10 weeks of age. A colostrum sample was taken immediately after calving and stored for subsequent Immunoglobin G (IgG) concentration analysis. Data were analysed using ANOVA with posthoc Tukey, Spearman correlation and stepwise backwards linear regression using SAS. Quantitative reverse transcription PCR was performed on the following immune genes: Interleukins IL1a and b, IL2, IL4, IL8, Tumour Necrosis Factor Alpha, Interferon-gamma, Lymphotoxin, Toll-Like Receptor, Nuclear factor of kappa light polypeptide gene enhancer in B cells 1 and 2, glucocorticoid receptor alpha, as well as the neutrophil genes that regulate inflammation: Fas, L-selectin, MMP-9 and BPI. The results show that compared with non-induced contemporaries, induction has no negative effect on dystocia or subsequent calf weight gain but can have a positive effect on colostral IgG concentration. Blood calcium concentrations on both D1 and D14 postcalving are associated with subsequent uterine health. Parturition events were reflected in temporal changes in the expression of the cytokines IFNγ, TNFα, IL1b, IL4, IL8 and Haptoglobin in the dams' blood, all of which are associated with the immune competence of the cow during this period. The conclusion is that induction of calving can have a positive effect on colostral IgG concentration. Calcium concentrations postcalving are associated with subsequent reproductive tract health. Events associated with the peri- and postpartum period are all reflected in temporal changes in immune function-related cytokines.

Anesthetic management for the peripartum care of women with Fontan physiology.

BACKGROUND: As outcomes for surgical palliation have improved, women with single ventricle congenital heart disease are surviving into their reproductive years and may become pregnant. The cardiovascular changes of pregnancy may stress the Fontan circulation and pose significant risk to the mother and fetus. METHODS: Pregnant women with Fontan physiology were identified from the Ahmanson/UCLA Adult Congenital Heart Disease Center database. A total of 37 pregnancies were identified between 2000 and 2019. Twenty live births from 19 patients were reviewed and compared for cardiac history, obstetric history, anesthetic management and cardiovascular outcomes. RESULTS: Median gestational age at delivery was 35 weeks. Ten of 20 births were by cesarean delivery. An epidural technique was used as the primary anesthetic for 19 deliveries and general anesthesia was used for one cesarean delivery. An arterial line was placed in the peripartum period for three deliveries. Central venous access was established in the peripartum period for one patient. The mean blood loss for cesarean deliveries was 626 mL (range 240-1200 mL). The mean net peri-operative intake/output was positive 93.5 mL. Three patients were briefly transferred to the intensive care unit postpartum for higher level monitoring and care. CONCLUSION: Epidural anesthesia is safe and effective for both vaginal and cesarean deliveries. Judicious fluid management is critical in minimizing postpartum cardiovascular complications. Many patients do not require a higher level of care, invasive monitoring or central venous access during the peripartum period.

Microsatellite Instability assessment in Black South African Colorectal Cancer patients reveal an increased incidence of suspected Lynch syndrome.

Microsatellite Instability (MSI) is a hallmark of colorectal cancer (CRC) and occurs in 15-16% of CRC. Molecular biological information of CRC in South Africa (SA) is largely unrecorded. This study was undertaken to determine the frequency of MSI, with particular reference to Lynch syndrome (LS) with a view to improve surveillance and prevention strategies. This was a retrospective study on CRC samples diagnosed between 2011-2015 at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Samples diagnosed between 2011-2012 were screened for MSI by PCR and mismatch repair (MMR) immunohistochemistry (IHC), and additional BRAFV600E mutational analysis performed. T-tests, Fischer's exact and Chi square statistical tests were applied. Twelve percent of patients displayed MSI, with increased frequency in black (15%) versus other ethnic group (OEG) (8%) patients. MSI patients were significantly younger than microsatellite stable (MSS) patients, however when stratified by ethnicity, black patients were predominantly younger (median age: 47), with increased MSH2/6 loss, and no BRAF mutations. These findings suggest a large proportion of young black SA CRC patients develop via the LS pathway due to earlier age onset and predominant MSH2/6 protein loss. SA patients of other ethnicities appear to follow the more well established sporadic MSI pathway.

Enhancing analytical accuracy of intravascular electrochemical oxygen sensors via nitric oxide release using S-nitroso-N-acetyl-penicillamine (SNAP) impregnated catheter tubing.

Implantable medical devices are an integral part of primary/critical care. However, these devices carry a high risk for blood clots, caused by platelet aggregation on a foreign body surface. This study focuses on the development of a simplified approach to create nitric oxide (NO) releasing intravascular electrochemical oxygen (O2) sensors with increased biocompatibility and analytical accuracy. The implantable sensors are prepared by embedding S-nitroso-N-acetylpenacillamine (SNAP) as the NO donor molecule in the walls of the catheter type sensors. The SNAP-impregnated catheters were prepared by swelling silicone rubber tubing in a tetrahydrofuran solution containing SNAP. Control and SNAP-impregnated catheters were used to fabricate the Clark-style amperometric PO2 sensors. The SNAP-impregnated sensors release NO under physiological conditions for 18 d as measured by chemiluminescence. The analytical response of the SNAP-impregnated sensors was evaluated in vitro and in vivo. Rabbit and swine models (with sensors placed in both veins and arteries) were used to evaluate the effects on thrombus formation and analytical in vivo PO2 sensing performance. The SNAP-impregnated PO2 sensors were found to more accurately measure PO2 levels in blood continuously (over 7 and 20 h animal experiments) with significantly reduced thrombus formation (as compared to controls) on their surfaces.

Meaning in Life in Earlier and Later Older-Adulthood: Confirmatory Factor Analysis and Correlates of the Meaning in Life Questionnaire.

OBJECTIVE: To validate the Meaning in Life Questionnaire (MLQ) in earlier and later older-adulthood, and examine its correlates. METHOD: Participants in earlier ( n = 341, M age = 68.5) and later older-adulthood ( n = 341, M age = 78.6) completed the MLQ and other measures. Confirmatory multigroup analysis, correlations, and regression models were conducted. RESULTS: A two-factor (presence and search), eight-item model of the MLQ had a good fit and was age-invariant. Presence and search for meaning were largely unrelated. Meaning was associated with life satisfaction, well-being across a range of domains, and psychological resources. Searching for meaning correlated negatively with these variables, but to a lesser degree in later older-adulthood. DISCUSSION: The MLQ is valid in older-adulthood. Meaning in life is psychologically adaptive in older-adulthood. Searching for meaning appears less important, especially in later older-adulthood. Findings are discussed in the context of aging and psychosocial development.

Anaerobic co-digestion of pig manure and food waste; effects on digestate biosafety, dewaterability, and microbial community dynamics.

This study assessed the effect of varying pig manure (PM)/food waste (FW) mixing ratio and hydraulic retention time (HRT) on methane yields, digestate dewaterability, enteric indicator bacteria and microbial communities during anaerobic co-digestion. Three 10 L digesters were operated at 39 °C, each with a PM/FW feedstock composition of 85%/15%, 63%/37% and 40%/60% (volatile solids basis). While the PM/FW ratio was different among reactors, the organic loading rate applied was equal, and increased stepwise with reducing HRT. The effects of three different HRTs were studied: 41, 29, and 21 days. Increasing the proportion of FW in the feedstock significantly increased methane yields, but had no significant effect on counts of enteric indicator bacteria in the digestate or specific resistance to filtration, suggesting that varying the PM/FW feedstock composition at the mixing ratios studied should not have major consequences for digestate disposal. Decreasing HRT significantly increased volumetric methane yields, increased digestate volatile solids concentrations and increased the proportion of particles >500 µm in the digestate, indicating that decreasing HRT to 21 days reduced methane conversion efficiency High throughput 16S rRNA sequencing data revealed that microbial communities were just slightly affected by changes in digester operating conditions. These results would provide information useful when optimizing the start-up and operation of biogas plants treating these substrates.

Low level exposure to inorganic mercury interferes with B cell receptor signaling in transitional type 1 B cells.

Mercury (Hg) has been implicated as a factor contributing to autoimmune disease in animal models and humans. However the mechanism by which this occurs has remained elusive. Since the discovery of B cells it has been appreciated by immunologists that during the normal course of B cell development, some immature B cells must be generated that produce immunoglobulin reactive to self-antigens (auto-antibodies). However in the course of normal development, the vast majority of immature auto-reactive B cells are prevented from maturing by processes collectively known as tolerance. Autoimmune disease arises when these mechanisms of tolerance are disrupted. In the B cell compartment, it is firmly established that tolerance depends in part upon negative selection of self-reactive immature (transitional type 1) B cells. In these cells negative selection depends upon signals generated by the B Cell Receptor (BCR), in the sense that those T1 B cells who's BCRs most strongly bind to, and so generate the strongest signals to self-antigens are neutralized. In this report we have utilized multicolor phosphoflow cytometry to show that in immature T1 B cells Hg attenuates signal generation by the BCR through mechanisms that may involve Lyn, a key tyrosine kinase in the BCR signal transduction pathway. We suggest that exposure to low, environmentally relevant levels of Hg, disrupts tolerance by interfering with BCR signaling in immature B cells, potentially leading to the appearance of mature auto-reactive B cells which have the ability to contribute to auto-immune disease.

Duration of benefit following completion of pulmonary rehabilitation in interstitial lung disease-an observational study.

BACKGROUND: It remains unclear for how long the benefits of pulmonary rehabilitation (PR) last in interstitial lung disease (ILD). An increasing number of ILD patients complete PR and it is vital they be offered the most beneficial approaches. METHODS: This is a retrospective, observational study of a cohort with ILD who had completed PR. Incremental shuttle walk (ISWT) and chronic respiratory disease questionnaire (CRDQ) were compared before PR, at course completion, and 6/12 months follow-up. Focus group discussions with ILD participants who had completed PR and their carers established qualitative views on existing and potential future PR provision. RESULTS: 79 participants with ILD were identified at course completion, with 39 followed to 12 months. 11 participants died during follow-up. Initial benefits from PR were not sustained at 6 months (ISWT change 0.0m (95% CI-23.2 to 23.2 m), CRDQ change 2.5 (95% CI-2.4 to 7.4)) and 12 months (ISWT change-0.7 m (95% CI-37.3 to 35.9 m), CRDQ change 4.0 (95% CI-2.2 to 10.2)). Continued home exercise gave longer lasting benefit in exercise capacity. Focus group discussions highlighted the value attached to PR and suggested areas for improvement. CONCLUSIONS: Standard PR gives initial benefits in participants with ILD who complete the course, however these are not sustained. Tailored approaches to this group would be appreciated by this group and should be explored.

Use of transbronchial cryobiopsy in the diagnosis of interstitial lung disease-a systematic review and cost analysis.

BACKGROUND: Histological diagnosis by surgical lung biopsy for interstitial lung disease (ILD) is currently limited. Transbronchial cryobiopsy via flexible bronchoscope may this for more patients. The relative costs, diagnostic yields and safety of this approach and more traditional approaches have not been determined. OBJECTIVES: To perform a systematic review and meta-analysis of transbronchial cryobiopsy, forceps transbronchial biopsy and video assisted (VATS) surgical lung biopsy assessing their relative diagnostic yields and safety. To perform a cost analysis to demonstrate any savings through change to the newer technique. METHODS: We performed a systematic review of the literature using MEDLINE and EMBASE for all original articles on the diagnostic yield and safety of transbronchial cryobiopsy, forceps transbronchial biopsy and VATS-biopsy in ILD up to February 2016. Data were extracted on yield and complication rates, in addition to study characteristics. Theoretical cost analysis was performed from local institution financial data, 2015-16 reimbursement tariffs and results of the systematic review. RESULTS: A meta-analysis of 11 investigations for transbronchial cryobiopsy, 11 for forceps transbronchial biopsy and 24 for VATS-biopsy revealed diagnostic yields of 84.4% (75.9-91.4%), 64.3% (52.6-75.1%) and 91.1% (84.9-95.7%), respectively. Pneumothorax occurred in 10% (5.4-16.1%) of transbronchial cryobiopsy procedures, moderate bleeding in 20.99% (5.6-42.8%), with three deaths reported. Surgical mortality was 2.3% (1.3-3.6%). Cost analysis demonstrated potential savings of £210 per patient in the first year and £647 in subsequent years. CONCLUSIONS: Transbronchial cryobiopsy represents a potentially cost-saving approach to improve histological diagnosis in ILD, however is accompanied by a significant risk of moderate bleeding.

Dietary n-3 PUFAs augment caspase 8 activation in Staphylococcal aureus enterotoxin B stimulated T-cells.

Epidemiological studies have linked consumption of n-3 PUFAs with a variety of beneficial health benefits, particularly with respect to putative anti-inflammatory effects. Unfortunately, many of these results remain somewhat controversial because in most instances there has not been a linkage to specific molecular mechanisms. For instance, dietary exposure to low levels of mercury has been shown to be damaging to neural development, but concomitant ingestion of n-3 PUFAs as occurs during consumption of fish, has been shown to counteract the detrimental effects. As the mechanisms mediating the neurotoxicity of environmental mercury are not fully delineated, it is difficult to conceptualize a testable molecular mechanism explaining how n-3 PUFAs negate its neurotoxic effects. However, environmental exposure to mercury also has been linked to increased autoimmunity. By way of a molecular understanding of this immuno-toxic association, disruption of CD95 signaling is well established as a triggering factor for autoimmunity, and we have previously shown that environmentally relevant in vitro and dietary exposures to mercury interfere with CD95 signaling. In particular we have shown that activation of caspase 8, as well as downstream activation of caspase 3, in response to CD95 agonist stimulation is depressed by mercury. More recently we have shown in vitro that the n-3 PUFA docosahexaenoic acid counteracts the negative effect of mercury on CD95 signaling by restoring caspase activity. We hypothesized that concomitant ingestion of n-3 PUFAs with mercury might be protective from the immuno-toxic effects of mercury, as it is with mercury's neuro-toxic effects, and in the case of immuno-toxicity this would be related to restoration of CD95 signal strength. We now show that dietary ingestion of n-3 PUFAs generally promotes CD95 signaling by upregulating caspase 8 activation. Apart from accounting for the ability of n-3 PUFAs to specifically counteract autoimmune sequelae of mercury exposure, this novel finding for the first time suggests a testable molecular mechanism explaining the overall anti-inflammatory properties of n-3 PUFAs.

An extremely rare case of a high-grade pleomorphic cardiac sarcoma and likely cerebral metastasis in a young patient.

To date, there have been less than a 100 confirmed case reports of primary cardiac malignant fibrous histiocytomas, a rare form of sarcoma. In this report, we discuss the case of a 15-year-old girl who initially presented with a histiocytic cerebral sarcoma that was treated with aggressive resection and chemotherapy. Three years later, the same patient developed increasing shortness of breath and was found to have a high-grade pleomorphic undifferentiated cardiac sarcoma that likely represents the primary tumour from which the cerebral lesion metastasised. This represents an extremely unique case; in 2010, a research group in Germany claimed the very first description of a true cardiac sarcoma with brain metastasis [1]. However, even as far back as 1960, there were three case reports [2] and more extensive sarcoma studies recently have revealed further cases [3]. Nevertheless, there have probably been less than 10 cases in the literature up until this point.

Characterisation of the Whole Blood mRNA Transcriptome in Holstein-Friesian and Jersey Calves in Response to Gradual Weaning.

Weaning of dairy calves is an early life husbandry management practice which involves the changeover from a liquid to a solid feed based diet. The objectives of the study were to use RNA-seq technology to examine the effect of (i) breed and (ii) gradual weaning, on the whole blood mRNA transcriptome of artificially reared Holstein-Friesian and Jersey calves. The calves were gradually weaned over 14 days (day (d) -13 to d 0) and mRNA transcription was examined one day before gradual weaning was initiated (d -14), one day after weaning (d 1), and 8 days after weaning (d 8). On d -14, 550 genes were differentially expressed between Holstein-Friesian and Jersey calves, while there were 490 differentially expressed genes (DEG) identified on d 1, and 411 DEG detected eight days after weaning (P < 0.05; FDR < 0.1). No genes were differentially expressed within breed, in response to gradual weaning (P > 0.05). The pathways, gene ontology terms, and biological functions consistently over-represented among the DEG between Holstein-Friesian and Jersey were associated with the immune response and immune cell signalling, specifically chemotaxis. Decreased transcription of several cytokines, chemokines, immunoglobulin-like genes, phagocytosis-promoting receptors and g-protein coupled receptors suggests decreased monocyte, natural killer cell, and T lymphocyte, chemotaxis and activation in Jersey compared to Holstein-Friesian calves. Knowledge of breed-specific immune responses could facilitate health management practices better tailored towards specific disease sensitivities of Holstein-Friesian and Jersey calves. Gradual weaning did not compromise the welfare of artificially-reared dairy calves, evidenced by the lack of alterations in the expression of any genes in response to gradual weaning.

Incidence and survival of children and young people with central nervous system embryonal tumours in the North of England, 1990-2013.

BACKGROUND: Medulloblastoma and primitive neuroectodermal tumours (PNET) are the most common central nervous system (CNS) embryonal tumours diagnosed in childhood. Survival outcomes are worse for children diagnosed with CNS PNET compared to medulloblastoma. Less is known about survival outcomes in teenagers and young adults (TYA). METHODS: Data were extracted from two population-based cancer registries of children and young people (0-24 years) in the north of England for all diagnoses of medulloblastoma and CNS PNET between 1990 and 2013. Incidence and survival trends were analysed using Poisson and Cox regression. RESULTS: Between 1990 and 2013, 197 medulloblastomas and 58 CNS PNET were diagnosed, age-standardised incidence rates of 3.8 and 1.5 per million, respectively. Medulloblastoma incidence decreased over time while there was no significant change in trend for CNS PNET. The overall 5-year survival rate was 54%. The risk of death was 2.4 times higher (95% confidence interval [CI] 1.6, 3.7) for patients with CNS PNET compared to medulloblastoma, after adjustment for patient characteristics. There was a 39% reduction (95% CI 0.43, 0.87) in the risk of death for patients diagnosed between 2000 and 2013 compared to 1990-1999. Risk of death did not differ for TYA (15-24 years) compared to children aged 5-9 years. CONCLUSIONS: Medulloblastoma incidence decreased over time and differences in survival between medulloblastoma and PNET emerged within the first-year post diagnosis leading to poorer outcomes for children and young adults diagnosed with PNET; however, a significant improvement in survival over time was observed.

Fertility and genomics: comparison of gene expression in contrasting reproductive tissues of female cattle.

To compare gene expression among bovine tissues, large bovine RNA-seq datasets were used, comprising 280 samples from 10 different bovine tissues (uterine endometrium, granulosa cells, theca cells, cervix, embryos, leucocytes, liver, hypothalamus, pituitary, muscle) and generating 260 Gbases of data. Twin approaches were used: an information-theoretic analysis of the existing annotated transcriptome to identify the most tissue-specific genes and a de-novo transcriptome annotation to evaluate general features of the transcription landscape. Expression was detected for 97% of the Ensembl transcriptome with at least one read in one sample and between 28% and 66% at a level of 10 tags per million (TPM) or greater in individual tissues. Over 95% of genes exhibited some level of tissue-specific gene expression. This was mostly due to different levels of expression in different tissues rather than exclusive expression in a single tissue. Less than 1% of annotated genes exhibited a highly restricted tissue-specific expression profile and approximately 2% exhibited classic housekeeping profiles. In conclusion, it is the combined effects of the variable expression of large numbers of genes (73%-93% of the genome) and the specific expression of a small number of genes (<1% of the transcriptome) that contribute to determining the outcome of the function of individual tissues.

Gonadotropin suppression in men leads to a reduction in claudin-11 at the Sertoli cell tight junction.

STUDY QUESTION: Are Sertoli cell tight junctions (TJs) disrupted in men undergoing hormonal contraception? SUMMARY ANSWER: Localization of the key Sertoli cell TJ protein, claudin-11, was markedly disrupted by 8 weeks of gonadotropin suppression, the degree of which was related to the extent of adluminal germ cell suppression. WHAT IS KNOWN ALREADY: Sertoli cell TJs are vital components of the blood-testis barrier (BTB) that sequester developing adluminal meiotic germ cells and spermatids from the vascular compartment. Claudin-11 knockout mice are infertile; additionally claudin-11 is spatially disrupted in chronically gonadotropin-suppressed rats coincident with a loss of BTB function, and claudin-11 is disorganized in various human testicular disorders. These data support the Sertoli cell TJ as a potential site of hormonal contraceptive action. STUDY DESIGN, SIZE, DURATION: BTB proteins were assessed by immunohistochemistry (n = 16 samples) and mRNA (n = 18 samples) expression levels in available archived testis tissue from a previous study of 22 men who had undergone 8 weeks of gonadotropin suppression and for whom meiotic and post-meiotic germ cell numbers were available. The gonadotropin suppression regimens were (i) testosterone enanthate (TE) plus the GnRH antagonist, acyline (A); (ii) TE + the progestin, levonorgestrel, (LNG); (iii) TE + LNG + A or (iv) TE + LNG + the 5α-reductase inhibitor, dutasteride (D). A control group consisted of seven additional men, with three archived samples available for this study. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Immunohistochemical localization of claudin-11 (TJ) and other junctional type markers [ZO-1 (cytoplasmic plaque), ß-catenin (adherens junction), connexin-43 (gap junction), vinculin (ectoplasmic specialization) and ß-actin (cytoskeleton)] and quantitative PCR was conducted using matched frozen testis tissue. MAIN RESULTS AND THE ROLE OF CHANCE: Claudin-11 formed a continuous staining pattern at the BTB in control men. Regardless of gonadotropin suppression treatment, claudin-11 localization was markedly disrupted and was broadly associated with the extent of meiotic/post-meiotic germ cell suppression; claudin-11 staining was (i) punctate (i.e. 'spotty' appearance) at the basal aspect of tubules when the average numbers of adluminal germ cells were <15% of control, (ii) presented as short fragments with cytoplasmic extensions when numbers were 15-25% of control or (iii) remained continuous when numbers were >40% of control. Changes in localization of connexin-43 and vinculin were also observed (smaller effects than for claudin-11) but ZO-1, ß-catenin and ß-actin did not differ, compared with control. LIMITATIONS, REASONS FOR CAUTION: Claudin-11 was the only Sertoli cell TJ protein investigated, but it is considered to be the most pivotal of constituent proteins given its known implication in infertility and BTB function. We were limited to testis samples which had been gonadotropin-suppressed for 8 weeks, shorter than the 74-day spermatogenic wave, which may account for the heterogeneity in claudin-11 and germ cell response observed among the men. Longer suppression (12-24 weeks) is known to suppress germ cells further and claudin-11 disruption may be more uniform, although we could not access such samples. WIDER IMPLICATIONS OF THE FINDINGS: These findings are important for our understanding of the sites of action of male hormonal contraception, because they suggest that BTB function could be ablated following long-term hormone suppression treatment. STUDY FUNDING/COMPETING INTERESTS: National Health and Medical Research Council (Australia) Program Grants 241000 and 494802; Research Fellowship 1022327 (to R.I.M.) and the Victorian Government's Operational Infrastructure Support Program. None of the authors have any conflicts to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Characterisation of haematological profiles and whole blood relative gene expression levels in Holstein-Friesian and Jersey bull calves undergoing gradual weaning.

Haematological profiles indicate the health status of an animal and can be used to identify sub-clinical stress responses. The objectives of the study were to examine (i) the effect of breed and plane of nutrition, on haematological profiles of artificially reared Holstein-Friesian and Jersey bull calves in response to gradual weaning, and (ii) the effect of breed on immune response genes in bovine whole blood using real-time quantitative PCR. Holstein-Friesian and Jersey bull calves were group housed indoors and individually fed using an automatic feeder. They were allocated to a high, medium or low plane of nutrition, based on milk replacer (MR) and concentrate. The nutrition treatments were calculated using National Research Council guidelines in order to achieve a high, medium or low growth rate for each respective breed. During the weaning phase MR was gradually reduced over a 14-day (d) period (d -13 to d 0). Calves were blood sampled on d -14, -6, -3, 0, 1, 3, 8 and 14 relative to weaning (d 0) for subsequent haematological analysis. On d -14, 1 and 8, a subset of eight Holstein-Friesian calves randomly selected from the medium nutrition treatment and eight Jersey calves randomly selected from the high nutrition treatment, were blood sampled for gene expression profiling, targeting biomarkers of weaning stress. These two treatment groups were chosen to examine the effect of breed on expression of the genes of interest, as energy intake and animal performance were similar. There was no effect of breed×plane of nutrition interaction nor effect of plane of nutrition on any variable measured (P>0.05). Gradual weaning produced differential biological responses in the two breeds evidenced by breed×time interactions for lymphocyte, monocyte and red blood cell number, plasma haemoglobin and haptoglobin concentrations (P<0.05). The typical stress response consisting of neutrophilia and lymphopaenia was not observed for any treatment. An immune response to gradual weaning was observed as the relative gene expression level of the pro-apoptotic gene, Fas, increased on d 1 relative to d -14 (P<0.05). Relative gene expression levels were greater in Jersey calves compared with Holstein-Friesian for the pro-inflammatory cytokine CXCL8 (P=0.05) and the glucocorticoid receptor, GRα (P<0.05). The increased levels of these transcripts suggest that Jersey calves may have a more sensitive immune system compared with Holstein-Friesian.

A parent-based intervention to promote healthy eating and active behaviours in pre-school children: evaluation of the MEND 2-4 randomized controlled trial.

BACKGROUND: There is a paucity of studies evaluating targeted obesity prevention interventions in pre-school children. OBJECTIVES: We conducted a randomized controlled trial to evaluate the efficacy of a parent-based obesity prevention intervention for pre-schoolers - MEND (Mind, Exercise, Nutrition … Do It!) 2-4 on child diet, eating habits, physical activity/sedentary behaviours, and body mass index (BMI). METHODS: Parent-child dyads attended 10 weekly 90-min workshops relating to nutrition, physical activity and behaviours, including guided active play and healthy snack time. Assessments were conducted at baseline, immediately post-intervention, and 6 and 12 months post-intervention; child intake of vegetables, fruit, beverages, processed snack foods, fussiness, satiety responsiveness, physical activity, sedentary behaviour and neophobia were assessed via parent proxy report. Parent and child height and weight were measured. RESULTS: Two hundred one parent-child dyads were randomized to intervention (n = 104) and control (n = 97). Baseline mean child age was 2.7 (standard deviation [SD] 0.6) years, and child BMI-for-age z-score (World Health Organization) was 0.66 (SD 0.88). We found significant positive group effects for vegetable (P = 0.01) and snack food (P = 0.03) intake, and satiety responsiveness (P = 0.047) immediately post-intervention. At 12 months follow-up, intervention children exhibited less neophobia (P = 0.03) than controls. CONCLUSION: Future research should focus on additional strategies to support parents to continue positive behaviour change. ACTRN12610000200088.

Trends in survival for teenagers and young adults with cancer in the UK 1992-2006.

BACKGROUND: Although relatively rare, cancer in teenagers and young adults (TYA) is the most common disease-related cause of death and makes a major contribution to years of life lost in this age group. There is a growing awareness of the distinctive needs of this age group and drive for greater understanding of how outcomes can be improved. We present here the latest TYA survival trends data for the United Kingdom (UK). METHODS: Using national cancer registry data, we calculated five-year relative survival for all 15-24 year olds diagnosed with cancer or a borderline/benign CNS tumour in the UK during the periods 1992-1996, 1997-2001 and 2002-2006. We analysed trends in survival for all cancers combined and for eighteen specified groups that together represent the majority of TYA cancers. We compared our data with published data for Europe, North America and Australia. RESULTS: Five-year survival for all cancers combined increased from 75.5% in 1992-1996 to 82.2% in 2002-2006 (P<0.001). Statistically significant improvements were seen for all disease groups except osteosarcoma, rhabdomyosarcoma, non-gonadal and ovarian germ cell tumours and ovarian and thyroid carcinomas. During the earliest time period, females had significantly better survival than males for five of the twelve non-gender-specific disease groups. By the latest period, only melanomas and non-rhabdomyosarcoma soft tissue sarcomas had differential survival by gender. Survival in the UK for the most recent period was generally similar to other comparable countries. CONCLUSION: Five-year survival has improved considerably in the UK for most cancer types. For some disease groups, there has been little progress, either because survival already approaches 100% (e.g. thyroid carcinomas) or, more worryingly for some cancers with poor outcomes, because they remain resistant to existing therapy (e.g. rhabdomyosarcoma). In addition, for a number of specific cancer types and for cancer as a whole males continue to have worse outcomes than females.

Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation.

BACKGROUND: LHX4 encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. OBJECTIVE/HYPOTHESIS: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. METHOD: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. RESULTS: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. CONCLUSION: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.