In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis.

During embryogenesis, haematopoietic and endothelial lineages emerge closely in time and space. It is thought that the first blood and endothelium derive from a common clonal ancestor, the haemangioblast. However, investigation of candidate haemangioblasts in vitro revealed the capacity for mesenchymal differentiation, a feature more compatible with an earlier mesodermal precursor. To date, no evidence for an in vivo haemangioblast has been discovered. Using single cell RNA-Sequencing and in vivo cellular barcoding, we have unravelled the ancestral relationships that give rise to the haematopoietic lineages of the yolk sac, the endothelium, and the mesenchyme. We show that the mesodermal derivatives of the yolk sac are produced by three distinct precursors with dual-lineage outcomes: the haemangioblast, the mesenchymoangioblast, and a previously undescribed cell type: the haematomesoblast. Between E5.5 and E7.5, this trio of precursors seeds haematopoietic, endothelial, and mesenchymal trajectories.

Accuracy and economic evaluation of screening tests for undiagnosed COPD among hypertensive individuals in Brazil.

In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources.ISRCTN registration number: 11377960.

The equity impact of brief opportunistic interventions to promote weight loss in primary care: secondary analysis of the BWeL randomised trial.

BACKGROUND: Guidelines recommend that clinicians should make brief opportunistic behavioural interventions to patients who are obese to increase the uptake of effective weight loss programmes. The objective was to assess the effect of this policy on socioeconomic equity. METHODS: One thousand eight hundred eighty-two consecutively attending patients with obesity and who were not seeking support for weight loss from their GP were enrolled in a trial. Towards the end of each consultation, GPs randomly assigned participants to one of two 30-s interventions. In the active intervention (support arm), the GP offered referral to a weight management group. In the control intervention (advice arm), the GP advised the patient that their health would benefit from weight loss. Agreement to attend a behavioural weight loss programme, attendance at the programme and weight loss at 12 months were analysed by socioeconomic status, measured by postcode using the Index of Multiple Deprivation (IMD). RESULTS: Mean weight loss was 2.43 kg (sd 6.49) in the support group and 1.04 kg (sd 5.50) for the advice only group, but these effects were moderated by IMD (p = 0.039 for the interaction). In the support arm, weight loss was greater in higher socioeconomic groups. Participants from lower socioeconomic backgrounds were more likely to accept the offer and equally likely to attend a weight loss referral but attended fewer sessions. Adjusting for these sequentially reduced the gradient for the association of socioeconomic status with weight loss from + 0.035 to - 0.001 kg/IMD point. In the advice only arm, 10% took effective action to promote weight loss. The decision to seek support for weight loss outside of the trial did not differ by socioeconomic status, but weight loss among deprived participants who used external support was greater than among more affluent participants (p = 0.025). CONCLUSION: Participants' responses to GPs' brief opportunistic interventions to promote weight loss differed by socioeconomic status and trial arm. In the support arm, more deprived people lost less weight because they attended fewer sessions at the programme. In the advice arm, more deprived people who sought and paid for support for weight loss themselves lost more weight than more affluent people who sought support. TRIAL REGISTRATION: This trial is registered with the ISRCTN registry, number ISRCTN26563137 . Date of registration: January 3, 2013; date of first participant recruited: June 4, 2014.

Smoking cessation and survival in lung, upper aero-digestive tract and bladder cancer: cohort study.

BACKGROUND: The aim was to examine the association between smoking cessation and prognosis in smoking-related cancer as it is unclear that cessation reduces mortality. METHODS: In this retrospective cohort study from 1999 to 2013, we assessed the association between cessation during the first year after diagnosis and all-cause and cancer-specific mortality. RESULTS: Of 2882 lung, 757 upper aero-digestive tract (UAT) and 1733 bladder cancer patients 27%, 29% and 21% of lung, UAT and bladder cancer patients quit smoking. In lung cancer patients that quit, all-cause mortality was significantly lower (HR: 0.82 (0.74-0.92), while cancer-specific mortality (HR: 0.89 (0.76-1.04) and death due to index cancer (HR: 0.90 (0.77-1.05) were non-significantly lower. In UAT cancer, all-cause mortality (HR: 0.81 (0.58-1.14), cancer-specific mortality (HR: 0.84 (0.48-1.45), and death due to index cancer (HR: 0.75 (0.42-1.34) were non-significantly lower. There was no evidence of an association between quitting and mortality in bladder cancer. The HRs were 1.02 (0.81-1.30) for all-cause, 1.23 (0.81-1.86) for cancer specific, and 1.25 (0.71-2.20) for death due to index cancer. These showed a non-significantly lower risk in sensitivity analyses. CONCLUSIONS: People with lung and possibly UAT cancer who quit smoking have a lower risk of mortality than people who continue smoking.

Assessing pain in patients.

This article defines pain and discusses options for pain assessment. Both unidimensional and multidimensional pain assessment scales are considered and described. Nursing skills required to carry out pain assessment are identified and discussed.

Delirium part one: clinical features, risk factors and assessment.

Delirium is a common and under-reported problem in older adults. A lack of consensus over the terminology used to describe delirium may contribute to its underdiagnosis, and a number of predisposing factors are linked to it. This article, the first of two, aims to define delirium, describe the different types and identify risk factors associated with its development. Delirium is an important condition as it has a deleterious effect on patient outcomes and quality of life if it is not detected early and managed effectively. The detection of delirium and a variety of assessment tools are also considered. Part two, to be published in next week's Nursing Standard, examines the nursing management of delirium.

You be the examiner!: "Model answers" that require critical thinking.

"You be the examiner!" is an online approach to providing students with immediate, readily accessible, and nonthreatening feedback on their understanding of key biochemical concepts. The feedback aims to affirm correct understanding and, where further study appears necessary, direct the student to the relevant sections of their textbook and/or lecturer-provided study notes. Rather than providing model answers to previous examination questions, "You be the examiner" asks the students to evaluate typical "student" answers to such questions. Instead of a single "correct" answer, students encounter a range of answers that they must assess for accuracy and appropriateness.

The physiological effects of ageing on the activities of living.

This article describes different theories of ageing. It examines the impact that physiological effects have on aspects of living for older people: eating and drinking, eliminating, mobilising, communicating and breathing.

Developmental shifts in cortical loci for face and object recognition.

Information on normal functional organization and development of the ventral processing stream in 5- to 11-year-old children is minimal. The present fMRI study identified neural correlates for face and object processing in children aged 5-8 and 9-11 years, with data from a similar adult study used for comparison. All age groups showed face-preferential activation in the ventral processing stream, but adults and children aged 9-11 years showed face-preferential loci near the classically defined fusiform face area, whereas children aged 5-8 years showed this activation in the posterior ventral processing stream. In addition, the degree of category-selectivity in other brain regions increased with age. Collectively, these developmental changes may reflect fine-tuning in visual recognition processes based on learning and experience.

Efficacy and safety of single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole, for the eradication of Helicobacter pylori: an international multicentre study.

BACKGROUND: The high prevalence of Helicobacter pylori resistance to metronidazole demands treatments more effective than standard bismuth-based triple therapy against these strains. AIM: To evaluate the H. pylori eradication rate in both metronidazole-sensitive and -resistant strains following quadruple therapy using single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole. METHODS: One hundred and seventy valid patients with duodenal ulcer, gastric ulcer or non-ulcer dyspepsia were treated in eight centres located in five countries. H. pylori was confirmed at baseline using 13C-urea breath test, histology and/or culture. Patients received three single-triple capsules q.i.d. and omeprazole, 20 mg b.d., for 10 days. Each capsule contained bismuth biskalcitrate, 140 mg (as 40 mg Bi2O3 equivalent), metronidazole, 125 mg, and tetracycline, 125 mg. 13C-Urea breath test was repeated at least 4 and 8 weeks post-treatment. RESULTS: Overall eradication rates were 93% (158/170) by modified intention-to-treat analysis and 97% (142/146) by per protocol analysis. Eradication rates were 93% (40/43) and 95% (38/40) for strains resistant to metronidazole and 95% (82/86) and 99% (75/76) for strains sensitive to metronidazole by modified intention-to-treat and per protocol analysis, respectively. CONCLUSION: This omeprazole-bismuth biskalcitrate-metronidazole-tetracycline 10-day regimen is a very effective and well-tolerated treatment, which overcomes metronidazole resistance.

Carbon monoxide decreases perfusion pressure in isolated human placenta.

Carbon monoxide (CO) is one of the metabolites formed via heme oxidation catalysed by the enzyme heme oxygenase (HO). Endogenous formation of CO, mediated by HO, has been noted in both placental and umbilical vessels. In blood vessels from different mammalian sources, it has been proposed that the vasodilator effect of CO is mediated via stimulation of soluble guanylyl cyclase (sGC) and consequent increased cGMP formation. The purpose of the present study was to determine the effect of exogenous CO on placental cotyledon perfusion pressure and to determine the role of sGC in the CO-induced decrease of perfusion pressure using the in vitro human placental perfusion preparation. A thromboxane A2 mimetic (U46619) was added to the foetal perfusion medium to constrict the placental blood vessels. Carbon monoxide was added to the foetal perfusion medium in increasing concentrations to determine its effect on placental perfusion pressure. Carbon monoxide produced a concentration-dependent decrease in placental perfusion pressure. The addition of ODQ, a sGC inhibitor, attenuated the CO-induced decrease in placental perfusion pressure, while addition of YC-1, an activator of sGC, augmented the CO-induced decrease in placental perfusion pressure. The data indicate that CO causes vasorelaxation of placental resistance blood vessels, in large part, via activation of sGC.

Bismuth-based quadruple therapy with bismuth subcitrate, metronidazole, tetracycline and omeprazole in the eradication of Helicobacter pylori.

BACKGROUND: A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg, metronidazole 250 mg and colloidal bismuth subcitrate 120 mg resulted in excellent Helicobacter pylori eradication rates (89.5%). The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline. METHODS: One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study. They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid (OBMT). Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer. Patients with irritable bowel syndrome, active ulcer or previous attempt at eradication, or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded. Eradication was determined by two (13)carbon urea breath tests done one and three months, respectively, after treatment. Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole. RESULTS: The overall per protocol eradication rate was 84%-89.5% in metronidazole-sensitive and 70.8% in metronidazole-resistant strains. Modified intent-to-treat analysis resulted in a 80% eradication rate--82.5% in metronidazole-sensitive and 66.7% in metronidazole-resistant strains. Only one patient discontinued treatment because of adverse events. CONCLUSIONS: The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on corticotrophin-releasing hormone, arginine vasopressin, and pro-opiomelanocortin mRNA levels in the hypothalamus of the cynomolgus monkey.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant that has profound deleterious effects on development and reproduction. TCDD may act at one or more levels to alter the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. The objective of this study was to investigate whether TCDD modulates neuroendocrine systems by altering gene expression of arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH), or pro-opiomelanocortin (POMC), which are important neuroregulators of the HPA and HPG axes. Four groups of female cynomolgus monkeys (Macaca fascicularis) were administered daily oral doses of gelatin capsule containing TCDD (0, 1, 5, or 25 ng/kg body weight) mixed with glucose 5 days a week for 1 year. At the end of the dosing period, animals were euthanized and brains were harvested. CRH, AVP, and POMC mRNA levels were semiquantified by in situ hybridization histochemistry on 30-microm coronal sections of the brain. Blood collected on the day of euthanasia was assayed for cortisol and progesterone. CRH mRNA levels in the paraventricular nucleus (PVN) were significantly increased by the 2 higher TCDD doses (5 and 25 ng/kg/day) compared to controls (p < 0.05). There was a trend towards increased AVP mRNA levels in both the supraoptic nucleus (SON) and PVN. No effect of TCDD on POMC was observed. Cortisol levels were significantly increased in TCDD-exposed animals. Progesterone concentrations and menstruation data indicated that TCDD did not interfere with ovulation. We conclude that TCDD stimulated the HPA axis by a central effect involving CRH, but had no effect on the HPG axis at the doses tested.

Nasogastric feeding in children and adolescents with eating disorders: toward good practice.

OBJECTIVE: This study aimed to provide an insight into the subjective experiences of nasogastric feeding from the perspective of patients with eating disorders and their parents. METHOD: A semistructured self-report questionnaire was completed by patients from two specialist eating disorders units who had received nasogastric feeding. Parents' views were also assessed via a similar self-report questionnaire. RESULTS: Diverse views were expressed by both patients and parents. Some regarded the experience of nasogastric feeding as wholly negative, but acknowledged the lack of suitable alternatives. Others had a more positive view and identified several helpful aspects. CONCLUSION: Reactions were generally more positive than had been anticipated. A number of useful suggestions were made regarding how to improve the procedure. These have informed the development of guidelines for good practice.

The role of gown and glove isolation and strict handwashing in the reduction of nosocomial infection in children with solid organ transplantation.

OBJECTIVE: Nosocomial infection is an important contributor to morbidity and mortality in pediatric solid organ transplantation. The relative effect of protective gown and glove isolation was compared with strict handwashing in pediatric intensive care unit (PICU) patients with solid organ transplantation. DESIGN/SETTING: A prospective, randomized design was used; children in a 23-bed PICU with solid organ transplantation were enrolled into a gown and glove protective isolation protocol or a strict handwashing protocol. PATIENTS: All children admitted to the PICU immediately after solid organ transplantation, excluding renal transplantation, and at subsequent readmissions to the PICU were eligible for the study. Children with current infection or known exposure to varicella were excluded from the study initially or at readmission. INTERVENTIONS: By using a block randomization design based on organ transplanted, age, and initial admission vs. readmission, each patient was randomized to either strict handwashing or protective gown and glove isolation intervention groups. MEASUREMENTS: We analyzed demographics, infection outcomes (defined according to Centers for Disease Control criteria), and monitoring of patient contacts in compliance with protocols. RESULTS: The infection rate in the overall PICU population did not change significantly from the year before the study compared with during the study (2.1 per 100 vs. 1.95 per 100 patient days; p =.4) The infection rate in the gown and glove group (2.3 per 100 patient days) was reduced significantly compared with the prestudy infection rate in the transplant population (4.9 per 100 patient days; p =.0008). Strict handwashing also significantly reduced the infection rate in the transplant population (3.0 per 100 patient days; p =.008). Compliance with gowning and gloving was 82% and compliance with handwashing was 76% (compared with 22% before study [p <.0001] and 52% after the study [p <.0001]). Despite an increased mean length of stay in the PICU in the gown and glove group (p =.014), there was a trend toward reduction in the incidence of infection (Fisher's exact test, p =.07; odds ratio,.76) in the gown and glove group. CONCLUSIONS: Increased compliance with handwashing was associated with a reduction in nosocomial infections, and gown and glove isolation appeared to have an additional protective effect. Some nosocomial infections may be preventable in the pediatric solid organ transplantation population.

Understanding allergies and their treatment.

Allergies are common and although their effects are often minor, they can be life threatening. The authors discuss the background to allergy and give guidance for prevention and management.

Bismuth-based triple therapy with bismuth subcitrate, metronidazole and tetracycline in the eradication of Helicobacter pylori: a randomized, placebo controlled, double-blind study.

OBJECTIVE: To determine the rate of Helicobacter pylori eradication following bismuth-based triple therapy with colloidal bismuth subcitrate, tetracycline hydrochloride and metronidazole. PATIENTS AND METHODS: One hundred and eleven patients were randomly assigned, in a two to one ratio, to colloidal bismuth subcitrate 120 mg qid plus metronidazole 250 mg qid plus tetracycline 500 mg qid (Gastrostat), or matching placebo tablets and capsules for 14 days. Presence or absence of H pylori was documented by histology at entry and at least 28 days after treatment. Patients had dyspeptic symptoms with or without a history of peptic ulcer. Patients with any previous attempt(s) at eradication of H pylori, who used bismuth, antibiotics, H2 receptor antagonists or proton pump inhibitors in the previous four weeks were excluded. RESULTS: Fifty-three of 59 (90%) patients on bismuth-based treatment and only one of 35 (3%) on placebo achieved eradication by per protocol analysis. Fifty-three of 65 (82%) patients on bismuth-based treatment achieved eradication, while only two of 34 (5%) achieved eradication on placebo by intention to treat analysis. Eradication rates for bismuth-based treatment across sites ranged from 83% to 100%. Only two patients in the bismuth-based treatment group (4%) and one in the placebo group (3%) discontinued treatment because of adverse events. CONCLUSIONS: Colloidal bismuth subcitrate plus metronidazole plus tetracycline, given in the doses studied for 14 days, is safe and highly effective against H pylori infection and would be appropriate as a first-line therapy for eradication.

Rabeprazole versus ranitidine for the treatment of erosive gastroesophageal reflux disease: a double-blind, randomized clinical trial. Raberprazole Study Group.

OBJECTIVE: The objective of this study was to compare the efficacy and safety of the proton pump inhibitor rabeprazole to that of the histamine-2 (H2)-receptor antagonist ranitidine in the treatment of erosive gastroesophageal reflux disease. The primary indicator of efficacy was the absence of esophageal erosions or ulcerations as determined by posttreatment endoscopy. Secondary indicators of efficacy included improvement in frequency and severity of daytime and nighttime heartburn. METHODS: A total of 338 patients were enrolled and randomly assigned to therapy with rabeprazole 20 mg once daily in the morning or to ranitidine 150 mg four times daily. At baseline and at 4 wk, patients underwent endoscopy for evaluation of esophageal lesions. Patients whose lesions healed by wk 4 had therapy discontinued; others remained on therapy and had repeat endoscopy at 8 wk. Also recorded at study visits were patients' ratings of heartburn symptoms and overall sense of well being, patients' reports of time lost from daily activities, antacid use, and adverse events. Serum gastrin levels were measured and argyrophil enterochromaffin-like cell histology evaluated at baseline and when the patient ended therapy. RESULTS: At wk 4, healing was observed in 59% (98/167) of patients assigned to rabeprazole therapy, compared with 36% (60/169) of those receiving ranitidine (p < 0.001). By 8 wk, healing was seen in 87% (146/167) and 66% (112/169) of patients in the rabeprazole and ranitidine groups, respectively (p < 0.001). There were also significant differences between the two groups favoring rabeprazole with respect to resolution or improvement of heartburn symptoms and improvement in sense of well-being. No drug-related serious adverse events were seen with either therapy; fewer patients assigned to rabeprazole had treatment-emergent signs and symptoms. Serum gastrin levels increased over baseline in the rabeprazole group, but the mean value remained within normal limits. CONCLUSIONS: Rabeprazole was superior to ranitidine in esophageal healing and symptom relief in patients with erosive gastroesophageal reflux disease, and was equally well tolerated.

Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130.

Suppressor of cytokine signaling-3 (SOCS-3) is one member of a family of intracellular inhibitors of signaling pathways initiated by cytokines that use, among others, the common receptor subunit gp130. The SH2 domain of SOCS-3 has been shown to be essential for this inhibitory activity, and we have used a quantitative binding analysis of SOCS-3 to synthetic phosphopeptides to map the potential sites of interaction of SOCS-3 with different components of the gp130 signaling pathway. The only high-affinity ligand found corresponded to the region of gp130 centered around phosphotyrosine-757 (pY757), previously shown to be a docking site for the tyrosine phosphatase SHP-2. By contrast, phosphopeptides corresponding to other regions within gp130, Janus kinase, or signal transducer and activator of transcription proteins bound to SOCS-3 with weak or undetectable affinity. The significance of pY757 in gp130 as a biologically relevant SOCS-3 docking site was investigated by using transfected 293T fibroblasts. Although SOCS-3 inhibited signaling in cells transfected with a chimeric receptor containing the wild-type gp130 intracellular domain, inhibition was considerably impaired for a receptor carrying a Y-->F point mutation at residue 757. Taken together, these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3.

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction.

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.