Candida catheter-related bloodstream infection in patients on home parenteral nutrition - Rates, risk factors, outcomes, and management.
Catheter-related bloodstream infections (CRBSIs) are life-threatening complications for home parenteral nutrition (HPN) patients. This review clarifies Candida CRBSI rates by species, risk factors, outcomes, and management to improve effectiveness of HPN programs. A review of Candida CRBSIs in HPN patients was conducted around the following questions: 1. How often do adult and paediatric HPN patients contract Candida CRBSIs? 2. What is the proportion of different Candida species? 3. What are the risk factors? 4. How are outcomes in Candida versus other CRBSIs? 5. What are current guidelines to manage Candida CRBSIs? Specifically, should catheters be removed? What antimicrobial therapy is indicated? Are catheter lock techniques effective? 20 studies were included - six paediatric and 14 adult. Candida represented 9.8% of paediatric CRBSIs and 11.7% of adult CRBSIs. Paediatric candidal CRBSIs featured these species: C. albicans (46.2%), C. parapsilosis (34.6%), Candida guilliermondii (11.5%), Candida tropicalis (3.8%), and mixed or other types of Candida (3.8%). Adult candidal CRBSIs featured these species: C. albicans (37.3%), C. glabrata (33.3%), C. parapsilosis (22.4%), mixed or other types of Candida (5.7%), and C. tropicalis (1.3%). Risk factors for paediatric HPN CRBSIs include underlying haematological disease and previous fungaemia. Candida infection is associated with mortality rates around 30%. In Candida CRBSIs, major guidelines advocate catheter removal prior to systemic antifungal treatment (fluconazole, amphotericin B, echinocandins), ideally until 14 days after the first negative blood culture; some studies suggest the possibility of systemic therapy while catheters remain in-situ to preserve crucial line access. Various catheter lock solutions are effective as treatment and prophylaxis, but are not yet firmly established. Candida CRBSI is a significant danger to HPN patients causing high mortality; gold standard treatment is catheter removal and antifungal treatment, although treatments with catheters in-situ and catheter locks as prophylaxis appear to be gaining traction.


Fourteen cases of imposed upper airway obstruction.
Imposed upper airway obstruction was diagnosed as the cause of recurrent and severe cyanotic episodes in 14 patients. Episodes started between 0.8 and 33 months of age (median 1.4) and occurred over a period of 0.8 to 20 months (median 3.5). Diagnosis was made by covert video surveillance, instituted after either (a) the observation that episodes began only in the presence of one person, or (b) characteristic findings on physiological recordings, lasting between 12 hours and three weeks, performed in hospital or at home. Surveillance was undertaken for between 15 minutes and 12 days (median 24 hours) and resulted in safety for the patient and psychiatric assessment of the parent: mother (n = 12), father (n = 1), and grandmother (n = 1). These revealed histories of sexual, physical, or emotional abuse (n = 11), self harm (n = 9), factitious illness (n = 7), eating disorder (n = 10), and previous involvement with a psychiatrist (n = 7). Management of the abusing parents is complex, but recognition of their psychosocial characteristics may allow earlier diagnosis. Imposed upper airway obstruction should be considered and excluded by physiological recordings in any infant or young child with recurrent cyanotic episodes. If physiological recordings fail to substantiate a natural cause for episodes, covert video surveillance may be essential to protect the child from further injury or death.


[Otorhinolaryngology, head and neck surgery in Kenya--consequences of demographic parameters].
In the time of evidence based medicine the analysis of the influence of demographic parameters and different environmental factors on the treatment concepts in a country is often neglected. This is also true for Otorhinolaryngology. An evaluation of the situation concerning distribution of physicians, diagnostic procedures and epidemiology in Kenya has been performed. These factors are discussed in consideration of their effect on the incidence of different diseases and their treatment under the specific socio-economic conditions for the otolaryngological situation in Kenya. In Kenya 28 otolaryngologists are registered that concentrate on few urban regions. Chronic otitis media, malignant tumors in the head and neck region and AIDS associated diseases have meanwhile increased dramatically. Numerous instruments and equipment for diagnosis are missing. Bigger equipment for CT scans are nearly exclusively used by private hospitals. Beside a better provision with different equipment for diagnosis it is especially the organization of certain training programmes where local physicians are further educated that may lead to an optimised medical care in Kenya.


Analgesic efficacy of tramadol/acetaminophen and propoxyphene/acetaminophen for relief of postoperative wound pain.
Weak opioid combined with acetaminophen (APAP) has been proven to provide better analgesic efficacy and cause fewer complications than either drug alone. However, there are questions about whether different opioids, tramadol and propoxyphene, provide similar efficacy or safety. Thus, we investigated Ultracet (37.5 mg tramadol/325 mg APAP) and Depain-X (65 mg propoxyphene/650 mg APAP). The primary aims of this study were to compare the analgesic efficacy and adverse effects of single-dose oral Ultracet versus Depain-X in acute postoperative pain. This was a randomized, open-label, active-controlled parallel study on patients with postsurgical pain. Sixty patients who sustained moderate postsurgical pain (visual analog scale(3)3 cm) after undergoing implantation of venous access were randomized to two groups to receive either Ultracetor Depain-X for postoperative analgesia. Assessment items included pain intensity and pain relief ratings at the first 4 hours, and adverse events. There were initially 107 patients who were enrolled in this trial, but up to 45 (42.1%) of them were withdrawn during the study. In these 62 patients who complied with treatment (Ultracet: Depain-X = 29: 33), pain relief scale indicated that Ultracet could provide a better analgesic effect than Depain-X provided at 1 hour (p < 0.05). At 4 hours, the pain score in the Ultracet group was significantly lower than that in the Depain-X group (p < 0.05). Adverse events, such as drowsiness, dizziness, and skin itching did not differ in both groups. Among patients with mild to moderate postoperative wound pain, single-dose Ultracet can provide slightly better analgesic efficacy than Depain-X in terms of onset and duration. Depain-X is no longer marketed in Europe, America, Taiwan and other countries, therefore, Ultracet can serve as a good substitute for treating postoperative pain.


Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo.
Current treatment modalities for malignant gliomas do not allow long-term survival. Here, we identify suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases (HDAC), as an effective experimental anti-glioma agent. Administration of SAHA to various glioma cell lines obtained from human, rat and mouse inhibited tumour cell growth in a range of 1-10 microm. This anti-glioma property is associated with up-regulation of the cell cycle control protein p21/WAF, as well as the induction of apoptosis. A novel tumour invasion model using slice cultures of rat brain corroborated the anti-glioma properties of SAHA in the organotypic brain environment. In this model, glioma invasion compromised adjacent brain parenchyma, and this tumour-associated cytotoxicity could be inhibited by SAHA. In addition, a 10-fold dose escalation experiment did not challenge the viability of cultured brain slices. In vivo, a single intratumoural injection of SAHA 7 days after orthotopic implantation of glioma cells in syngeneic rats doubled their survival time. These observations identify chromatin-modifying enzymes as possible and promising targets for the pharmacotherapy of malignant gliomas.


Focused electron beam induced deposition: A perspective.
Focused electron beam induced deposition (FEBID) is a direct-writing technique with nanometer resolution, which has received strongly increasing attention within the last decade. In FEBID a precursor previously adsorbed on a substrate surface is dissociated in the focus of an electron beam. After 20 years of continuous development FEBID has reached a stage at which this technique is now particularly attractive for several areas in both, basic and applied research. The present topical review addresses selected examples that highlight this development in the areas of charge-transport regimes in nanogranular metals close to an insulator-to-metal transition, the use of these materials for strain- and magnetic-field sensing, and the prospect of extending FEBID to multicomponent systems, such as binary alloys and intermetallic compounds with cooperative ground states. After a brief introduction to the technique, recent work concerning FEBID of Pt-Si alloys and (hard-magnetic) Co-Pt intermetallic compounds on the nanometer scale is reviewed. The growth process in the presence of two precursors, whose flux is independently controlled, is analyzed within a continuum model of FEBID that employs rate equations. Predictions are made for the tunability of the composition of the Co-Pt system by simply changing the dwell time of the electron beam during the writing process. The charge-transport regimes of nanogranular metals are reviewed next with a focus on recent theoretical advancements in the field. As a case study the transport properties of Pt-C nanogranular FEBID structures are discussed. It is shown that by means of a post-growth electron-irradiation treatment the electronic intergrain-coupling strength can be continuously tuned over a wide range. This provides unique access to the transport properties of this material close to the insulator-to-metal transition. In the last part of the review, recent developments in mechanical strain-sensing and the detection of small, inhomogeneous magnetic fields by employing nanogranular FEBID structures are highlighted. FEBID has now reached a state of maturity that allows a shift of the focus towards the development of new application fields, be it in basic research or applied. This is shown for selected examples in the present review. At the same time, when seen from a broader perspective, FEBID still has to live up to the original idea of providing a tool for electron-controlled chemistry on the nanometer scale. This has to be understood in the sense that, by providing a suitable environment during the FEBID process, the outcome of the electron-induced reactions can be steered in a controlled way towards yielding the desired composition of the products. The development of a FEBID-specialized surface chemistry is mostly still in its infancy. Next to application development, it is this aspect that will likely be a guiding light for the future development of the field of focused electron beam induced deposition.


A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers.
This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex (®), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole. NCT01323465.


Psychological questionnaires: do "abnormal" scores precede or follow first-time low back pain?
A prospective study of psychological risk factors for first-time low back pain with repeated use of psychological questionnaires. To measure the reproducibility of scores from psychological questionnaires, and to compare this with changes that follow an individual's first attack of back pain. Secondly, to determine which scores predict first-time back pain. "Abnormal" psychometric scores are associated with several aspects of back pain behavior. Little is known, however, about their reproducibility or long-term stability, and there has been no definitive answer to the question: which comes first, "abnormal" scores or low back pain? 403 volunteers with no history of "serious" low back pain (defined as pain requiring medical attention or absence from work) participated in a functional spinal assessment. At the time of initial assessment and at 6-month intervals thereafter, the volunteers completed the following questionnaires: the Health Locus of Control, which was subdivided into three sections labelled "Internal," "Powerful others," and "Chance"; the Modified Somatic Perception Questionnaire; and the Zung depression scale. Scores from the Modified Somatic Perception Questionnaire and from the Zung depression scale were added to form a measure of psychological distress. Additional questionnaires inquired about any back pain experienced in the previous 6 months. Only three volunteers had left the study at the 18-month follow-up. At that time 162 participants had reported "any" low back pain, of which 79 were "serious." Intraclass correlation coefficients for scores repeated after 6 months ranged from 0.67-0.80, and reproducibility of scores was equally high between the 0-, 6-, 12- and 18-month assessments. None of the scores were affected by "any" low back pain, and only the Modified Somatic Perception Questionnaire scores changed after "serious" back pain was reported. In a multivariate analysis, the most significant predictor of first time "serious" or "any" back pain was a history of non-"serious" back pain (P < 0.001). Of the psychological factors, the sum of Modified Somatic Perception Questionnaire scores and Zung questionnaire scores was the best predictor of "serious" back pain (P = 0.037), and the Modified Somatic Perception Questionnaire score was the best predictor of "any" back pain (P = 0.002). The 25% of participants with the highest sum of scores from the Modified Somatic Perception Questionnaire and Zung questionnaire was 2.7 times more likely to develop "serious" back pain than the 25% with the lowest sum of these scores. Nevertheless, after accounting for the affects of a history of non-"serious" back pain, psychometric scores predicted less than an additional 3% of reported back pain. The scores from the Modified Somatic Perception Questionnaire and Zung questionnaire were reproducible over 18 months and were affected little by first episodes of back pain; yet these scores were significant predictors of it. "Abnormal" scores from these questionnaires precede back pain in a small number of people.


Regulatory circuit for responses of nitrogen catabolic gene expression to the GLN3 and DAL80 proteins and nitrogen catabolite repression in Saccharomyces cerevisiae.
We demonstrate that expression of the UGA1, CAN1, GAP1, PUT1, PUT2, PUT4, and DAL4 genes is sensitive to nitrogen catabolite repression. The expression of all these genes, with the exception of UGA1 and PUT2, also required a functional GLN3 protein. In addition, GLN3 protein was required for expression of the DAL1, DAL2, DAL7, GDH1, and GDH2 genes. The UGA1, CAN1, GAP1, and DAL4 genes markedly increased their expression when the DAL80 locus, encoding a negative regulatory element, was disrupted. Expression of the GDH1, PUT1, PUT2, and PUT4 genes also responded to DAL80 disruption, but much more modestly. Expression of GLN1 and GDH2 exhibited parallel responses to the provision of asparagine and glutamine as nitrogen sources but did not follow the regulatory responses noted above for the nitrogen catabolic genes such as DAL5. Steady-state mRNA levels of both genes did not significantly decrease when glutamine was provided as nitrogen source but were lowered by the provision of asparagine. They also did not respond to disruption of DAL80.


Mid-term outcomes of concomitant surgical ablation of atrial fibrillation in patients undergoing cardiac surgery for hypertrophic cardiomyopathy†.
Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and it is often poorly tolerated because of loss of atrial contraction and reduced filling time with rapid ventricular rates. Restoring sinus rhythm is of great clinical benefit to HCM patients. Very few data exist regarding surgical ablation of concomitant AF in this setting. The aim of this study was to evaluate the mid-term outcome of surgical AF ablation in patients who underwent cardiac surgery due to HCM. Thirty-one consecutive patients with primary HCM and drug-refractory symptomatic AF underwent surgical ablation with concomitant septal myectomy (77%) and/or mitral valve repair/replacement (39%). Follow-up was 97% complete with a median of 6.4 years [3.8-9.1]. Hospital mortality was 6% and the overall survival at 7 years was 87 ± 6.1%. No stroke and thromboembolic events were documented at follow-up. The arrhythmia-free survival off antiarrhythmic drugs was 82 ± 7.3% at 1 year and 52 ± 10.2% at 6 years. The 1- and 6-year arrhythmia control (maintenance of sinus rhythm with or without antiarrhythmic drugs) was 96 ± 3.5 and 80 ± 8.1%, respectively. The recurrent arrhythmia was AF in all patients. No predictors of AF recurrence were detected. Concomitant surgical ablation of AF is a reasonable treatment option for drug refractory AF in patients with HCM undergoing surgical myectomy and/or mitral valve surgery. However, chronic antiarrhythmic drugs are needed to achieve a satisfactory mid-term arrhythmia control.


Association of 4-hydroxynonenal with classical adipokines and insulin resistance in a Chinese non-diabetic obese population.
The prevalence of obesity is increasing worldwide. Oxidative stress plays an etiological role in a variety of obesity-related metabolic disorders. 4-hydroxynonenal (4-HNE) is the most abundant and reactive aldehydic product derived from the peroxidation of n-6 polyunsaturated fatty acids with diverse biological effects that are not well detailed. Obesity is associated with decreased plasma adiponectin concentrations and increased production of lipid peroxidation products, including 4-HNE, in adipose tissue. There may be some association between the level of adipokines and 4-HNE. To analyze the associations between 4-HNE and classical adipokines, namely, adiponectin and leptin in a Chinese population, the plasma 4-HNE, adiponectin and leptin levels of 160 non-diabetic obese (NDO) patients and 160 healthy subjects were determined by ELISA, and their associations with adiposity, glucose, lipid profiles, insulin secretion and insulin sensitivity were studied. Plasma 4-HNE levels were significantly increased in patients with NDO compared with healthy controls (p < 0.01). 4-HNE was negatively correlated with adiponectin and positively correlated with leptin. The plasma levels of 4-HNE were significantly correlated to several parameters involved in body mass index (BMI) and insulin resistance (IR). The 4-HNE levels were positively correlated with BMI and negatively correlated with insulin sensitivity. We conclude that 4-HNE is associated with the secretion of adiponectin and leptin and is correlated with IR in NDO humans. These findings indicate a pro-inflammatory role of 4-HNE in NDO patients, which supports the potential role of 4-HNE in the development of obesity-related disorders.


Alignment of an interferometric gravitational wave detector.
Interferometric gravitational wave detectors are designed to detect small perturbations in the relative lengths of their kilometer-scale arms that are induced by passing gravitational radiation. An analysis of the effects of imperfect optical alignment on the strain sensitivity of such an interferometer shows that to achieve maximum strain sensitivity at the Laser Interferometer Gravitational Wave Observatory requires that the angular orientations of the optics be within 10(-8) rad rms of the optical axis, and the beam must be kept centered on the mirrors within 1 mm. In addition, fluctuations in the input laser beam direction must be less than 1.5 x 10(-14) rad/ radicalHz in angle and less than 2.8 x 10(-10) m/ radicalHz in transverse displacement for frequencies f > 150 Hz in order that they not produce spurious noise in the gravitational wave readout channel. We show that seismic disturbances limit the use of local reference frames for angular alignment at a level approximately an order of magnitude worse than required. A wave-front sensing scheme that uses the input laser beam as the reference axis is presented that successfully discriminates among all angular degrees of freedom and permits the implementation of a closed-loop servo control to suppress the environmentally driven angular fluctuations sufficiently.


Inferring Beliefs and Desires From Emotional Reactions to Anticipated and Observed Events.
Researchers have long been interested in the relation between emotion understanding and theory of mind. This study investigates a cue to mental states that has rarely been investigated: the dynamics of valenced emotional expressions. When the valence of a character's facial expression was stable between an expected and observed outcome, children (N = 122; M = 5.0 years) recovered the character's desires but did not consistently recover her beliefs. When the valence changed, older but not younger children recovered both the characters' beliefs and desires. In contrast, adults jointly recovered agents' beliefs and desires in all conditions. These results suggest that the ability to infer mental states from the dynamics of emotional expressions develops gradually through early and middle childhood.


Troponin Testing in the Emergency Department: Real world experience.
The aim of this study was to examine patterns of troponin testing in the emergency department of a large tertiary care hospital in Oman and to determine its effect on patient management, including length of hospital stay (LOS). This retrospective study analysed the medical records of all adult patients undergoing troponin testing in the emergency department of the Sultan Qaboos University Hospital, Muscat, Oman, during the month of July 2015. Patients who presented with an ST-elevation myocardial infarction were excluded. A total of 4,845 patients attended the emergency department during the study period; of these, troponin tests were ordered for 588 patients. The majority of the patients had negative troponin test results (81.3%). Chest pain, palpitations and breathlessness were the most common presenting complaints for those with positive troponin results. However, 41.8% of patients did not have any cardiac symptoms. Individuals with positive troponin tests had a significantly longer LOS compared to those with negative tests (mean: three versus one day; P = 0.001). In total, only 28.2% of those with positive troponin test results had final diagnoses associated with a cardiac condition, such as heart failure, an acute coronary syndrome (ACS), atrial fibrillation or other types of arrhythmia. A positive troponin test was associated with increased LOS; however, only a small proportion of these patients had a final diagnosis associated with a cardiac condition. Guidelines should be provided to ensure that troponin testing is performed only in cases where an ACS is suspected.


Textured Hive Interiors Increase Honey Bee (Hymenoptera: Apidae) Propolis-Hoarding Behavior.
Numerous papers have shown that propolis contributes favorably to worker honey bee (Apis mellifera L.) immune response and colony social immunity. Moreover, resin-foraging specialists are more sensitive than pollen foragers to tactile information in the nest interior, and they respond to these stimuli by collecting more resin. In this study, we show that in-hive propolis deposition is increased, compared with nonmodified controls, with any one of the three methods for increasing textural complexity of hive wall interior surfaces: 1) plastic propolis trap material stapled to wall interior, 2) parallel saw kerfs cut into wall interior, or 3) roughening wall interior with a mechanized wire brush. Pairwise comparisons showed that propolis deposition was not significantly different among the three textural treatments; however, textural treatments interacted with time to show a more consistent benefit from plastic propolis trap material or roughened interior surface over saw kerfs. Although direct health benefits were not measured, this work shows that it is comparatively simple to increase propolis deposition above background levels by increasing textural stimuli in hive interiors.


Experimental myocardial infarction in the cat. I. Reversible decline in contractility of noninfarcted muscle.
The contractile state of the noninfarcted myocardium was examined in adult cats after myocardial infarction produced by ligation of several branches of the left coronary artery. At 2 days, 7 days, and 6 weeks after infarction, and after determination of intracardiac pressures, papillary muscles were exicised from the noninfarcted segment of the right ventricle and attached to a myograph for analysis of contractile function. One week after infarction there was a decline in actively developed force at Lmax, caused by a decrease in the rate of force development. In addition, the response to procedures that augment myocardial contractility, such as paired stimulation and increasing the frequency of electrical stimulation, was significantly depressed. Two days after infarction, changes were less significant, although similar in direction. Six weeks after infarction, developed force at Lmax had returned to normal values. The response to procedures augmenting contractility also had returned to normal. There appears to be a distinct, reversible loss of contractility in the remaining viable myocardium in the early phase after experimental infarction.


Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats.
Constitutive nitric oxide synthase (cNOS) with insufficient cofactor (6R)-5,6,7,8-tetrahydrobiopterin (H4B) may generate damaging superoxide (O2-). This study was designed to determine whether cNOS-dependent generation of O2- occurs in spontaneously hypertensive rats (SHR) before the onset of hypertension. Aortas from 4-wk-old SHR and Wistar-Kyoto rats were used. cNOS was stimulated by calcium ionophore A23187. In situ measurements of nitric oxide and hydrogen peroxide by electrochemical sensors and O2- production by chemiluminescence method were performed. Isometric tension was continuously recorded. H4B by high performance liquid chromatography and [3H]citrulline assay were determined in homogenized tissue. The A23187-stimulated production of O2- and its superoxide dismutase product hydrogen peroxide were significantly higher, whereas nitric oxide release was reduced in SHR aortas, with opposite results in the presence of exogenous H4B. Furthermore, NG-monomethyl-L-arginine inhibited the generation of cNOS-dependent O2- by approximately 70%. Natural H4B levels were similar in both strains; however, equivalent cNOS activity required additional H4B in SHR. The endothelium-dependent relaxations to A23187 were significantly inhibited by catalase, and enhanced by superoxide dismutase, only in SHR; however, these enzymes had no effect in the presence of H4B. Thus, dysfunctional cNOS may be a source of O2- in prehypertensive SHR and contribute to the development of hypertension and its vascular complications.


Enteral nutritional support and use of diabetes-specific formulas for patients with diabetes: a systematic review and meta-analysis.
The aim of this systematic review was to determine the benefits of nutritional support in patients with type 1 or type 2 diabetes. Studies utilizing an enteral nutritional support intervention (oral supplements or tube feeding) were identified using electronic databases and bibliography searches. Comparisons of interest were nutritional support versus routine care and standard versus diabetes-specific formulas (containing high proportions of monounsaturated fatty acids, fructose, and fiber). Outcomes of interest were measures of glycemia and lipid status, medication requirements, nutritional status, quality of life, complications, and mortality. Meta-analyses were performed where possible. A total of 23 studies (comprising 784 patients) of oral supplements (16 studies) and tube feeding (7 studies) were included in the review, and the majority compared diabetes-specific with standard formulas. Compared with standard formulas, diabetes-specific formulas significantly reduced postprandial rise in blood glucose (by 1.03 mmol/l [95% CI 0.58-1.47]; six randomized controlled trials [RCTs]), peak blood glucose concentration (by 1.59 mmol/l [86-2.32]; two RCTs), and glucose area under curve (by 7.96 mmol.l(-1).min(-1) [2.25-13.66]; four RCTs, i.e., by 35%) with no significant effect on HDL, total cholesterol, or triglyceride concentrations. In addition, individual studies reported a reduced requirement for insulin (26-71% lower) and fewer complications with diabetes-specific compared with standard nutritional formulas. This systematic review shows that short- and long-term use of diabetes-specific formulas as oral supplements and tube feeds are associated with improved glycemic control compared with standard formulas. If such nutritional support is given long term, this may have implications for reducing chronic complications of diabetes, such as cardiovascular events.


Improved immunogenicity with high-dose seasonal influenza vaccine in HIV-infected persons: a single-center, parallel, randomized trial.
HIV-infected persons have less robust antibody responses to influenza vaccines. To compare the immunogenicity of high-dose influenza vaccine with that of standard dosing in HIV-positive participants. Randomized, double-blind, controlled trial. (ClinicalTrials.gov: NCT01262846) The MacGregor Clinic of the Hospital of the University of Pennsylvania, Philadelphia, from 27 October 2010 to 27 March 2011. HIV-infected persons older than 18 years. Participants were randomly assigned to receive either a standard dose (15 mcg of antigen per strain) or a high dose (60 mcg/strain) of the influenza trivalent vaccine. The primary end point was the rate of seroprotection, defined as antibody titers of 1:40 or greater on the hemagglutination inhibition assay 21 to 28 days after vaccination. The primary safety end point was frequency and intensity of adverse events. Secondary end points were seroconversion rate (defined as a greater than 4-fold increase in antibody titers) and the geometric mean antibody titer. 195 participants enrolled, and 190 completed the study (93 in the standard-dose group and 97 in the high-dose group). The seroprotection rates after vaccination were higher in the high-dose group for the H1N1 (96% vs. 87%; treatment difference, 9 percentage points [95% CI, 1 to 17 percentage points]; P = 0.029), H3N2 (96% vs. 92%; treatment difference, 3 percentage points [CI, -3 to 10 percentage points]; P = 0.32), and influenza B (91% vs. 80%; treatment difference, 11 percentage points [CI, 1 to 21 percentage points]; P = 0.030) strains. Both vaccines were well-tolerated, with myalgia (19%), malaise (14%), and local pain (10%) the most frequent adverse events. The effectiveness of the vaccine in preventing clinical influenza was not evaluated. The number of participants with CD4 counts less than 0.200 × 109 cells/L was limited. HIV-infected persons reach higher levels of influenza seroprotection if vaccinated with the high-dose trivalent vaccine than with the standard-dose. National Institute of Allergy and Infectious Diseases and Center for AIDS Research of the University of Pennsylvania.


'All her children are born that way': gendered experiences of stigma in families affected by sickle cell disorder in rural Kenya.
To explore early experiences of sickle cell disorder (SCD) in families with a young affected child, and the way these experiences influence relations within families. To consider ways in which stigma could be counteracted in health and research programmes in sub Saharan Africa. A qualitative study was conducted in a rural area of coastal Kenya including in-depth interviews with 13 families affected by SCD and 12 staff of a local biomedical research progamme. Purposive selection aimed to maximize diversity in socioeconomic and educational status, religion, severity of illness burden and religion amongst families and draw on relevant experience for staffs. Interviews were recorded, transcribed and analysed using the constant comparative method for family interviews and a thematic framework approach for staff data. Low initial recognition of SCD and its cause were associated with lay practices of surveillance within affected families, contributing to stigmatisation that occurred independently of genetic knowledge. Blame was often placed on mothers, including a risk of blame for misaligned paternity. Mothers are often particularly affected by SCD through the loss of independent livelihoods and their limited options in coping with this chronic condition. Mothers of children with SCD were particularly vulnerable to stigmatisation within families, with underlying structural influences that suggest these findings may apply to other similar settings in Africa, and have relevance for other genetic conditions. The potential, nature and form of stigmatisation point to the role of effective communication and SCD management in addressing for blame and discriminative effects of having a child with SCD. The findings highlight the importance of broader social programmes targeting underlying gender and economic inequalities.


Structural design of graphene for use in electrochemical energy storage devices.
There are many practical challenges in the use of graphene materials as active components in electrochemical energy storage devices. Graphene has a much lower capacitance than the theoretical capacitance of 550 F g(-1) for supercapacitors and 744 mA h g(-1) for lithium ion batteries. The macroporous nature of graphene limits its volumetric energy density and the low packing density of graphene-based electrodes prevents its use in commercial applications. Increases in the capacity, energy density and power density of electroactive graphene materials are strongly dependent on their microstructural properties, such as the number of defects, stacking, the use of composite materials, conductivity, the specific surface area and the packing density. The structural design of graphene electrode materials is achieved via six main strategies: the design of non-stacking and three-dimensional graphene; the synthesis of highly packed graphene; the production of graphene with a high specific surface area and high conductivity; the control of defects; functionalization with O, N, B or P heteroatoms; and the formation of graphene composites. These methodologies of structural design are needed for fast electrical charge storage/transfer and the transport of electrolyte ions (Li(+), H(+), K(+), Na(+)) in graphene electrodes. We critically review state-of-the-art progress in the optimization of the electrochemical performance of graphene-based electrode materials. The structure of graphene needs to be designed to develop novel electrochemical energy storage devices that approach the theoretical charge limit of graphene and to deliver electrical energy rapidly and efficiently.


Salmonella typing in New South Wales: current methods and application of improved epidemiological tools.
Salmonellosis caused by enteropathogens of the genus Salmonella is a major public health concern in Australia. Serotyping is usually performed in enteric reference laboratories for the initial characterisation and differentiation of Salmonella species. Further strain identification within serovars may be achieved by phage typing and this is used as an epidemiological tool for outbreak investigations. Phage typing has limited discriminatory ability and the necessity of sending specimens interstate from NSW for this test causes delays in recognising outbreaks and reduces the likelihood of identifying the source. Multilocus variable-number tandem-repeat analysis has a high discriminatory power and faster turnaround time, and is the method of choice for outbreak investigation. Additionally, a newly developed multiplex PCR-based reverse line blot hybridisation system is able to identify most of the phage types prevalent in NSW. Combining these last two molecular methods will significantly enhance outbreak investigations and surveillance of Salmonella infections in NSW.


Hemiconvulsion-hemiplegia-epilepsy syndrome: clinical course and neuroradiological features in a 20-month-old girl.
Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome involves initial sudden and prolonged unilateral convulsive seizures, followed by transient or permanent hemiplegia and epilepsy during infancy or early childhood. Seizures are prolonged, difficult to control and sometimes may require surgery. Hemiplegia varies in intensity, differs from Todd paralysis and disappears in about 20% of cases. Neuroimaging characteristically shows brain atrophy more pronounced on the hemisphere contralateral to the side of hemiplegia with dilation of the ventricular system. A 20-month-old girl presented with left hemiconvulsions and left hemiplegia lasting for a prolonged period. Seizures failed to resolve with various anticonvulsants even after many physician contacts. Characteristic neuroimaging findings, seizure control with carbamazepine and valproate, subsequent recovery of hemiplegia and attainment of developmental milestones observed on follow-up confirmed HHE syndrome. The case highlights the need for good seizure control in this syndrome.


Autism Spectrum Disorder Among US Children (2002-2010): Socioeconomic, Racial, and Ethnic Disparities.
To describe the association between indicators of socioeconomic status (SES) and the prevalence of autism spectrum disorder (ASD) in the United States during the period 2002 to 2010, when overall ASD prevalence among children more than doubled, and to determine whether SES disparities account for ongoing racial and ethnic disparities in ASD prevalence. We computed ASD prevalence and 95% confidence intervals (CIs) from population-based surveillance, census, and survey data. We defined SES categories by using area-level education, income, and poverty indicators. We ascertained ASD in 13 396 of 1 308 641 8-year-old children under surveillance. The prevalence of ASD increased with increasing SES during each surveillance year among White, Black, and Hispanic children. The prevalence difference between high- and low-SES groups was relatively constant over time (3.9/1000 [95% CI = 3.3, 4.5] in 2002 and 4.1/1000 [95% CI = 3.6, 4.6] in the period 2006-2010). Significant racial/ethnic differences in ASD prevalence remained after stratification by SES. A positive SES gradient in ASD prevalence according to US surveillance data prevailed between 2002 and 2010, and racial and ethnic disparities in prevalence persisted during this time among low-SES children.


p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis.
Mutations of the p53 tumor suppressor gene have been described in several subtypes of non-Hodgkin's lymphoma, but the incidence of p53 mutations in mantle cell lymphoma (MCL) is unknown. We hypothesized that cases of MCL with a variant or high-grade cytology would have a higher likelihood of p53 mutations than typical MCL. We were also interested in the prognostic significance of p53 mutations in MCL. Therefore, a series of 53 well-characterized cases of MCL with DNA from 62 tissue samples were analyzed by the polymerase chain reaction with denaturing gradient gel electrophoresis for exons 5-8 of p53. Immunoperoxidase studies with the antibody DO-7 to p53 protein were also performed on frozen sections. We found mutations of the p53 gene in 8 of the 53 cases (15%) of MCL. Missense mutations predominated, and 50% of the mutations occurred at known p53 hotspot codons. Of 21 cases with variant cytology (ie, anaplastic or blastic), 6 (28.6%) had p53 mutations as compared with only 2 of 32 cases (6.3%) with typical MCL cytology (P = .05), and p53 mutations preceded the development of variant cytology in 2 patients. Overexpression of p53 protein was observed in 6 of the 8 cases (75%) with p53 mutations and in none of the 45 wild-type cases. The median survival of the cases with mutant p53 was only 1.3 years (all died), whereas the median survival of cases with germline p53 was 5.1 years (P = .023). These results suggest that mutations of p53 may be one mechanism involved in the development of variant forms of MCL and indicate that p53 mutations in MCL predict a poor prognosis.


Pediatric cervical spine injuries: report of 102 cases and review of the literature.
To evaluate and review their experience with pediatric cervical injuries and factors affecting outcome, the authors conducted a retrospective clinical study of 102 cases (65% boys, 35% girls) of pediatric cervical spine injuries treated in the last decade. This study is an extension of and comparison with their earlier experience. Patients were divided into two age groups-birth to 9 years (Group I) and 10 to 16 years of age (Group 2)- and managed according to status at presentation and type of injury. Thirty patients were managed surgically and 72 non-surgically (42 wore a halo brace and 30 wore hard collars or custom-molded braces). Motor vehicle accidents were the most common cause of injury, and 40% were associated with head injury. Patients in the younger-age group (Group 1) sustained more neurological injuries than the older patients in Group 2, and most injuries were in the upper cervical spine. Of the 38 children in Group 1, in 39% a subluxation was present and in 29% a fracture or fracture/subluxation was demonstrated. Of the patients in Group 2, 80% had sustained fractures or fracture/subluxations. Vertebral fractures were the most common radiological findings (32%). At late follow-up review (mean 5 years), solid fusions were demonstrated in all patients. Neurological deterioration did not occur in any patient. The mortality rate was 16%. Compared with the authors' earlier report, the incidence of cases with pediatric cervical injuries increased, as did the number managed surgically. Various fusion techniques were used, and neurological and fusion outcomes improved as compared with the previous report. The prognosis of neurological recovery from pediatric cervical spine injuries is related to the severity of the initial neurological injury. Management must be tailored to the patient's age, neurological status, and type and level of injury. Compared with our earlier experience, fusion and instrumentation procedures were used more frequently. Different types of fusion and instrumentation procedures can be performed safely in children and produce good outcomes.


Ultrasensitive gas detection of large-area boron-doped graphene.
Heteroatom doping is an efficient way to modify the chemical and electronic properties of graphene. In particular, boron doping is expected to induce a p-type (boron)-conducting behavior to pristine (nondoped) graphene, which could lead to diverse applications. However, the experimental progress on atomic scale visualization and sensing properties of large-area boron-doped graphene (BG) sheets is still very scarce. This work describes the controlled growth of centimeter size, high-crystallinity BG sheets. Scanning tunneling microscopy and spectroscopy are used to visualize the atomic structure and the local density of states around boron dopants. It is confirmed that BG behaves as a p-type conductor and a unique croissant-like feature is frequently observed within the BG lattice, which is caused by the presence of boron-carbon trimers embedded within the hexagonal lattice. More interestingly, it is demonstrated for the first time that BG exhibits unique sensing capabilities when detecting toxic gases, such as NO2 and NH3, being able to detect extremely low concentrations (e.g., parts per trillion, parts per billion). This work envisions that other attractive applications could now be explored based on as-synthesized BG.


Advances in oligonucleotide drug delivery.
Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.


The AMA1-RON complex drives Plasmodium sporozoite invasion in the mosquito and mammalian hosts.
Plasmodium sporozoites that are transmitted by blood-feeding female Anopheles mosquitoes invade hepatocytes for an initial round of intracellular replication, leading to the release of merozoites that invade and multiply within red blood cells. Sporozoites and merozoites share a number of proteins that are expressed by both stages, including the Apical Membrane Antigen 1 (AMA1) and the Rhoptry Neck Proteins (RONs). Although AMA1 and RONs are essential for merozoite invasion of erythrocytes during asexual blood stage replication of the parasite, their function in sporozoites was still unclear. Here we show that AMA1 interacts with RONs in mature sporozoites. By using DiCre-mediated conditional gene deletion in P. berghei, we demonstrate that loss of AMA1, RON2 or RON4 in sporozoites impairs colonization of the mosquito salivary glands and invasion of mammalian hepatocytes, without affecting transcellular parasite migration. Three-dimensional electron microscopy data showed that sporozoites enter salivary gland cells through a ring-like structure and by forming a transient vacuole. The absence of a functional AMA1-RON complex led to an altered morphology of the entry junction, associated with epithelial cell damage. Our data establish that AMA1 and RONs facilitate host cell invasion across Plasmodium invasive stages, and suggest that sporozoites use the AMA1-RON complex to efficiently and safely enter the mosquito salivary glands to ensure successful parasite transmission. These results open up the possibility of targeting the AMA1-RON complex for transmission-blocking antimalarial strategies.


A project to reduce the rate of central line associated bloodstream infection in ICU patients to a target of zero.
Central venous catheters (CVCs) are life-saving and the majority of patients in intensive care units (ICUs) have them placed in order to receive medicine and fluids. However, the use of these catheters can result in serious bloodstream infections. The rate of Central Line Associated Blood Stream Infection (CLABSI) in Adult Intensive Care Units (ICUs) at King Abdulaziz Medical City Jeddah (KAMC-J) at the start of the project was 2.0/1000 line days in 2008. The Central Line (CL) Bundle by the Institute of Healthcare Improvement (IHI) was implemented at the same time with monitoring of compliance to the CL Bundle. The compliance to CL Bundle was very low at 37% in the same period. A multidisciplinary team was created to improve the compliance to the CL bundle which was expected to have an impact on the rate of CLABSI to achieve zero CLABSI events. The team continued to monitor and evaluate the progress on the compliance to the bundle as well as monitoring the CLABSI events using National Healthcare Safety Network diagnostic criteria. The real reduction in the rate of CLABSI was achieved in 2010 with 0.7/1,000 device days when the compliance to CL Bundle reached up to 98% in that year and 100% in the next two subsequent years. The project still continued and the rate continued to drop and the ultimate target of zero CLABSI was achieved in the year 2014 and maintained in the year 2015 with a sustained compliance of 100% to the CL Bundle. Successful implementation of CL Bundle can help in reducing the rates of CLABSI and achieving zero CLABSI events for a sustained period.


Loss of hematopoietic stem cell self-renewal after bone marrow transplantation.
The quality of long-term hematopoietic engraftment after bone marrow transplantation (BMT) has not been well characterized. Clinical autologous BMT involves removal of less than 5% of the total content of the recipient marrow followed by ablation of the remaining marrow and reinfusion. To study long-term consequences of transplanting limited numbers of BM stem cells further, we evaluated the hematopoietic reserve in recipient animals after transplantation of varying quantities of BM. Recipient animals demonstrated a donor BM cell dose-dependent decrease in stem cell content and self-renewal capacity that was not reflected in peripheral blood (PB) counts or BM cellularity. This decrease was observed after initial BM recovery and did not change with time after transplantation, demonstrating a permanent loss in BM self-renewal capacity. In addition, animals alive at 3 months, a time selected to allow BM recovery, also demonstrated a donor BM cell dose-dependent decrease in survival at 1 year. These results emphasize the importance of optimizing stem cell number in BMT.


Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) as a Biomarker in the Mouse Model of Experimental Autoimmune Myocarditis (EAM).
Vascular cell adhesion molecule-1 (VCAM-1) is strongly upregulated in hearts of mice with coxsackie virus-induced as well as in patients with viral infection-triggered dilated cardiomyopathy. Nevertheless, the role of its soluble form as a biomarker in inflammatory heart diseases remains unclear. Therefore, we investigated whether plasma levels of soluble VCAM-1 (sVCAM-1) directly correlated with disease activity and progression of cardiac dysfunction in the mouse model of experimental autoimmune myocarditis (EAM). EAM was induced by immunization of BALB/c mice with heart-specific myosin-alpha heavy chain peptide together with complete Freund`s adjuvant. ELISA revealed strong expression of cardiac VCAM-1 (cVCAM-1) throughout the course of EAM in immunized mice compared to control animals. Furthermore, sVCAM-1 was elevated in the plasma of immunized compared to control mice at acute and chronic stages of the disease. sVCAM-1 did not correlate with the degree of acute cardiac inflammation analyzed by histology or cardiac cytokine expression investigated by ELISA. Nevertheless, heart to body weight ratio correlated significantly with sVCAM-1 at chronic stages of EAM. Cardiac systolic dysfunction studied with positron emission tomography indicated a weak relationship with sVCAM-1 at the chronic stage of the disease. Our data provide evidence that plasma levels of sVCAM-1 are elevated throughout all stages of the disease but showed no strong correlation with the severity of EAM.


Improving the Management of Atrial Fibrillation in General Practice: Protocol for a Mixed Methods Study.
Atrial fibrillation (AF) is one of the commonest arrhythmias observed in general practice. The thromboembolic complications of AF include transient ischemic attack, stroke, and pulmonary embolism. Early recognition of AF can lead to early intervention with managing the risks of these complications. The primary aim of this study is to investigate if patients are managed in general practice according to current national guidelines. In addition, the study will evaluate the impact of direct oral anticoagulant use with respect to AF complications in a real-world dataset. The secondary aims of the study are to develop a dashboard that will allow monitoring the management of AF in general practice and evaluate the usability of the dashboard. The study was conducted in 2 phases. The initial phase was a quantitative analysis of routinely collected primary care data from the Oxford Royal College of General Practitioners Research and Surveillance Center (RCGP RSC) sentinel network database. AF cases from 2009 to 2019 were identified. The study investigated the impact of the use of anticoagulants on complications of AF over this time period. We used this dataset to examine how AF was managed in primary care during the last decade. The second phase involved development of an online dashboard for monitoring management of AF in general practice. We conducted a usability evaluation for the dashboard to identify usability issues and performed enhancements to improve usability. We received funding for both phases in January 2019 and received approval from the RCGP RSC research committee in March 2019. We completed data extraction for phase 1 in May 2019 and completed analysis in December 2019. We completed building the AF dashboard in May 2019. We started recruiting participants for phase 1 in May 2019 and concluded data collection in July 2019. We completed data analysis for phase 2 in October 2019. The results are expected to be published in the second half of 2020. As of October 2020, the publications reporting the results are under review. Results of this study will provide an insight into the current trends in management of AF using real-world data from the Oxford RCGP RSC database. We anticipate that the outcomes of this study will be used to guide the development and implementation of an audit-based intervention tool to assist practitioners in identifying and managing AF in primary care. RR1-10.2196/21259.


A field study to assess the degradation and transport of diuron and its metabolites in a calcareous soil.
An experimental plot has been established on a calcareous soil in southern England to investigate the fate and transport of diuron (N'-[3,4-dichlorophenyl]-N,N-dimethylurea), a commonly used phenylurea herbicide. An agricultural grade of diuron was applied to the soil surface at a rate of 6.7 kg/ha along with a potassium bromide conservative tracer applied at 200 kg/ha, in early January, 2001. Hand augured samples were taken at regular intervals over the next 50 days, with samples collected down to 54 cm. Porewaters were extracted from the soil cores by using high speed centrifugation and the supernatant fluids were retained for analysis by HPLC, for diuron and three of its metabolites, N'-[3,4-dichlorophenyl]-N,N-methylurea (DCPMU), N'-3,4-dichlorophenylurea (DCPU) and 3,4-dichloroaniline (DCA). The centrifuged soil was retained and then extracted with methanol prior to HPLC analysis for the same suite of phenylureas. A mass balance approach showed large variations in diuron distribution, but on average accounted for 104% of the diuron applied. Concentrations of diuron and its metabolites were roughly five times higher in the soil than in the soil porewaters. After 50 days, metabolites comprised 10% of the total diuron present in the porewater and 20% of the total diuron sorbed to the soil matrix. After 36 days, a large pulse of diuron and DCPMU appeared in the porewaters and soil matrix at a depth of 54 cm, travelling an average of 0.15 cm/day faster than Br. A preferential route for diuron transport is suggested. There is evidence to suggest that degradation occurs at depth as well as at the soil surface. Metabolites generally appear to move more slowly than the parent compound. All metabolites were encountered, but interpreting transport and degradation processes simultaneously proved beyond the scope of the study. Diuron was detected once in a shallow (5 m) observation well, situated on the experimental plot. High concentrations of diuron and metabolites were still present in the soil and soil solutions after 50 days and remain as a source of potential groundwater contamination.


Effect of supplementary feeding on the prevention of mild-to-moderate wasting in conditions of endemic malnutrition in Guatemala.
To estimate the effect of supplementary feeding on the prevention of wasting in preschool children in a rural area of Guatemala with a high prevalence of malnutrition. Children aged 6-48 months, with a weight-for-length exceeding 90% of that of the median NCHS/WHO/CDC reference population, received either Atole, a drink with a high protein and moderate energy content, or Fresco, a drink with no protein and a low energy content. Children consuming amounts of Atole equivalent to more than 10% of the age-adjusted recommended dietary intake for energy were termed "supplemented." A comparable group of children consuming Fresco was termed "non-supplemented". The energy intake in the supplemented group was higher than that in the non-supplemented group by 16-18% of the recommended daily intake. The corresponding difference in protein intake was 45-80% of the recommended daily intake. The children were followed up at intervals of three or six months in order to evaluate their weight-for-length development. The difference between supplemented and non-supplemented children in the proportions maintaining their weight-for-length category at the end of the study intervals represented the prevention of wasting attributable to supplementary feeding (attributable prevention). Households were used as units of analysis in order to avoid cluster effects. The attributable prevention in children aged 6-24 months with weight-for-length between 90% and 99.9% of the reference population at entry ranged from 0.21 to 0.26 and was statistically significant after three and six months of supplementation. However, it was not significant in children at or above 100% weight-for-length or in older children. Children above 100% weight-for-length did not become overweight as a result of supplementation. Supplementary feeding of children aged 6-24 months in populations with inadequate dietary intakes can prevent the onset of wasting in a large proportion of children.


The Effect of Carbohydrate Mouth Rinsing on Multiple Choice Reaction Time During Amateur Boxing
To examine whether the use of a carbohydrate mouth rinse (CMR) can improve multiple choice reaction time in amateur boxers during sparring. A total of 8 male amateur boxers (age 22 [3] y, stature 1.78 [0.07] m, mass 73.6 [14.2] kg) with at least 18 months of experience in the sport volunteered to participate in the study. All participants attended a familiarization session, followed by an experimental (CMR; 6% dextrose) and placebo trials in a randomized order. Participants undertook 3 × 2 minutes of sparring against an ability- and size-matched (stature and mass) opponent. Multiple choice reaction time and perceived exertion were measured before round 1 and then after each round. The respective mouth rinse was administered in a 25-mL solution for 10 seconds before each round. Magnitude-based inferences were used to compare the results of each round (mean difference; ±90% confidence limits). The CMR was unlikely to have a beneficial effect on multiple choice reaction time compared with placebo (mean ± 90% confidence limits: 5 ± 9.5, 4 ± 3.4, -1 ± 8.5 lights for rounds 1 to 3, respectively) and had a possibly harmful effect on perceived exertion in round 1 (10 ± 20). There was an unlikely harmful effect on perceived exertion in rounds 2 (1 ± 12) and 3 (9 ± 23). There is no evidence to support the use of CMR during sparring in amateur boxers.


ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making.
Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.


Semi-automatic 3D-volumetry of liver metastases from neuroendocrine tumors to improve combination therapy with 177Lu-DOTATOC and 90Y-DOTATOC.
Patients with neuroendocrine tumors (NET) often present with disseminated liver metastases and can be treated with a number of different nuclides or nuclide combinations in peptide receptor radionuclide therapy (PRRT) depending on tumor load and lesion diameter. For quantification of disseminated liver lesions, semi-automatic lesion detection is helpful to determine tumor burden and tumor diameter in a time efficient manner. Here, we aimed to evaluate semi-automated measurement of total metastatic burden for therapy stratification. Nineteen patients with liver metastasized NET underwent contrast-enhanced 1.5 T MRI using gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid. Liver metastases (n=1537) were segmented using Fraunhofer MEVIS Software for three-dimensional (3D) segmentation. All lesions were stratified according to longest 3D diameter >20 mm or ≤20 mm and relative contribution to tumor load was used for therapy stratification. Mean count of lesions ≤20 mm was 67.5 and mean count of lesions >20 mm was 13.4. However, mean contribution to total tumor volume of lesions ≤20 mm was 24%, while contribution of lesions >20 mm was 76%. Semi-automatic lesion analysis provides useful information about lesion distribution in predominantly liver metastasized NET patients prior to PRRT. As conventional manual lesion measurements are laborious, our study shows this new approach is more efficient and less operator-dependent and may prove to be useful in the decision making process selecting the best combination PRRT in each patient.


Gold-catalyzed direct arylation.
Biaryls (two directly connected aromatic rings, Ar(1)-Ar(2)) are common motifs in pharmaceuticals, agrochemicals, and organic materials. Current methods for establishing the Ar(1)-Ar(2) bond are dominated by the cross-coupling of aryl halides (Ar(1)-X) with aryl metallics (Ar(2)-M). We report that, in the presence of 1 to 2 mole percent of a gold catalyst and a mild oxidant, a wide range of arenes (Ar(1)-H) undergo site-selective arylation by arylsilanes (Ar(2)-SiMe(3)) to generate biaryls (Ar(1)-Ar(2)), with little or no homocoupling (Ar(1)-Ar(1)/Ar(2)-Ar(2)). Catalysis proceeds at room temperature and tolerates a broad range of functional groups, including those incompatible with cross-coupling. These features expedite biaryl preparation, as demonstrated by synthesis of the nonsteroidal anti-inflammatory diflunisal.


Identification of the histidyl residue obligatory for the catalytic activity of the human H+/peptide cotransporters PEPT1 and PEPT2.
Histidyl residues are known to be essential for the catalytic function of the H(+)-coupled peptide transporters expressed in the intestine and the kidney, most likely participating in the binding and translocation of H+. Three histidyl residues are conserved among the intestinal and renal peptide transporters (PEPT1 and PEPT2, respectively) from different animal species. In hPEPT1, these residues are His-57, His-121, and His-260. The corresponding residues in hPEPT2 are His-87, His-142, and His-278. We have individually mutated each of these histidyl residues in hPEPT1 and in hPEPT2 and compared the catalytic function of the mutants with that of their respective wild type transporters by expressing the transporters in Xenopus laevis oocytes and also in HeLa cells. His-57 in hPEPT1 and His-87 in hPEPT2 were found to be absolutely essential for catalytic activity because the corresponding mutants had no detectable peptide transport activity. His-121 in hPEPT1 is not essential since mutation of this residue did not impair transport function. His-142 in hPEPT2 was found to play a significant role in the maintenance of transport function but was not found to be obligatory because the mutant had appreciable transport activity. The obligatory histidyl residue (His-57 in hPEPT1 and His-87 in hPEPT2) is located in an almost identical topological position in both transporters, near the extracellular surface of the second putative transmembrane domain. The second conserved histidyl residue is located in the fourth putative transmembrane domain in hPEPT1 as well as in hPEPT2. The third conserved histidyl residue is present in the cytoplasmic loop between the transmembrane domains 6 and 7 and is unlikely to play any significant role in the binding and translocation of H+ and this was supported by the findings that mutation of this histidyl residue in hPEPT1 did not interfere with transport function. The loss of transport function of hPEPT1 and hPEPT2, when His-57 in hPEPT1 and His-87 in hPEPT2 were mutated, was not due to alterations in protein expression because the expression levels of these mutants were similar to those of the respective wild type transporters in HeLa cells as assessed by immunoblot analysis. Confocal analysis of immunofluorescence in X. laevis oocytes expressing the wild type and the three histidine mutants of hPEPT1 showed that the transporter protein is expressed exclusively in the plasma membrane and that the level of expression is comparable among the wild type and the three mutants. These site-directed mutagenesis studies clearly show that His-57 in hPEPT1 and His-87 in hPEPT2 are the most critical histidyl residues necessary for the catalytic function of these transporters.


Spinal Cord Stimulation in Failed Back Surgery Syndrome: Review of Clinical Use, Quality of Life and Cost-Effectiveness.
Failed back surgery syndrome (FBSS) is complex and recurrent chronic pain after spinal surgery. Several important patient and surgery related risk factors play roles in development of FBSS. Inadequate selection of the candidates for the spinal surgeries is one of the most crucial causes. The guidelines suggest that conservative management featuring pharmacologic approaches and rehabilitation should be introduced first. For therapy-refractory FBSS, spinal cord stimulation (SCS) is recommended in selected patients. Treatment efficacy for FBSS has increased over the years with the majority of patients experiencing pain relief and reduced medicinal load. Improved quality of life can also be achieved using SCS. Cost-effectiveness of SCS still remains unclear. However evidence for SCS role in FBSS is controversial, SCS can be beneficial for carefully classified patients.


Ciprofloxacin does not Prolong the QTc Interval: A Clinical Study in ICU Patients and Review of the Literature.
Ciprofloxacin may prolong the QT interval and increase the risk of Torsade de Pointes (TdP). Intravenous administration of ciprofloxacin in patients with additional risks may elevate the risk of QTc interval prolongation. We prospectively assessed whether intravenous ciprofloxacin prolongs the QT interval in patients with additional co-morbidities and risk factors. We also reviewed the literature on the QT prolonging effect or TdP inducing effect of ciprofloxacin. ICU Patients who were treated with intravenous ciprofloxacin as part of their therapy were recruited. ECG was recorded within 60 min before start and in the last 30 min of 1 h infusion, or within 30 min after the end of ciprofloxacin infusion. QT interval was corrected for the heart rate using both Bazett's and Fridericia's formula. The changes were analyzed using the paired Student's t-test. Ten patients were included in the study (average age 74-y, 6 males). The average baseline QTc interval corrected with Bazett's formula was 448 ms that was shortened during or after ciprofloxacin infusion by 3 ms and 2 ms based on Bazett's (p=0.67) and Fridericia's (p=0.68) formula, respectively. No observational study or cohort study thus far has shown that ciprofloxacin has a QT prolonging effect or increases the risk of TdP or (cardiovascular) mortality. Conclusion. Based on our results and the results of previous studies, it is unlikely that ciprofloxacin has a clinically relevant QT prolonging effect or an increased risk of TdP. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Endonucleolytic RNA cleavage by a eukaryotic exosome.
The exosome is a major eukaryotic nuclease located in both the nucleus and the cytoplasm that contributes to the processing, quality control and/or turnover of a large number of cellular RNAs. This large macromolecular assembly has been described as a 3'-->5' exonuclease and shown to contain a nine-subunit ring structure evolutionarily related to archaeal exosome-like complexes and bacterial polynucleotide phosphorylases. Recent results have shown that, unlike its prokaryotic counterparts, the yeast and human ring structures are catalytically inactive. In contrast, the exonucleolytic activity of the yeast exosome core was shown to be mediated by the RNB domain of the eukaryote-specific Dis3 subunit. Here we show, using in vitro assays, that yeast Dis3 has an additional endoribonuclease activity mediated by the PIN domain located at the amino terminus of this multidomain protein. Simultaneous inactivation of the endonucleolytic and exonucleolytic activities of the exosome core generates a synthetic growth phenotype in vivo, supporting a physiological function for the PIN domain. This activity is responsible for the cleavage of some natural exosome substrates, independently of exonucleolytic degradation. In contrast with current models, our results show that eukaryotic exosome cores have both endonucleolytic and exonucleolytic activities, mediated by two distinct domains of the Dis3 subunit. The mode of action of eukaryotic exosome cores in RNA processing and degradation should be reconsidered, taking into account the cooperation between its multiple ribonucleolytic activities.


Exploring validation of a graphic symbol questionnaire to measure participation experiences of youth in activity settings.
Participation has a subjective and private dimension, and so it is important to hear directly from youth about their experiences in various activity settings, the places where they "do things" and interact with others. To meet this need, our team developed the Self-Reported Experiences of Activity Settings (SEAS) measure, which demonstrated good-to-excellent measurement properties. To address the needs of youth who could benefit from graphic symbol support, the SEAS-PCSTM, 1 was created. The purpose of this paper is to describe the development of SEAS-PCS and the preliminary study that explores the equivalency of the SEAS and SEAS-PCS. The SEAS and SEAS-PCS were compared in terms of the equivalency of meaning of stimulus items by 11 professionals and five adults who used augmentative and alternative communication, were familiar with PCS, and were fluent readers. Out of 22 items, 68% were rated as highly similar on a 5-point scale (M = 4.14; SD = .70; mdn = 4; range: 2.81-5.00). Subsequently, the 32% of the SEAS-PCS items that were rated below 4 were modified based on the participants' specific comments. Further work is required to validate the SEAS-PCS. The next step could involve exploring the views of youth who use AAC.


Editorial Commentary: Confirming Intuitive Thoughts in Hip Preservation.
In a biomechanical laboratory study of 63 bovine hip labra examining suture configuration, passer size, and radiofrequency treatment, superior biomechanical properties were found for vertical and oblique sutures compared with horizontal sutures, smaller puncture holes were better compared with large bore holes in the labra, and radiofrequency strengthened labra only when horizontal suture configuration was used. The authors appropriately acknowledge that suture anchor type, presence or absence of knots, and bone quality based on patient demographics and considering various regions of the acetabular rim are additional important factors. Although the authors wisely advocate caution in extrapolation to in vivo behavior, this study represents an important addition to our understanding of the importance of suture configuration in labral repair in the hip. Given the findings of this study and the present state of the art, the current winning formula appears to be labral base refixation with vertical or oblique mattress configuration, performed with small diameter suture passage devices.


Nitric oxide release is induced by dopamine during illumination of the carp retina: serial neurochemical control of light adaptation.
Several lines of indirect evidence have suggested that nitric oxide may play an important role during light adaptation of the vertebrate retina. We aimed to verify directly the effect of light on nitric oxide release in the isolated carp retina and to investigate the relationship between nitric oxide and dopamine, an established neuromodulator of retinal light adaptation. Using a biochemical nitric oxide assay, we found that steady or flicker light stimulation enhanced retinal nitric oxide production from a basal level. The metabotropic glutamate receptor agonist L-amino-4-phosphonobutyric acid, inhibited the light adaptation-induced nitric oxide production suggesting that the underlying cellular pathway involved centre-depolarizing bipolar cell activity. Application of exogenous dopamine to retinas in the dark significantly enhanced the basal production of nitric oxide and importantly, inhibition of endogenous dopaminergic activity completely suppressed the light-evoked nitric oxide release. The effect of dopamine was mediated through the D1 receptor subtype. Imaging of the nitric oxide-sensitive fluorescent indicator 4,5-diaminofluorescein di-acetate in retinal slices revealed that activation of D1 receptors resulted in nitric oxide production from two main spatial sources corresponding to the photoreceptor inner segment region and the inner nuclear layer. The results taken together would suggest that during the progression of retinal light adaptation there is a switch from dopaminergic to nitrergic control, probably to induce further neuromodulatory effects at higher levels of illumination and to enable more efficient spreading of the light adaptive signal.


The comparability of in vitro and ex vivo studies on the percutaneous permeation of topical formulations containing Ibuprofen.
In order to avoid in vivo experiments and to gain information about the suitability of surrogates for skin replacement, Franz-type diffusion cell experiments were conducted by using three ibuprofen-containing formulations (cream, gel and microgel) on bovine split-skin samples and cellophane membranes. Moreover, ex vivo examinations were performed on the isolated perfused bovine udder, to study the comparability of in vitro and ex vivo experimental set-ups. Depending on the formulation, noticeable differences in the permeation of Ibuprofen occurred in vitro (udder skin) and ex vivo (isolated perfused bovine udder), but not in the cellophane membrane. The rates of ibuprofen permeability (cream > gel > microgel) and adsorption into the skin (gel > microgel > cream) varied with the formulation, and were probably caused by differences in the ingredients. Furthermore, different storage conditions and seasonal variation in the collection of the skin samples probably led to differences in the amounts of ibuprofen adsorption apparent in the isolated bovine udder and udder skin. In vitro diffusion experiments should be preferred to experiments on isolated organs with regard to the costs involved, the throughput, and the intensity of labour required, unless metabolism of the drug in the skin, or cell-cell interactions are of particular interest.


Inhibition and acclimation of photosynthesis to heat stress is closely correlated with activation of ribulose-1,5-bisphosphate Carboxylase/Oxygenase
Increasing the leaf temperature of intact cotton (Gossypium hirsutum L.) and wheat (Triticum aestivum L.) plants caused a progressive decline in the light-saturated CO2-exchange rate (CER). CER was more sensitive to increased leaf temperature in wheat than in cotton, and both species demonstrated photosynthetic acclimation when leaf temperature was increased gradually. Inhibition of CER was not a consequence of stomatal closure, as indicated by a positive relationship between leaf temperature and transpiration. The activation state of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), which is regulated by Rubisco activase, was closely correlated with temperature-induced changes in CER. Nonphotochemical chlorophyll fluorescence quenching increased with leaf temperature in a manner consistent with inhibited CER and Rubisco activation. Both nonphotochemical fluorescence quenching and Rubisco activation were more sensitive to heat stress than the maximum quantum yield of photochemistry of photosystem II. Heat stress led to decreased 3-phosphoglyceric acid content and increased ribulose-1, 5-bisphosphate content, which is indicative of inhibited metabolite flow through Rubisco. We conclude that heat stress inhibited CER primarily by decreasing the activation state of Rubisco via inhibition of Rubisco activase. Although Rubisco activation was more closely correlated with CER than the maximum quantum yield of photochemistry of photosystem II, both processes could be acclimated to heat stress by gradually increasing the leaf temperature.


Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke.
and purpose: Currently there is no effective treatment for neonatal arterial ischemic stroke (AIS). Cannabidiol (CBD) is neuroprotective in models of newborn hypoxic-ischemic brain damage and adult stroke. The purpose of this work was to study the protective effect of CBD in a neonatal rat model of AIS. Middle Cerebral Artery Occlusion (MCAO) was achieved in neonatal Wistar rats by introducing a nylon filament to the left MCA for 3 h; 15 min after removing the occluder vehicle (MCAO-V) or CBD single dose 5 mg/kg (MCAO-C) were administered i. p. Similarly manipulated but non-occluded rats served as controls (SHM). A set of behavioral tests was then conducted one week (P15) or one month (P38) after MCAO. Brain damage was then assessed by magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (H+-MRS) and histologic (TUNEL for cell death, immunohistochemistry for neuron, astrocyte and microglia identification) studies. CBD administration improved neurobehavioral function regarding strength, hemiparesis, coordination and sensorimotor performance as assessed at P15 and P38. MRI indicated that CBD did not reduce the volume of infarct but reduced the volume of perilesional gliosis. H+-MRS indicated that CBD reduced metabolic derangement and excitotoxicty, and protected astrocyte function. Histologic studies indicated that CBD reduced neuronal loss and apoptosis, and modulated astrogliosis and microglial proliferation and activation. CBD administration after MCAO led to long-term functional recovery, reducing neuronal loss and astrogliosis, and modulating apoptosis, metabolic derangement, excitotoxicity and neuro-inflammation.


Enhancer-mediated role for polyomavirus middle T/small T in DNA replication.
A major role for polyomavirus middle T/small T antigens in viral DNA synthesis was uncovered by examining the replication of middle T/small T-deficient mutants (hr-t mutants). hr-t mutants in the A2 genetic background showed a 16- to 100-fold defect in genome accumulation relative to the wild type when infections were carried out in exponentially growing NIH 3T3 cells in medium supplemented with low levels of serum (< 2.0%). A proportional decrease in the level of viral early transcripts was also seen. The replication defect of the hr-t mutants was partially overcome in the presence of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. The defect was also alleviated by a duplication encompassing the alpha core enhancer domain that contains binding sites for the transcriptional activators PEA1/AP-1 and PEA3/c-ets. Such a duplication is present in all naturally occurring hr-t mutants and absent in the A2 strain. The effects of 12-O-tetradecanoylphorbol-13-acetate and alpha core duplication were additive but did not fully complement the absence of middle T/small T. In mixed infection competition experiments with two hr-t mutants, a genome that carried an alpha core duplication had a replication advantage (up to 17-fold) over a genome without duplication. This result demonstrates that one effect of the duplication is exerted directly at the level of DNA replication. The advantage of the duplication-bearing genome was established during the earliest stages of replication and was not further amplified in later rounds of replication. In the presence of middle T/small T, both genomes replicated to high levels and the advantage of the duplication-bearing genome was eliminated. On the basis of these results, we propose that factors that bind the alpha core domain (presumably PEA1 and PEA3) are present in limiting amounts in exponentially growing NIH 3T3 cells and play a crucial role in polyomavirus DNA replication. We further suggest that middle T and/or small T stimulates viral DNA replication by activating these factors. The fact that all middle T-/small T-defective hr-t mutants have evolved to contain enhancer duplications that encompass the PEA1 and PEA3 binding sites in the alpha core domain and partially restore their replication defect (A. Amalfitano, M. C. Chen, and M. Fluck, unpublished data) provides an adequate explanation for the fact that the importance of the role of the middle T and/or small T function in DNA replication has not been recognized previously. Much evidence is available in support of separate elements of this model.(ABSTRACT TRUNCATED AT 400 WORDS)


Active medulloblastoma enhancers reveal subgroup-specific cellular origins.
Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.


Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain.
Transient ischemia-induced perturbations in calcium homeostasis have been proposed to lead to pathological activation of the cysteine protease calpain I and subsequent delayed neuronal death in the CA1 region of hippocampus. We report here on the design and characterization of antibodies selective for calpain-generated fragments of brain spectrin, and their use for immunoblot and immunohistochemical analyses of calpain activation following cerebral ischemia in the gerbil. Although spectrin was susceptible to degradation in vitro by many mammalian proteases, only calpain degraded spectrin to generate fragments immunoreactive with the antibodies. Following 5 min of global ischemia, immunoreactivity for calpain-degraded spectrin was rapidly (within 30 min) and markedly elevated in the perikarya and dendrites of several populations of forebrain neurons. The rapid calpain activation was completely prevented by the NMDA receptor antagonist MK-801. At later times postischemia, but prior to frank neuronal necrosis, calpain-degraded spectrin was restricted to hippocampal area CA1 pyramidal neurons. Silver impregnation histochemistry confirmed that neuronal damage was confined to area CA1. The results indicate that while nonpathological NMDA receptor stimulation can activate calpain, only those neurons showing sustained calpain activation are destined to die.


Birth outcomes following zidovudine exposure in pregnant women: the Antiretroviral Pregnancy Registry.
Potential risk of adverse birth outcomes associated with the use of antiretrovirals in human immunodeficiency virus (HIV)-infected women during pregnancy must be assessed. Data through June 1995 are reported from the worldwide Antiretroviral Pregnancy Registry on the incidence of structural birth defects following prenatal exposure to zidovudine. Healthcare professionals register pregnant women anonymously. Follow-up is at time of delivery. Results are reviewed semi-annually by an advisory committee, which follows the Centers for Disease Control and Prevention (CDC) guidelines for definitions of birth defects. From 1989 through to 30 June, 1995, 198 outcomes involving exposure to zidovudine were reported. Of 73 first-trimester exposures, outcomes included one infant with a birth defect. Of 125 exposures in the second and third trimesters, six infants were reported with birth defects. Data on other antiretrovirals are insufficient for analysis. The Registry findings to date do not show an increase in the number of birth defects (1/63 in the first trimester, or 1.59%, 95% CI 0.083%, 9.69%) following prenatal zidovudine exposure when compared with that expected in the general population; however, the number of outcomes to date represents a sample of insufficient size for developing precise estimates regarding the teratogenic risk of zidovudine.


Caring for vulnerable children: challenges of mothering in the Australian foster care system.
Foster carers have a significant responsibility in caring for vulnerable children. In order to support and facilitate foster carers it is important to understand how they perceive and fulfil this responsibility. A qualitative story-telling study, informed by feminist perspectives, was used to conduct in-depth, semi-structured interviews with 20 women providing long-term foster care in Australia. Thematic analysis revealed these women characterised themselves as mothers, rather than paid carers, to the long-term foster children in their care. Using this maternal self-perception as the starting point, this paper reveals some of the challenges and difficulties participants encountered when mothering within the confines of the child protection system. Implications for nursing practice are discussed. These implications focus on ways that nurses can effectively support foster carers, thus optimising the health and well-being of the vulnerable children in their care.


An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice.
Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents. To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition. C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT). Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p<0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT. Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.


Mechanical and finite element evaluation of a bioprinted scaffold following recellularization in a rat subcutaneous model.
Tissue engineered heart valves (TEHV) provide several advantages over currently available aortic heart valve replacements. Bioprinting provides a patient-specific means of developing a TEHV scaffold from imaging data, and the capability to embed the patient's own cells within the scaffold. In this work we investigated the remodeling capacity of a collagen-based bio-ink by implanting bioprinted disks in a rat subcutaneous model for 2, 4 and 12 weeks and evaluating the mechanical response using biaxial testing and subsequent finite element (FE) modeling. Samples explanted after 2 and 4 weeks showed inferior mechanical properties compared to native tissues while 12 week explants showed a mechanical response of similar magnitude but did not demonstrate the anisotropy present in native tissues. In the FE analysis, the model utilizing mechanical properties from samples explanted after 12 weeks showed the closest mechanical behavior to the native tissues. However, in diastole native tissues showed higher stress in the leaflet belly and lower strain at the commissures compared to 12 week explants, likely due to the anisotropy present in the native tissues. Thus, either further remodeling is required in situ in the aortic valve position or by in vitro preconditioning in an environment such as a bioreactor. Regardless, these results demonstrate the utility of FE analysis to optimize bioprinting process parameters for the most favorable in vivo mechanical performance.


The role of presenilin cofactors in the gamma-secretase complex.
Mutations in presenilin genes account for the majority of the cases of the familial form of Alzheimer's disease (FAD). Presenilin is essential for gamma-secretase activity, a proteolytic activity involved in intramembrane cleavage of Notch and beta-amyloid precursor protein (betaAPP). Cleavage of betaAPP by FAD mutant presenilin results in the overproduction of highly amyloidogenic amyloid beta42 peptides. gamma-Secretase activity requires the formation of a stable, high-molecular-mass protein complex that, in addition to the endoproteolysed fragmented form of presenilin, contains essential cofactors including nicastrin, APH-1 (refs 15-18) and PEN-2 (refs 16, 19). However, the role of each protein in complex formation and the generation of enzymatic activity is unclear. Here we show that Drosophila APH-1 (Aph-1) increases the stability of Drosophila presenilin (Psn) holoprotein in the complex. Depletion of PEN-2 by RNA interference prevents endoproteolysis of presenilin and promotes stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Co-expression of Drosophila Pen-2 with Aph-1 and nicastrin increases the formation of Psn fragments as well as gamma-secretase activity. Thus, APH-1 stabilizes the presenilin holoprotein in the complex, whereas PEN-2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex.


Zooplankton-based reactors for tertiary wastewater treatment: A pilot-scale case study.
Nature-based wastewater treatments are an economic and sustainable alternative to intensive technologies in rural areas, although their efficiency needs to be improved. This study explores technological co-operation between zooplankton (e.g., Daphnia magna) and bacterial and algal biofilms in a 1.5 m3 zooplankton-based reactor for the on-site treatment of secondary urban wastewater. The efficiency of the reactor was evaluated over a 14-month period without any maintenance. The results suggest a low seasonality effect on nutrient polishing (organic matter and nitrogen) and the removal of solids (TSS and turbidity). The best performance, involving a decrease in organic carbon, nitrogen, E. coli loads, and solid content was achieved in winter when operating the reactor at 750 L d-1. Under these conditions, the quality of the effluent water was suitable for its reuse for six different purposes in conformance with Spanish legislation. These results demonstrate that the zooplankton-based reactor presented here can be used as an eco-sustainable tertiary treatment to provide water suitable for reuse. On-site research revealed that the robustness of the reactor against temperature and oxygen fluctuations needs to be improved to ensure good performance throughout the year.


Remote monitoring after recent hospital discharge in patients with heart failure: a systematic review and network meta-analysis.
Readmission to hospital for heart failure is common after recent discharge. Remote monitoring (RM) strategies have the potential to deliver specialised care and management and may be one way to meet the growing needs of the heart failure population. To determine whether RM strategies improve outcomes for adults who have been recently discharged (<28 days) following an unplanned admission due to heart failure. Systematic review and network meta-analysis. Fourteen electronic databases (including MEDLINE, EMBASE and PsycINFO) were searched to January 2012, and supplemented by hand-searching relevant articles. All randomised-controlled trials (RCTs) or observational cohort studies with a contemporaneous control group were included. RM interventions included home telemonitoring (TM) (including implanted monitoring devices) with medical support provided during office hours or 24/7 and structured telephone support (STS) programmes delivered via human-to-human contact (HH) or human-to-machine interface (HM). Data were extracted and validity was assessed independently by two reviewers. Twenty-one RCTs that enrolled 6317 patients were identified (11 studies evaluated STS (10 of which were HH, while 1 was HM), 9 studies assessed TM, and 1 study assessed both STS and TM). No trial of implanted monitoring devices met the inclusion criteria. Compared with usual care, although not reaching statitistical significance, RM trended to reduce all-cause mortality for STS HH (HR: 0.77, 95% credible interval (CrI): 0.55, 1.08), TM during office hours (HR: 0.76, 95% CrI: 0.49, 1.18) and TM24/7 (HR: 0.49, 95% CrI: 0.20, 1.18). Exclusion of one trial that provided better-than-usual support to the control group rendered each of the above comparisons statistically significant. No beneficial effect on mortality was observed with STS HM. Reductions were also observed in all-cause hospitalisations for TM interventions but not for STS interventions. Care packages generally improved health-related quality-of-life and were acceptable to patients. STS HH and TM with medical support provided during office hours showed beneficial trends, particularly in reducing all-cause mortality for recently discharged patients with heart failure. Where 'usual' care is less good, the impact of RM is likely to be greater.