Improvement of fluid balance monitoring through education and rationalisation.
Fluid input/output charts in hospital inpatients are a valuable source of information for doctors reviewing intravenous fluid prescription, but are notorious for being incomplete and inaccurate. Lack of awareness of the importance of fluid balance amongst nursing staff and an excess of unnecessary monitoring are two factors contributing to the problem. We conducted a quality improvement project on the respiratory ward in a large district general hospital aiming to specifically address these two factors. Pre-intervention audit showed that only 53% of input/output monitoring was clinically indicated, with an average chart completion of 50%. Using e-Learning and verbal presentation to raise awareness around fluid balance, we implemented a new system whereby daily medical review of charts lead to rationalisation of monitoring. Post-intervention audit showed a 93% reduction in unnecessary monitoring, with corresponding increases in completion (40%) and accuracy (48%) of remaining charts. In conclusion, education has enabled a culture change on the ward that has drastically increased the quality of fluid balance monitoring.


Professional and practice characteristics associated with self-efficacy in assessment and intervention among social workers in aging.
This study examined professional and practice characteristics associated with assessment and intervention self-efficacy among gerontological social workers in Ontario, Canada who participated in online surveys. Results from multivariate analyses indicated that higher client acuity, longer duration of practice experience, smaller caseloads, and a greater proportion of clients 85 and over were significantly associated with greater assessment self-efficacy. Greater client acuity and smaller caseloads were also significantly associated with greater intervention self-efficacy. Implications for education include the importance of providing practical experience with the oldest old and with clients with greater biopsychosocial complexity. Also recommended is the need for manageable caseloads, especially when older adults with complex needs are part of the practice milieu.


Resource predictability and host specificity in fleas: the effect of host body mass.
Ecological specialization is hypothesized to result from the exploitation of predictable resource bases. For parasitic organisms, one prediction is that parasites of large-bodied host species, which tend to be long-lived, should specialize on these hosts, whereas parasites of small host species, which represent more ephemeral and less predictable resources, should become generalists. We tested this prediction by quantifying the association between the level of host specificity of fleas and the mean body mass of their mammalian hosts, using published data from 2 large, distinct geographical regions (South Africa and northern North America). In general, we found supporting evidence that flea host specificity, measured either as the number of host species exploited or their taxonomic distinctness, became more pronounced with increasing host body mass. There were, however, some discrepancies among the results depending on the different measures of host specificity, the geographical region studied, or whether we used the raw values or phylogenetically independent contrasts. These are discussed with respect to other forces acting on the evolution of host specificity in parasites, as well as in the context of the regions' contrasting evolutionary histories. Overall, though, our findings indicate that the exploitation of large-bodied, and therefore long-lived, host species has promoted specialization in fleas, most likely because these hosts represent predictable resources.


Influence of Sustained Low-Efficiency Dialysis Treatment on Isavuconazole Plasma Levels in Critically Ill Patients.
Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 μg/ml; P < 0.001). However, even after SLED treatment, isavuconazole concentrations exceeded the in vivo MICs for several relevant Aspergillus species.


Frontal Bone Healing Is Sensitive to Wnt Signaling Inhibition via Lentiviral-Encoded Beta-Catenin Short Hairpin RNA.
The Wnt/β-catenin signaling pathway plays an integral role in skeletal biology, spanning from embryonic skeletal patterning through bone maintenance and bone repair. Most experimental methods to antagonize Wnt signaling in vivo are either systemic or transient, including genetic approaches, use of small-molecule inhibitors, or neutralizing antibodies. We sought to develop a novel, localized model of prolonged Wnt/β-catenin signaling blockade by the application and validation of a lentivirus encoding β-catenin short hairpin RNA (shRNA). Efficacy of lentiviral-encoded β-catenin shRNA was first confirmed in vitro using bone marrow mesenchymal stromal cells, and in vivo using an intramedullary long bone injection model in NOD SCID mice. Next, the effects of β-catenin knockdown were assessed in a calvarial bone defect model, in which the frontal bone demonstrates enhanced bone healing associated with heightened Wnt/β-catenin signaling. Lentivirus encoding either β-catenin shRNA or random sequence shRNA with enhanced green fluorescent protein (control) was injected overlying the calvaria of NOD SCID mice and bone defects were created in either the frontal or parietal bones. Among mice treated with lentivirus encoding β-catenin shRNA, frontal bone defect healing was significantly reduced by all radiographic and histologic metrics. In contrast, parietal bone healing was minimally impacted by β-catenin shRNA. In aggregate, our data document the application and validation of a lentivirus encoding β-catenin shRNA model that represents an easily replicable tool for examining the importance of locoregional Wnt/β-catenin signaling in bone biology and regeneration.


Management Strategies for Patients with Hilar Cholangiocarcinomas: Challenges and Solutions.
Advances in imaging, pathology and therapy have resulted in major improvements in the management of cholangiocarcinomas; the mortality has come down and with it there has been an improved 5-year survival. Surgical resection remains the treatment of choice and reports from high volume centres have shown an increase in resectability rates, R0 resection, a decrease in mortality and an improvement in 5-year survival; however, the operative morbidity remains high, pointing towards the complexity of the management of these difficult lesions. Complete excision is also often limited by the locally advanced nature of the disease at the time of diagnosis and a proportion of patients who were earlier deemed resectable on imaging are found to have unresectable disease at the time of operation. Neoadjuvant therapy has had only a limited impact on survival. Liver transplantation is also an option in a few patients following strict criteria for selection. Since the large majority of patients are only diagnosed at the late stages of the disease palliation (endoscopic or surgical) is an important part of treatment. Portal vein embolisation and pre-operative biliary drainage have had a major impact on outcomes. Major liver resection with caudate lobe removal remains the standard operation and procedures like routine vascular resection and liver transplant should only be carried out in experienced centres. Improvements in both neo as well as adjuvant therapy may lead to a standardized protocol in the future, as well as an improvement in survival.


Flying high: a theoretical analysis of the factors limiting exercise performance in birds at altitude.
The ability of some bird species to fly at extreme altitude has fascinated comparative respiratory physiologists for decades, yet there is still no consensus about what adaptations enable high altitude flight. Using a theoretical model of O(2) transport, we performed a sensitivity analysis of the factors that might limit exercise performance in birds. We found that the influence of individual physiological traits on oxygen consumption (Vo2) during exercise differed between sea level, moderate altitude, and extreme altitude. At extreme altitude, haemoglobin (Hb) O(2) affinity, total ventilation, and tissue diffusion capacity for O(2) (D(To2)) had the greatest influences on Vo2; increasing these variables should therefore have the greatest adaptive benefit for high altitude flight. There was a beneficial interaction between D(To2) and the P(50) of Hb, such that increasing D(To2) had a greater influence on Vo2 when P(50) was low. Increases in the temperature effect on P(50) could also be beneficial for high flying birds, provided that cold inspired air at extreme altitude causes a substantial difference in temperature between blood in the lungs and in the tissues. Changes in lung diffusion capacity for O(2), cardiac output, blood Hb concentration, the Bohr coefficient, or the Hill coefficient likely have less adaptive significance at high altitude. Our sensitivity analysis provides theoretical suggestions of the adaptations most likely to promote high altitude flight in birds and provides direction for future in vivo studies.


Residents' and attending physicians' handoffs: a systematic review of the literature.
Effective communication is central to patient safety. There is abundant evidence of negative consequences of poor communication and inadequate handoffs. The purpose of the current study was to conduct a systematic review of articles focused on physicians' handoffs, conduct a qualitative review of barriers and strategies, and identify features of structured handoffs that have been effective. The authors conducted a thorough, systematic review of English-language articles, indexed in PubMed, published between 1987 and June 2008, and focused on physicians' handoffs in the United States. The search strategy yielded 2,590 articles. After title review, 401 were obtained for further review by trained abstractors. Forty-six articles met inclusion criteria, 33 (71.7%) of which were published between 2005 and 2008. Content analysis yielded 91 handoffs barriers in eight major categories and 140 handoffs strategies in seven major categories. Eighteen articles involved research on handoffs. Quality assessment scores for research studies ranged from 1 to 13 (possible range 1-16). One third of the reviewed research studies obtained quality scores at or below 8, and only one achieved a score of 13. Only six studies included any measure of handoff effectiveness. Despite the negative consequences of inadequate physicians' handoffs, very little research has been done to identify best practices. Many of the existing peer-reviewed studies had design or reporting flaws. There is remarkable consistency in the anecdotally suggested strategies; however, there remains a paucity of evidence to support these strategies. Overall, there is a great need for high-quality handoff outcomes studies focused on systems factors, human performance, and the effectiveness of structured protocols and interventions.


Mitochondrial oxidative stress and the metabolic syndrome.
The current epidemic of the metabolic syndrome in the developed world is largely due to overnutrition and lack of physical activity. However, the underlying causes by which chronic overnutrition interacts with genotype and physical inactivity to generate the metabolic syndrome phenotype are complex, and include multiple metabolic and physiological alterations. Mitochondrial oxidative stress has been suggested to contribute to the metabolic syndrome, but the mechanisms and significance are unclear. Here we review how disruption of mitochondrial metabolism and increased oxidative stress may occur during overnutrition coupled with limited physical activity. From this we suggest a unifying hypothesis to integrate what is known about mitochondrial involvement in the metabolic syndrome that points to testable hypotheses and novel therapeutic approaches.


Genetic costructure in a meta-community under threat of habitat fragmentation.
Habitat fragmentation increasingly threatens the services provided by natural communities and ecosystem worldwide. An understanding of the eco-evolutionary processes underlying fragmentation-compromised communities in natural settings is lacking, yet critical to realistic and sustainable conservation. Through integrating the multivariate genetic, biotic and abiotic facets of a natural community module experiencing various degrees of habitat fragmentation, we provide unique insights into the processes underlying community functioning in real, natural conditions. The focal community module comprises a parasitic butterfly of conservation concern and its two obligatory host species, a plant and an ant. We show that both historical dispersal and ongoing habitat fragmentation shape population genetic diversity of the butterfly Phengaris alcon and its most limited host species (the plant Gentiana pneumonanthe). Genetic structure of each species was strongly driven by geographical structure, altitude and landscape connectivity. Strikingly, however, was the strong degree of genetic costructure among the three species that could not be explained by the spatial variables under study. This finding suggests that factors other than spatial configuration, including co-evolutionary dynamics and shared dispersal pathways, cause parallel genetic structure among interacting species. While the exact contribution of co-evolution and shared dispersal routes on the genetic variation within and among communities deserves further attention, our findings demonstrate a considerable degree of genetic parallelism in natural meta-communities. The significant effect of landscape connectivity on the genetic diversity and structure of the butterfly also suggests that habitat fragmentation may threaten the functioning of the community module on the long run.


Aerodynamic and acoustic characteristics of voice before and after adduction arytenopexy and medialization laryngoplasty with GORE-TEX in patients with unilateral vocal fold immobility.
Multiple surgical techniques have been developed to restore function in patients with vocal fold paralysis (VFP), ranging from open laryngeal framework procedures to endoscopic injection techniques. In our experience, adduction arytenopexy (AA) and medialization laryngoplasty with GORE-TEX (MLG), with or without cricothyroid subluxation (CTS), together offer patients optimal improvement in voice, based on the subjective change in voice quality and patient feedback obtained. In this study, we analyze objective voice parameters in these patients before and after surgery. The objective of this retrospective chart review is to demonstrate the change in aerodynamic and acoustic properties of voice in patients with VFP who undergo combined AA and MLG, with or without CTS. Seventy-five patients underwent combined AA and MLG between May 2001 and September 2006; 28 completed both preoperative and postoperative voice evaluation including aerodynamic and acoustic testing. Retrospective chart review is used to compare pre- and postoperative voice parameters in these patients. Statistically significant increases in mean maximum phonation time (MPT) and mean intensity of "/pae/" during aerodynamic testing, with a statistically significant decrease in mean glottal airflow were observed. A notable increase in mean glottal resistance was not statistically significant. No significant change was observed in the other parameters tested. Mean MPT increased and mean glottal airflow decreased. These objective results correlate with patients' subjective improvement. However, while "objective," acoustic and aerodynamic testing are effort dependent, and thus may not be as reliable as other tools in measuring postsurgical voice outcomes. Patient surveys may be the best means of gauging surgical success.


Okadaic Acid Mimics Nitrogen-Stimulated Transcription of the NADH-Glutamate Synthase Gene in Rice Cell Cultures.
Okadaic acid (OKA), a potent and specific inhibitor of protein serine/threonine phosphatases 1 and 2A, induced the accumulation of NADH-glutamate synthase (GOGAT) mRNA within 4 h in rice (Oryza sativa L.) cell cultures. In contrast to the transient accumulation of NADH-GOGAT mRNA by NH(4)(+), OKA caused a continuous accumulation for at least 24 h. The induction of NADH-GOGAT mRNA by OKA was not inhibited in the presence of methionine sulfoximine, which inhibited the NH(4)(+)-induced accumulation of mRNA. These results suggest that the OKA-sensitive protein phosphatase is involved in the regulation of NADH-GOGAT gene expression and probably plays a role in the signal transduction pathway downstream from NH(4)(+), although a signal transduction pathway other than that of nitrogen sensing could be responsible. Nuclear run-on assays demonstrated that the accumulation of NADH-GOGAT mRNA induced by the supply of either NH(4)(+) or OKA was mainly regulated at the transcription level. OKA effects were synergistic to the NH(4)(+)-induced expression of the NADH-GOGAT gene. In the presence of K-252a, a protein kinase inhibitor, the accumulation of NADH-GOGAT mRNA induced by either NH(4)(+) or OKA was reduced. The possible roles of protein phosphatases in the regulation of NADH-GOGAT gene expression are discussed.


Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus-negative and combined Merkel cell carcinoma: A retrospective study.
Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin that is associated with Merkel cell polyomavirus (MCPyV). The clinical appearance and demographic characteristics of this tumor have been described using the mnemonic AEIOU: asymptomatic, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed fair skin. In addition, MCC can be categorized based on morphology as pure MCC or combined MCC that exhibits neuroendocrine and other phenotypic elements. There is limited information regarding the clinical characteristics and prognosis of combined MCC. This retrospective study aimed to identify factors, such as ulceration or hyperkeratosis, that could predict MCPyV status and morphological variants. Twenty patients with MCC were divided into groups based on MCPyV status and morphology: MCPyV-positive or MCPyV-negative MCC and pure or combined MCC. The patients' MCPyV status was immunohistochemically determined using the CM2B4 antibody to the MCPyV large T-antigen. The patients' clinicopathological characteristics were evaluated to identify predictors of MCPyV-negative MCC and combined MCC. The presence of ulceration/hyperkeratosis predicted the presence of MCPyV-negative MCC (80% of cases) and combined MCC (50% of cases). None of the 10 patients with MCPyV-positive MCC had ulceration/hyperkeratosis. The clinical presence of ulceration/hyperkeratosis may help guide the diagnosis of MCPyV-negative MCC and combined MCC.


The role of membrane components on the oleosome lubrication properties.
Oleosomes are natural oil droplets with a unique phospholipid/protein membrane, abundant in plant seeds, from which they can be extracted and used in emulsion-based materials, such as foods, cosmetics and pharmaceutics. The lubrication properties of such materials are essential, on one hand, due to the importance of the in-mouth creaminess for the consumed products or the importance of spreading the topical creams. Therefore, here, we will evaluate the lubrication properties of oleosomes, and how these properties are affected by the components at the oleosome membrane. Oleosomes were extracted, and their oral lubricating properties were evaluated using tribology. To understand the influence of the oil droplet membrane composition, reconstituted oleosomes were also studied, with membranes that differed in protein/lecithin ratio. Additionally, whey protein- and lecithin-stabilised emulsions were used as reference samples. Confocal laser scattering microscopy was used to study the samples visually before and after tribological analysis. Oleosomes followed a ball-bearing mechanism, which was probably related to their high physical stability due to the presence of membrane proteins. When the membrane protein concentration at the surface was reduced, the droplet stability weakened, leading to plating-out lubrication. Following our results, we elucidated the oleosome lubrication mechanism and showed their possible control by changing the membrane composition.


National Scale-Up of Results-Based Financing in Primary Health Care: The Case of Armenia.
Abstract-Results-based financing (RBF) has been integrated into the national health care financing system of Armenia covering all primary health care (PHC) facilities in the country. The RBF program contributed to a substantial increase in the utilization of PHC services and improved provider performance. Based on document and literature review and key informant interviews and focus group discussions, this article describes the successful scale-up and integration of RBF into Armenia's primary health care system throughout the period 2000-2015. The article shows how an interaction of contextual factors, actors, and processes contributed to the successful scale-up and integration of RBF into Armenia's primary health care system. Though international agencies, in this case the United States Agency for International Development (USAID), had a significant influence on the introduction and initial design of the RBF scheme, an important enabler was a well-sequenced reform process that included the most politically important stakeholders, including the State Health Agency. Embedding of RBF in national regulatory frameworks and the provision of funds from the national budget were also key contributors to success. Finally, an important enabler to the subsequent scale-up and integration of RBF into the PHC system was its introduction as part of a larger reform of the primary health care system.


The Olecranon Osteotomy-Facilitated Elbow Release (OFER).
Elbow contractures can cause functional limitation, and treatment can be challenging. The purpose of this article is to describe a novel technique that releases posttraumatic elbow contractures through an olecranon osteotomy and report the outcomes. Thirty-five patients with refractory posttraumatic elbow contracture who underwent an olecranon osteotomy-facilitated elbow release (OFER) procedure were included in the study. The average patient age was 39.5 years (range, 18 to 63 years), and the mean duration of follow-up was 37.2 months (range, 24 to 72 months). Preoperative and postoperative data included age, sex, cause of contracture, previous surgical procedures, active elbow range of motion, Disabilities of the Arm, Shoulder and Hand (DASH) scores, visual analog scale pain scores, and radiographs. Intraoperative tourniquet time and complications were recorded. The mean preoperative elbow motion arc was 33° (51° to 84° of flexion). Postoperatively, the motion arc improved significantly (p < 0.001) to 110° (16° to 126° of flexion). The mean visual analog pain scale score improved from 6.3 preoperatively to 1.4 at the time of follow-up (p < 0.001). The mean DASH score improved from 57.5 preoperatively to 10.9 postoperatively (p < 0.001). The maximal improvement in the motion arc occurred at a mean of 8.7 weeks. There was 1 postoperative ulnar neurapraxia that resolved spontaneously. The intraoperative tourniquet time averaged 27 minutes (range, 18 to 45 minutes). The average time until radiographic evidence of union of the olecranon osteotomy site was 6.6 weeks (range, 5.7 to 7.7 weeks). The OFER is a safe and effective means of treating posttraumatic elbow contractures, and is an alternative to traditional open or arthroscopic techniques. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Hypovitaminosis D in medical inpatients.
Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D deficiency among patients hospitalized on a general medical service is unknown. We assessed vitamin D intake, ultraviolet-light exposure, and risk factors for hypovitaminosis D and measured serum 25-hydroxyvitamin D, parathyroid hormone, and ionized calcium in 290 consecutive patients on a general medical ward. A total of 164 patients (57 percent) were considered vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, < or = 15 ng per milliliter), of whom 65 (22 percent) were considered severely vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, <8 ng per milliliter). Serum 25-hydroxyvitamin D concentrations were related inversely to parathyroid hormone concentrations. Lower vitamin D intake, less exposure to ultraviolet light, anticonvulsant-drug therapy, renal dialysis, nephrotic syndrome, hypertension, diabetes mellitus, winter season, higher serum concentrations of parathyroid hormone and alkaline phosphatase, and lower serum concentrations of ionized calcium and albumin were significant univariate predictors of hypovitaminosis D. Sixty-nine percent of the patients who consumed less than the recommended daily allowance of vitamin D and 43 percent of the patients with vitamin D intakes above the recommended daily allowance were vitamin D-deficient. Inadequate vitamin D intake, winter season, and housebound status were independent predictors of hypovitaminosis D in a multivariate model. In a subgroup of 77 patients less than 65 years of age without known risk factors for hypovitaminosis D, the prevalence of vitamin D deficiency was 42 percent. Hypovitaminosis D is common in general medical inpatients, including those with vitamin D intakes exceeding the recommended daily allowance and those without apparent risk factors for vitamin D deficiency.


USSTRIDE program is associated with competitive Black and Latino student applicants to medical school.
We compared MCAT scores, grade point averages (GPAs), and medical school acceptance rates of Black and Latino students in an outreach program called Undergraduate Science Students Together Reaching Instructional Diversity and Excellence (USSTRIDE) to non-USSTRIDE students. We hypothesized that Black and Latino participants in USSTRIDE had higher acceptance rates to medical school, higher MCAT scores, and college GPAs when compared to other Black and Latino medical school applicants from our institution. The academic performance (GPAs and MCAT scores) and acceptance and matriculation rate data on all Black and Latino Florida State University applicants to any medical school from 2008 to 2012 were collected from the AIS/AMCAS database and separated into two comparison groups (USSTRIDE vs. Non-USSTRIDE). Independent sample T-tests and chi-square analysis, Cohen's D test, and odds ratios were determined. Average science GPA was 3.47 for USSTRIDE students (n=55) and 3.45 for non-USSTRIDE students (n=137, p=0.68, d=0.0652). Average cumulative GPA was 3.57 for USSTRIDE students and 3.54 for non-USSTRIDE students (p=0.45, d=0.121). Average MCAT score was 23 for USSTRIDE students and 25 for non-USSTRIDE students (p=0.02, d=0.378). Twenty-three percent of accepted USSTRIDE students and 29% of accepted non-USSTRIDE students had multiple acceptances (p=0.483, OR 1.38, 95% CI 0.52-3.88). Forty-nine percent of non-USSTRIDE students and 75% of USSTRIDE students matriculated in medical school (p=0.001, OR 3.13 95% CI 1.51-6.74). About 78.6% of USSTRIDE students matriculated at FSU's medical school compared to 36.2% of non-USSTRIDE students (p<0.01). USSTRIDE and non-USSTRIDE students had similar science and cumulative GPAs. USSTRIDE students' MCAT scores were lower but acceptance rates to medical school were higher. Participation in USSTRIDE is associated with increased acceptance rates for Black and Latino students to our medical school. This finding is true for other medical schools as USSTRIDE students are as likely as non-USSTRIDE students to have multiple acceptances.


MRI features of gastrocnemius musculotendinopathy in herding dogs.
Pelvic limb lameness that was localized clinically to the lateral gastrocnemius head was observed in dogs without history of trauma. The aim of this retrospective study was to describe magnetic resonance imaging (MRI) findings of this condition. Nine dogs were identified, eight Border Collies and one Australian Shepherd. They all had chronic pelvic limb lameness; no signs of joint effusion or instability were present. In MR images there was high signal intensity in the lateral head of the gastrocnemius muscle around the sesamoid bone in T2-weighted, T2*-weighted, and STIR images and an iso- to mildly hyperintense signal in T1-weighted images with marked contrast enhancement. The abnormal signal intensity most likely represents a myotendinous strain. The breed affiliation to Border Collies is striking, and a relation to biomechanical forces or motion pattern may be possible. Except for the dog with the most extensive lesion all dogs had an excellent outcome.


Thermal stimulation of the hypothalamus does not evoke the acute-phase reaction.
Interleukin-1 (IL1) injected into the preoptic-anterior hypothalamus (POAH) induces, besides fever, the hepatic synthesis of acute-phase glycoproteins. Since the febrigenic action of IL1 may involve thermosensitive neurons in the POAH, this study examined whether such neurons also might mediate the acute-phase response (APR). The POAH of six adult NZW rabbits was cooled (Tpo = 34.4 +/- 0.4 degrees C [mean +/- SD]) or heated (40.6 +/- 0.2 degrees C) continuously for 2.5 hr (so as to mimic the mean febrile course following a bolus microinjection of IL1 into the POAH). The ambient temperature (Ta) was 23.5 +/- 1.0 degrees C. Expectedly, core temperature fell and skin temperature rose on POAH heating, and the opposite occurred on POAH cooling. However, no statistically significant changes in the plasma levels of Fe, Zn, Cu, and N-acetylneuraminic acid, as indices of the APR, were induced by these treatments. These results indicate, therefore, that the central actions of IL1 in inducing fever and the APR are separate, and that the APR is not mediated through stimulation of thermosensitive units in the POAH.


Stereotactic radiosurgery for arteriovenous malformations, Part 3: outcome predictors and risks after repeat radiosurgery.
The object of this study was to evaluate the outcomes and risks of repeat stereotactic radiosurgery (SRS) for incompletely obliterated cerebral arteriovenous malformations (AVMs). Between 1987 and 2006, Gamma Knife surgery was performed in 996 patients with AVMs. During this period, repeat SRS was performed in 105 patients who had incompletely obliterated AVMs at a median of 40.9 months after initial SRS (range 27.5-139 months). The median AVM target volume was 6.4 cm(3) (range 0.2-26.3 cm(3)) at initial SRS but was reduced to 2.3 cm(3) (range 0.1-18.2 cm(3)) at the time of the second procedure. The median margin dose at both initial SRS and repeat SRS was 18 Gy. The actuarial rate of total obliteration by angiography or MR imaging after repeat SRS was 35%, 68%, 77%, and 80% at 3, 4, 5, and 10 years, respectively. The median time to complete angiographic or MR imaging obliteration after repeat SRS was 39 months. Factors associated with a higher rate of AVM obliteration were smaller residual AVM target volume (p = 0.038) and a volume reduction of 50% or more after the initial procedure (p = 0.014). Seven patients (7%) had a hemorrhage in the interval between initial SRS and repeat SRS. Seventeen patients (16%) had hemorrhage after repeat SRS and 6 patients died. The cumulative actuarial rates of new AVM hemorrhage after repeat SRS were 1.9%, 8.1%, 10.1%, 10.1%, and 22.4% at 1, 2, 3, 5, and 10 years, respectively, which translate to annual hemorrhage rates of 4.05% and 1.79% of patients developing new post-repeat-SRS hemorrhages per year for Years 0-2 and 2-10 following repeat SRS. Factors associated with a higher risk of hemorrhage after repeat SRS were a greater number of prior hemorrhages (p = 0.008), larger AVM target volume at initial SRS (p = 0.010), larger target volume at repeat SRS (p = 0.002), initial AVM volume reduction less than 50% (p = 0.019), and a higher Pollock-Flickinger score (p = 0.010). Symptomatic adverse radiation effects developed in 5 patients (4.8%) after initial SRS and in 10 patients (9.5%) after repeat SRS. Prior embolization (p = 0.022) and a higher Spetzler-Martin grade (p = 0.004) were significantly associated with higher rates of adverse radiation effects after repeat SRS. Delayed cyst formation occurred in 5 patients (4.8%) at a median of 108 months after repeat SRS (range 47-184 months). Repeat SRS for incompletely obliterated AVMs increases the eventual obliteration rate. Hemorrhage after obliteration did not occur in this series. The best results for patients with incompletely obliterated AVMs were seen in patients with a smaller residual nidus volume and no prior hemorrhages.


Systemic sclerosis: state of the art on clinical practice guidelines.
Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains 'Vascular & Ulcers' (ie, non-pharmacological approach to digital ulcer), 'PAH' (ie, screening and treatment), 'Treatment' and 'Juveniles' (ie, evaluation of juveniles with Raynaud's phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-)pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation.


Automatic Detection of Depression in Speech Using Ensemble Convolutional Neural Networks.
This paper proposes a speech-based method for automatic depression classification. The system is based on ensemble learning for Convolutional Neural Networks (CNNs) and is evaluated using the data and the experimental protocol provided in the Depression Classification Sub-Challenge (DCC) at the 2016 Audio-Visual Emotion Challenge (AVEC-2016). In the pre-processing phase, speech files are represented as a sequence of log-spectrograms and randomly sampled to balance positive and negative samples. For the classification task itself, first, a more suitable architecture for this task, based on One-Dimensional Convolutional Neural Networks, is built. Secondly, several of these CNN-based models are trained with different initializations and then the corresponding individual predictions are fused by using an Ensemble Averaging algorithm and combined per speaker to get an appropriate final decision. The proposed ensemble system achieves satisfactory results on the DCC at the AVEC-2016 in comparison with a reference system based on Support Vector Machines and hand-crafted features, with a CNN+LSTM-based system called DepAudionet, and with the case of a single CNN-based classifier.


Arterial wave reflection during antihypertensive therapy with barnidipine: a 6-month, open-label study using an integrated cardiovascular ultrasound approach in patients with newly diagnosed hypertension.
Increased central aortic pressure resulting from large artery stiffening and increased wave reflection is associated with higher hypertension-related morbidity. The goal of this study was to evaluate the effects of a vasodilator-based therapy with the calcium channel blocker barnidipine on arterial stiffness, wave reflection, and left ventricular (LV) performance using an integrated cardiovascular ultrasound approach (including wave intensity analysis). Newly diagnosed, previously untreated patients with grade 1 or 2 essential hypertension (systolic blood pressure [BP] > or =140 and <180 mm Hg, and/or diastolic BP > or =90 and <110 mm Hg), and with no signs of clinical cardiovascular disease, were eligible for study. Carotid artery mechanics were investigated at baseline and after 3 and 6 months of barnidipine therapy (10-20 mg once daily, according to an open-label design) using a double-beam carotid ultrasound technique. This provided a simultaneous recording of diameter-derived pressure and flow velocity signals and allowed analysis of wave intensity. Indices of local arterial stiffness and wave reflection, as well as separated forward and backward pressure waves, were estimated. LV geometry, mass, and systolic and diastolic performance were also assessed using Doppler echocardiography. All ultrasound examinations and readings were performed by investigators blinded to patient demographics and treatment phase. Normotensive control subjects (office BP <140/90 mm Hg) were included as a reference group. Twenty-one white, treatment-naive patients with hypertension (mean [SD] age, 58 [8] years; 14 males; mean body mass index, 27 [5] kg/m(2); mean BP, 159 [14]/96 [5] mm Hg) were enrolled. Twenty normotensive subjects comprised the control group. Compared with the control subjects, patients with hypertension had a higher mean augmentation index ([AIx] 22.0% [7.0%] vs 13.1% [5.2%]; P < 0.01), Peterson's pressure-strain elastic modulus (175 [49] vs 126 [41] kPa; P < 0.01), and forward and backward pressure waves (137 [17] vs 108 [7] mm Hg [P < 0.001] and 21 [6] vs 17 [5] mm Hg [P < 0.05], respectively) at baseline. After 6 months of barnidipine treatment, mean office BP in the patients with hypertension decreased from 159 (14)/96 (5) mm Hg at baseline to 138 (16)/81 (9) mm Hg (P < 0.001) due to a significant reduction in forward and backward pressure waves, and AIx decreased to 17.0% (8.0%) (P < 0.01); there were no significant changes in indices of intrinsic arterial stiffness. A significant direct relationship between AIx and pulse pressure (r = 0.45 [P < 0.05]) was observed at baseline in hypertensive patients but not after therapy (r = 0.26 [P = NS]). Mean stress-adjusted LV midwall shortening increased from 110% (17%) at baseline to 118% (13%) at 6 months (P < 0.05), which was comparable to baseline values in the control subjects (119% [10%]). In these middle-aged patients with newly diagnosed mild to moderate hypertension, vasodilator therapy with barnidipine reduced central BP by a parallel reduction of forward and backward pressure waves, together with a later arrival of the reflected waves, with no significant changes in intrinsic arterial stiffness.


Caribbean multi-centre study of Klebsiella pneumoniae: whole-genome sequencing, antimicrobial resistance and virulence factors.
The surveillance of antimicrobial-resistant isolates has proven to be one of the most valuable tools to understand the global rise of multidrug-resistant bacterial pathogens. We report the first insights into the current situation in the Caribbean, where a pilot project to monitor antimicrobial resistance (AMR) through phenotypic resistance measurements combined with whole-genome sequencing was set up in collaboration with the Caribbean Public Health Agency (CARPHA). Our first study focused on Klebsiella pneumoniae, a highly relevant organism amongst the Gram-negative opportunistic pathogens worldwide causing hospital- and community-acquired infections. Our results show that not only carbapenem resistance, but also hypervirulent strains, are circulating in patients in the Caribbean. Our current data does not allow us to infer their prevalence in the population. We argue for the urgent need to further support AMR surveillance and stewardship in this almost uncharted territory, which can make a significant impact on the reduction of antimicrobial usage. This article contains data hosted by Microreact (https://microreact.org).


Binding of metal ions to polysaccharides. V. Potentiometric, spectroscopic, and viscosimetric studies of the binding of cations to chondroitin sulfate and chondroitin in neutral and acidic aqueous media.
Binding of cations to chondroitin sulfate A and C, chondroitin, and D-glucuronate was investigated in neutral and acidic aqueous media using H+, Cu2+, and Na+ ion-specific electrodes, viscometry, electron spin resonance (esr), and ligand-field spectroscopy. Site binding to the carboxylate group and only electrostatic interaction with the sulfate group could describe the results well. The nitrogen atom of the N-acetyl group appeared not to be involved in bonding of cations to chondroitin(sulfate) systems. The interaction of the divalent metal ions follows the Irving-Williams series. The value of the electrostatic potential at the carboxylate group of chondroitin(sulfate), as experienced by a cation, was determined in dependence of cation bonding. It proved to be difficult to establish the composition of a complex of a metal ion with a polyion by means of a molar ratio curve.


Breast cancer risk among Finnish cabin attendants: a nested case-control study.
Earlier studies have found increased breast cancer risk among female cabin crew. This has been suggested to reflect lifestyle factors (for example, age at first birth), other confounding factors (for example, age at menarche), or occupational factors such as exposure to cosmic radiation and circadian rhythm alterations due to repeated jet lag. To assess the contribution of occupational versus lifestyle and other factors to breast cancer risk among cabin attendants in Finland. A standardised self-administered questionnaire on demographic, occupational, and lifestyle factors was given to 1041 cabin attendants. A total of 27 breast cancer cases and 517 non-cases completed the questionnaire. Breast cancer diagnoses were confirmed through the Finnish Cancer Registry. Exposure to cosmic radiation was estimated based on self-reported flight history and timetables. A conditional logistic regression model was used for analysis. In the univariate analysis, family history of breast cancer (OR = 2.67, 95% CI: 1.00 to 7.08) was the strongest determinant of breast cancer. Of occupational exposures, sleep rhythm disruptions (OR = 1.72, 95% CI: 0.70 to 4.27) were positively related and disruption of menstrual cycles (OR = 0.71, 95% CI: 0.26 to 1.96) negatively related to breast cancer. However, both associations were statistically non-significant. Cumulative radiation dose (OR = 0.99, 95% CI: 0.83 to 1.19) showed no effect on breast cancer. Results suggest that breast cancer risk among Finnish cabin attendants is related to well established risk factors of breast cancer, such as family history of breast cancer. There was no clear evidence that the three occupational factors studied affected breast cancer risk among Finnish flight attendants.


Tobacco use among school personnel in Orissa.
Tobacco use prevalence, knowledge and attitude was assessed among school personnel in Orissa. A single cluster sample design with probability proportional to the enrolment in grades VIII-X was used. Statistical analysis was clone using SUDAAN and the C-sample procedure in Epi-Info. The school response rate was 100%. Over 72% of school personals participated in the survey, the proportion of men being 84%. Current cigarette smoking, bidi smoking and smokeless tobacco use was reported by 26.8%, 30.1% and 38.8% school personnel respectively. Current daily cigarette smoking, bidi smoking and smokeless tobacco use reported by 18.3%, 16.6% and 24.2% school personnel respectively. Men reported significantly more all kinds of daily tobacco use as compared to women. School tobacco control policy on three scales was reported poor (25-39%). However most of the school personnel felt need for such policies (88-98%). Teaching and training on tobacco was reported low (22.7%-35.9%). Most of the school personnel (87-95%) were supportive on different measures on tobacco control issues. Introduction of comprehensive school policies and enforcement on tobacco use may help to reduce adolescent and school personnel tobacco use.


A novel anticancer property of Lycium barbarum polysaccharide in triggering ferroptosis of breast cancer cells.
Breast cancer is one of the most malignant tumors and is associated with high mortality rates among women. Lycium barbarum polysaccharide (LBP) is an extract from the fruits of the traditional Chinese herb, L. barbarum. LBP is a promising anticancer drug, due to its high activity and low toxicity. Although it has anticancer properties, its mechanisms of action have not been fully established. Ferroptosis, which is a novel anticancer strategy, is a cell death mechanism that relies on iron-dependent lipid reactive oxygen species (ROS) accumulation. In this study, human breast cancer cells (Michigan Cancer Foundation-7 (MCF-7) and MD Anderson-Metastatic Breast-231 (MDA-MB-231)) were treated with LBP. LBP inhibited their viability and proliferation in association with high levels of ferroptosis. Therefore, we aimed to ascertain whether LBP reduced cell viability through ferroptosis. We found that the structure and function of mitochondria, lipid peroxidation, and expression of solute carrier family 7 member 11 (SLC7A11, also known as xCT, the light-chain subunit of cystine/glutamate antiporter system Xc-) and glutathione peroxidase 4 (GPX4) were altered by LBP. Moreover, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), rescued LBP-induced ferroptosis-associated events including reduced cell viability and glutathione (GSH) production, accumulation of intracellular free divalent iron ions and malondialdehyde (MDA), and down-regulation of the expression of xCT and GPX4. Erastin (xCT inhibitor) and RSL3 (GPX4 inhibitor) inhibited the expression of xCT and GPX4, respectively, which was lower after the co-treatment of LBP with Erastin and RSL3. These results suggest that LBP effectively prevents breast cancer cell proliferation and promotes ferroptosis via the xCT/GPX4 pathway. Therefore, LBP exhibits novel anticancer properties by triggering ferroptosis, and may be a potential therapeutic option for breast cancer.


Percutaneous core needle biopsy for small (≤ 10 mm) lung nodules: accurate diagnosis and complication rates.
To evaluate accurate diagnosis and complication rates of percutaneous core needle biopsy (PCNB) with an automated gun for small lung nodules that are 10 mm or less in diameter. Forty-two cases of small lung nodules with diameters ≤ 10 mm (mean diameter, 9 mm) that received a PCNB were included in this study. Imaging guidance was fluoroscopy in 30 cases and computed tomography (CT) in 12 cases. Accurate diagnosis was achieved with the initial PCNB in 88.1% (37/42) of cases. Accurate diagnosis rates were 86.7% (26/30) with fluoroscopic guidance and 91.7% (11/12) with CT guidance (P > 0.05). The complication rate of PCNB was 7.1% (3/42), including hemoptysis (n=2) and pneumothorax (n=1). The complication rate was 6.7% (2/30) with fluoroscopic guidance and 8.3% (1/12) with CT guidance (P > 0.05). CONCLUSION PCNB: with an automated gun is useful for the pathologically conclusive diagnosis of small lung nodules (≤ 10 mm in diameter) using fluoroscopic or CT guidance.


Holliday junction-containing DNA structures persist in cells lacking Sgs1 or Top3 following exposure to DNA damage.
The Sgs1-Rmi1-Top3 "dissolvasome" is required for the maintenance of genome stability and has been implicated in the processing of various types of DNA structures arising during DNA replication. Previous investigations have revealed that unprocessed (X-shaped) homologous recombination repair (HRR) intermediates persist when S-phase is perturbed by using methyl methanesulfonate (MMS) in Saccharomyces cerevisiae cells with impaired Sgs1 or Top3. However, the precise nature of these persistent DNA structures remains poorly characterized. Here, we report that ectopic expression of either of two heterologous and structurally unrelated Holliday junction (HJ) resolvases, Escherichia coli RusA or human GEN1(1-527), promotes the removal of these X-structures in vivo. Moreover, other types of DNA replication intermediates, including stalled replication forks and non-HRR-dependent X-structures, are refractory to RusA or GEN1(1-527), demonstrating specificity of these HJ resolvases for MMS-induced X-structures in vivo. These data suggest that the X-structures persisting in cells with impaired Sgs1 or Top3 contain HJs. Furthermore, we demonstrate that Sgs1 directly promotes X-structure removal, because the persistent structures arising in Sgs1-deficient strains are eliminated when Sgs1 is reactivated in vivo. We propose that HJ resolvases and Sgs1-Top3-Rmi1 comprise two independent processes to deal with HJ-containing DNA intermediates arising during HRR in S-phase.


β-Carotene 15,15'-oxygenase inhibits cancer cell stemness and metastasis by regulating differentiation-related miRNAs in human neuroblastoma.
Neuroblastoma (NB) is the most common pediatric malignancy and is considered to possess cancer stem cells (CSCs) properties which can drive tumor initiation and metastasis. β-carotene 15,15'-oxygenase (BCO1) is the main enzyme that catalyzes the first step in vitamin A biosynthesis from pro-vitamin A carotenoids. Retinoids (vitamin A) play a critical role in NB differentiation. However, the biological functions of BCO1 in NB remained to be elucidated. Here, we investigated the effects of BCO1 on NB CSCs with stably expressing BCO1 in NB cells. We show that BCO1 significantly suppressed self-renewal and markers of NB CSCs. Moreover, BCO1 inhibited the metastatic potential of NB cells and suppressed the enzymatic activity and expression of MMPs, as well as expression of HIF-1α and its downstream targets. In vivo, BCO1 reduced the metastatic incidence and volumes of metastatic tumors and downregulated the expression of CSCs markers, MMPs, and HIF-1α in tumor tissues of a mouse xenograft model. A possible mechanism underlying the anti-cancer activities of BCO1 is proposed based on miRNAs sequencing array data which suggests a role for BCO1 in regulating miRNAs associated with neuronal differentiation, cell-cell adhesion, and the Wnt signaling pathway. Thus, our results demonstrate new chemotherapeutic roles for BCO1 in malignant NB that mediate suppression of cancer stemness and metastasis.


Methanol oxidation on Fe2O3 catalysts and the effects of surface Mo.
The adsorption of methanol on haematite has been investigated using temperature programmed methods, combined with in situ DRIFTS. Model catalysts based on this material have then been made with a shell-core configuration of molybdenum oxide monolayers on top of the haematite core. These are used as models of industrial iron molybdate catalysts, used to selectively oxidise methanol to formaldehyde, one of the major chemical outlets for methanol. Haematite itself is completely ineffective in this respect since it oxidises it to CO2 and the DRIFTS shows that this occurs by oxidation of methoxy to formate at around 200 °C. The decomposition behaviour is affected by the absence or presence of oxygen in the gas phase; oxygen destabilises the methoxy and enhances formate production. In contrast, when a monolayer of molybdena is placed onto the surface by incipient wetness, and it remains there after calcination, the pathway to formate production is blocked and formaldehyde is the main gas phase product in TPD after methanol dosing.


Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure-Activity Analysis.
The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure-activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site's preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulky tert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model.


[Foamy carcinoma of the prostate].
We report the first case of prostatic foamy gland carcinoma in the Spanish literature. Case of a 69-year-old male who consulted for PSA elevation up to 101 ng/ml. Transrectal ultrasound showed a heterogeneous gland with a hipoechogenic area in the right lobe and possible capsular disruption. Six ultrasound guided needle biopsies were performed. The samples from the right lobe were reported as Gleason 6 foamy cell prostatic adenocarcinoma. Prostatic foamy cell carcinoma is a rare tumor, and so are its bibliographic references. Its cells lack of prominent nucleus and nucleoli. They show a plentiful and xanthomatous cytoplasm, with abundant intracytoplasmic pink secretions characteristically. It may be mistaken with low grade adenocarcinomas, and it is essential to differentiate it from the clear cell prostatic adenocarcinoma, prostatic adenosis, and even from benign prostatic hyperplasia. It usually has an intermediate grade, with a Gleason score greater than 4.


Effects of maternal bisphenol A diglycidyl ether exposure during gestation and lactation on behavior and brain development of the offspring.
Bisphenol A diglycidyl ether (BADGE) is an epoxy resin used for the inner coating of canned food and beverages. BADGE can easily migrate from the containers and become a contaminant. In this study, we examined the effects of BADGE exposure to the dams on the behavioral, structural, and developmental abnormalities in the offspring. Female pregnant mice were fed with a diet containing BADGE (0.15 or 1.5 mg/kg/day) during gestation and lactation periods. In an open field test, the time spent in the corner area significantly increases in male mice of high-dose BADGE group at 5 weeks old. The histological analysis using offspring brain at postnatal day 1 delivered from BADGE (1.5 mg/kg/day)-treated dams demonstrates that positive signals of Forkhead box P2- and COUP-TF interacting protein 2 are restricted in each cortical layer, but not in the control brain. In addition, the maternal BADGE exposure reduces nestin-positive fibers of the radial glia and T-box transcription factor 2-positive intermediate progenitors in the inner subventricular zone. Furthermore, a direct BADGE exposure promotes neurite outgrowth and neuronal connection in the primary cultured cortical neurons. These data suggest that maternal BADGE exposure can accelerate neuronal differentiation in fetuses and induce anxiety-like behavior in juvenile mice.


BRAF(V600E) mutation and the biology of papillary thyroid cancer.
BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.


The Relation Between Variability of Intact Parathyroid Hormone, Calcium, and Cardiac Mortality in Hemodialysis Patients.
Chronic kidney disease-mineral and bone disorder (CKD-BMD) is a condition known to be associated with cardiovascular disease and mortality in hemodialysis (HD) patients. The relation between calcium (Ca), phosphorus (P), and intact parathyroid hormone (iPTH) variability in HD patients and cardiac mortality is unknown. The purpose of this study was to assess the relation between variability in these parameters and cardiac mortality. Baseline demographic and biochemical parameters of 218 HD patients together with Ca values corrected with albumin and P values measured on a monthly basis and iPTH levels measured at 3-monthly intervals were recorded over 2 years. Standard deviation (SD) and smoothness index (SI) for each parameter were calculated to assess Ca, P, and iPTH variability. The relations between all parameters and cardiac mortality were then analyzed. Cardiac mortality was observed in 38 patients in the 2-year study period. Nonsurviving patients' ages, systolic and diastolic blood pressure (DBP), high sensitivity C-reactive protein (HsCRP) levels, mean iPTH, and SD iPTH were significantly higher than those of surviving patients, while albumin levels, SI iPTH and SI Ca were significantly lower. Age, low albumin, high DBP, SI iPTH, and SI Ca were identified as independent predictors of cardiac mortality at multivariate analysis. Our study shows that Ca and iPTH variability affect cardiac mortality independently of mean and baseline values. When supported by further studies, the relation between Ca and iPTH variability and cardiac mortality in HD patients can lead to a new perspective in terms of prognosis and treatment planning.


An aminophospholipid translocase associated with body fat and type 2 diabetes phenotypes.
We have shown that a region on proximal mouse chromosome 7, near the pink-eyed (p) dilution locus, contains an ATPase (pfatp), a putative aminophospholipid translocase. Studies have suggested that this gene is a prime candidate for modulating body fat or involved in lipid metabolism in mouse and humans. Toward further analyses, our objective was to generate the complete genomic structures of mouse and human genes. The genomic structure of mouse pfatp was deduced by comparing the full-length cDNA sequence with the genomic sequence derived from a mouse BAC. The human ortholog was identified from the National Center for Biotechnology Information database. Full-length cDNA was generated, and the corresponding genomic structure was deduced from the Human Genome Database. Murine pfatp, and its human ortholog, PFATP, belong to class V of the third subfamily of P-type ATPases. The gene organization is strikingly similar in both organisms and all exon-intron junctions are conserved. A putative promoter region of PFATP contains a strong CpG island. The 5' untranslated regions of the two cDNAs have potential binding sites for multiple transcription factors, including Sp1, USF, AP1, and AP2, involved in adipogenesis and adipocyte metabolism. We report the generation of the complete genomic structure of a novel aminophospholipid translocase in mice and humans. Because the exact biological role and the subsequent relevance of these ATPases to obesity and diabetes are unknown, these data help to delineate the role of these genes in lipid/adipocyte metabolism.


Competition and Caries on Enamel of a Dual-Species Biofilm Model with Streptococcus mutans and Streptococcus sanguinis.
Imbalances within the dental biofilm trigger dental caries, currently considered a dysbiosis and the most prevalent noncommunicable disease. There is still a gap in knowledge about the dynamics of enamel colonization by bacteria from the dental biofilm in caries. The aim, therefore, was to test whether the sequence of enamel colonization by a typically commensal and a cariogenic species modifies biofilm's cariogenicity. Dual-species biofilms of Streptococcus mutans and Streptococcus sanguinis on saliva-coated enamel slabs were inoculated in different sequences: S. mutans followed by S. sanguinis (Sm-Ss), S. sanguinis followed by S. mutans (Ss-Sm), S. mutans and S. sanguinis inoculated at the same time (Sm=Ss), and the single-species controls S. mutans followed by S. mutans (Sm-Sm) and S. sanguinis followed by S. sanguinis (Ss-Ss). Biofilms were exposed to 10% sucrose 3 times per day for 5 days, and the slabs/biofilms were retrieved to assess demineralization, viable cells, biomass, proteins, polysaccharides, and H2O2 production. Compared with Sm-Sm, primary inoculation with S. sanguinis reduced demineralization (P < 0.05). Both Ss-Sm and Sm=Ss sequences showed reduction in biomass, protein, and polysaccharide content (P < 0.05). The highest S. sanguinis viable count and H2O2 production level and the lowest acidogenicity were observed when S. sanguinis colonized enamel before S. mutans (P < 0.05). Initial enamel adherence with commensal biofilms seems to induce more intense competition against more typically cariogenic species, reducing cariogenicity.IMPORTANCE The concept of caries as an ecological disease implies the understanding of the intricate relationships among the populating microorganisms. Under frequent sugar exposure, some bacteria from the dental biofilm develop pathogenic traits that lead to imbalances (dysbiosis). Depending on which microorganism colonizes the dental surface first, different competition strategies may be developed. Studying the interactions in the entire dental biofilm is not an easy task. In this study, therefore, we modeled the interplay among these microorganisms using a caries-inducing species (S. mutans) and a health-associated species (S. sanguinis). Initial enamel adherence with S. sanguinis seems to induce more intense competition against typically caries-inducing species. Besides continuous exposure with sugars, early colonization of the enamel by highly cariogenic species like S. mutans appears to be needed to develop caries lesions as well. Promoting early colonization by health-associated bacteria such as S. sanguinis could help to maintain oral health, delaying dysbiosis.


Therapeutic efficacy of 188Re-liposome in a C26 murine colon carcinoma solid tumor model.
Nanoliposomes are good drug delivery systems that allow the encapsulation of drugs into vesicles for their delivery. The objective of this study is to investigate the therapeutic efficacy of a new radio-therapeutics of (188)Re-labeled pegylated liposome in a C26 murine colon carcinoma solid tumor model. The safety of (188)Re-liposome was evaluated before radiotherapy treatment. The anti-tumor effect of (188)Re-liposome was assessed by tumor growth inhibition, survival ratio and ultrasound imaging. Apoptotic marker in tumor was also evaluated by the TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) method after injection of (188)Re-liposome. The group treated with (188)Re-liposome displayed slight loss in body weight and decrease in white blood cell (WBC) count 7 to 14 days post-injection. With respect to therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI = 0.140; 80 day) than those treated with anti-cancer drug 5-FU (MGI = 0.195; 69 day) and untreated control mice (MGI = 0.413; 48 day). The ultrasound imaging showed a decrease in both tumor volume and number of blood vessels. There were significantly more apoptotic nuclei (TUNEL-positive) in (188)Re-liposome-treated mice at 8 h after treatment than in control mice. These results evidenced the potential benefits achieved by oncological application of the radio-therapeutics (188)Re-liposome for adjuvant cancer treatment.


[The systematic position of mites of the genus Larinyssus Strandtmann (Gamasoidea, Rhinonyssidae), parasitizing gulls].
A study was carried out of the variability of mited colledted from 6 species of birds as follows: Larus argentatus Pontopp., L. minutus Pall., Gelochelidon nilotica Gm., Chlidonias leucoptera (Temm.), Ch. nigra (L.) and Sterna hirundo L. Structural peculiarities characteristic of the parasites of the above species have been revealed. The mites from St. hirundo were isolated into a distinct species, Larinyssus substerna sp. n., which is most close to L. sterna Fain, 1972. The new species differs from L. sterna in a smaller size of gnathosoma and chelicerae, lesser number of hypostomal setae and the presence of pigidial shields.


Spatial memory impairment and changes in hippocampal morphology are triggered by high-fat diets in adolescent mice. Is there a role of leptin?
Recent evidence has established that consumption of high-fat diets (HFD) is associated with deficits in hippocampus-dependent memory. Adolescence is an important period for shaping learning and memory acquisition that could be particularly sensitive to the detrimental effects of HFD. In the current study we have administered this kind of diets to both adolescent (5-week old) and young adult (8-week old) male C57BL mice during 8 weeks and we have evaluated its effect on (i) spatial memory performance in the novel location recognition (NLR) paradigm, and (ii) spine density and neural cell adhesion molecule (NCAM) expression in hippocampal CA1 pyramidal neurons. In order to characterize the eventual involvement of central leptin receptors we have also investigated the functionality of leptin receptors within the hippocampus. Here we report that animals that started to consume HFD during the adolescence were less efficient than their control counterparts in performing spatial memory tasks. In contrast to that, mice that were submitted to HFD during the young adult period displayed intact performance in the NLR test. In mice receiving HFD from the adolescence, the behavioral impairment was accompanied by an increase of dendritic spine density in CA1 pyramidal neurons that correlated with the up-regulation of neural cell adhesion molecule (NCAM) in this area. Deficits in spatial memory occurred concomitantly with a desensitization of the proteinkinase B (Akt) pathway coupled to hippocampal leptin receptors. In contrast, the STAT3 pathway remained unaffected by HFD. All effects of HFD were long-lasting because they remained intact even after 5 weeks of food restriction. Our results provide further evidence of the susceptibility of the hippocampus to HFD in adolescent individuals and suggest that leptin signaling integrity in this brain area is pivotal for memory performance.


Responsiveness of ventrobasal thalamic neurons after suppression of S1 cortex in the anesthetized rat.
Corticofugal influences on the responses of ventrobasal (VB) thalamic neurons to repetitive stimuli were studied in anesthetized rats by suppressing primary somatosensory (S1) electrocortical activity with topically applied lidocaine. Effective concentrations of lidocaine were confined to S1 and immediately adjacent cortex and suppressed evoked S1 responses and corticofugal discharges. Suppression of S1 cortex reduced the average number of spikes discharged by 83 VB neurons in response to each of 25 electrical somatic stimuli delivered at frequencies ranging from 1 to 50 Hz. Of 20 units studied both before and after S1 suppression, 14 (70%) showed a similar reduced response to repetitive stimuli. Cortical suppression produced no consistent changes in spontaneous activity, somatic stimulus threshold, response latency, or size of receptive field. There was no significant difference in the effect of cortical suppression on the responsiveness of 8 VB neurons to repetitive medial lemniscal, as compared to somatic, stimuli. We conclude that, in the anesthetized rat, S1 corticofugal activity facilitates somato-sensory transmission to VB neurons and that this facilitation is mediated, at least in part, by corticothalamic neurons.


Supraventricular Tachycardia Associated With Severe Anemia.
We present the unusual case of a 7-year-old girl with severe iron-deficiency anemia who concurrently was determined to be in a supraventricular tachycardia (SVT) rhythm. To our knowledge, the association of anemia with SVT has not been reported previously. We review the presentation of SVT, management strategies for treating both severe anemia and SVT, risks and benefits of using the classic treatments for SVT in a severely anemic patient and discuss iron-deficiency anemia-related cardiac disease.


Airway Remodeling Factors During Early-Life Rhinovirus Infection and the Effect of Premature Birth.
Background: Early rhinovirus (RV) infection is a strong risk factor for asthma development. Airway remodeling factors play a key role in the progression of the asthmatic condition. We hypothesized that RV infection in young children elicits the secretion of growth factors implicated in airway remodeling and asthma progression. Methods: We examined the nasal airway production of remodeling factors in children ( ≤ 2 years old) hospitalized due to PCR-confirmed RV infection. Airway remodeling proteins included: MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, TIMP-2, EGF, Angiopoietin-2, G-CSF, BMP-9, Endoglin, Endothelin-1, Leptin, FGF-1, Follistatin, HGF, HB-EGF, PLGF, VEGF-A, VEGF-C, VEGF-D, FGF-2, TGF-β1, TGF-β2, TGF-β3, PDGF AA, PDGF BB, SPARC, Periostin, OPN, and TGF-α. Results: A total of 43 young children comprising RV cases (n = 26) and uninfected controls (n = 17) were included. Early RV infection was linked to (1) enhanced production of several remodeling factors (e.g., HGF, TGFα), (2) lower MMP-9/TIMP-2 and MMP-2/TIMP-2 ratios, and (3) increased MMP-10/TIMP-1 ratios. We also found that relative to term infants, severely premature children had reduced MMP-9/TIMP-2 ratios at baseline. Conclusion: RV infection in young children elicits the airway secretion of growth factors implicated in angiogenesis, fibrosis, and extracellular matrix deposition. Our results highlight the potential of investigating virus-induced airway remodeling growth factors during early infancy to monitor and potentially prevent chronic progression of respiratory disorders in all ages.


Frontostriatal grey matter atrophy in amyotrophic lateral sclerosis A visual rating study.
Amyotrophic lateral sclerosis (ALS) is characterised by frontostriatal grey matter changes similar to those in frontotemporal dementia (FTD). However, these changes are usually detected at a group level, and simple visual magnetic resonance imaging (MRI) cortical atrophy scales may further elucidate frontostriatal changes in ALS. To investigate whether frontostriatal changes are detectable using simple visual MRI atrophy rating scales applied at an individual patient level in ALS. 21 ALS patients and 17 controls were recruited and underwent an MRI scan. Prefrontal cortex sub-regions of the medial orbitofrontal cortex (MOFC), lateral orbitofrontal cortex (LOFC) and anterior cingulate cortex (ACC), striatal sub-regions of the caudate nucleus (CN) and nucleus accumbens (NAcc) were rated using visual grey matter atrophy 5-point Likert scales. Significantly higher atrophy ratings in the bilateral MOFC only in ALS patients versus controls was observed (p<.05). Patients with greater MOFC atrophy had significantly higher atrophy of the CN (p<.05) and LOFC (p<.05). Use of simple visual atrophy rating scales on an individual level reliably detects frontostriatal deficits specific to ALS, showing MOFC atrophy differences with associated CN and LOFC atrophy. This is an applicable method that could be used to support clinical diagnosis and management.


Preoperative Cognitive Performance Dominates Risk for Delirium Among Older Adults.
Cognitive impairment is a well-recognized risk factor for delirium. Our goal was to determine whether the level of cognitive performance across the nondemented cognitive ability spectrum is correlated with delirium risk and to gauge the importance of cognition relative to other known risk factors for delirium. The Successful Aging after Elective Surgery study enrolled 566 adults aged ≥70 years scheduled for major surgery. Patients were assessed preoperatively and daily during hospitalization for the occurrence of delirium using the Confusion Assessment Method. Cognitive function was assessed preoperatively with an 11-test neuropsychological battery combined into a composite score for general cognitive performance (GCP). We examined the risk for delirium attributable to GCP, as well as demographic factors, vocabulary ability, and informant-rated cognitive decline, and compared the strength of association with risk factors identified in a previously published delirium prediction rule for delirium. Delirium occurred in 135 (24%) patients. Lower GCP score was strongly and linearly predictive of delirium risk (relative risk = 2.0 per each half standard deviation difference in GCP score, 95% confidence interval, 1.5-2.5). This effect was not attenuated by statistical adjustment for demographics, vocabulary ability, and informant-rated cognitive decline. The effect was stronger than, and largely independent from, both standard delirium risk factors and comorbidity. Risk of delirium is linearly and strongly related to presurgical cognitive performance level even at levels above the population median, which would be considered unimpaired.


Effects of the Family Bereavement Program on academic outcomes, educational expectations and job aspirations 6 years later: the mediating role of parenting and youth mental health problems.
Experiencing the death of a parent during childhood is associated with a variety of difficulties, including lower academic achievement, that have implications for functioning in childhood and adulthood. This study examines effects of the Family Bereavement Program (FBP), a preventive intervention for parentally-bereaved youth and their caregivers, on grade point averages (GPA), educational expectations and job aspirations of youths 6 years after the intervention. A total of 244 bereaved youths ages 8-16 and their caregivers were randomized to either the FBP or a comparison group that received books about bereavement. Assessments occurred at pretest, post-test, and 11-month and 6-year follow-ups. Direct program effects on educational outcomes and job aspirations 6 years later were non-significant, although the program improved educational expectations for children with fewer behavior problems at program entry, and GPA for younger children. Mediational pathways for program effects on educational outcomes were also tested. Program-induced improvements in effective parenting at 11-month follow-up were associated with higher GPAs at 6-year follow-up for youth who were younger or for whom more time had passed since the loss. Program-induced improvements in parenting and teacher-rated youth mental health problems at the 6-year follow-up mediated program effects on youths' educational expectations for those with fewer behavior problems at program entry. The implications of these findings for understanding processes related to academic and educational outcomes following the death of a parent and for prevention efforts to help bereaved and other high-risk children succeed in school are discussed.


Intravenous sildenafil in right ventricular dysfunction with pulmonary hypertension following a heart transplant.
The objective of the present work is to describe the experience with intravenous (IV) sildenafil in heart transplant (HT) patients with reactive pulmonary hypertension (PH) who developed right ventricular dysfunction (RVD) in the immediate postoperative period. The first 5 patients who received IV sildenafil followinga HT are presented. The HTs took place between March 2011 and September 2012 in patients aged 37 to 64 years; all patients were male. Prior to the HT, mean pulmonary artery pressure (mPAP) was 32-56 mmHg. In all cases, the hemodynamic study demonstrated PH reactivity (positive vasodilator test with nitric oxide). All 5 patients developed RVD with hemodynamic instability immediately after the HT, despite the administration of nitric oxide from the time of intubation prior to the implant, optimal medical treatment in all cases, and a ventricular assist in 2 cases. In all patients, IV sildenafil was initiated at 10 mg/8 h for 48 h and was subsequently increased to 20 mg/8 h. in its oral formulation until discharge from the hospital. The change in pulmonary pressure was assessed using a Swan-Ganz catheter. Ventricular function was assessed using echocardiography. Length of stay in the Resuscitation Unit and mid-term survival were also assessed. Average time of extracorporeal circulation was 200 ± 110 min and organ ischemic time was 210 ± 95 min. All of the patients demonstrated pulmonary and systemic hemodynamic improvement, as well as recovery of right ventricular function after completing the treatment with IV sildenafil. The stay in the Resuscitation Unit lasted 3-25 days. All the patients were discharged from hospital with no mortality to date. Intravenous sildenafil improves right ventricle hemodynamics associated with pulmonary hypertension post-HT. Prophylactic prevention with this drug could be indicated for patients with reactive PH who are about to receive a transplant.


Neurodevelopmental assessment of children with congenital heart diseases using Trivandrum developmental screening chart.
Congenital heart diseases (CHDs) are one of the most important congenital anomalies in children which have high-risk for neurodevelopment delay. This study was conducted to determine the proportion of developmental delay in children with CHD and comparison of delay between acyanotic and cyanotic heart diseases in children. A cross-sectional study was conducted on children admitted in pediatric ward of rural hospital from 6 month to 6 years of age who are diagnosed with CHD by 2D ECHO and further classified into acyanotic congenital heart disease (ACHD) and cyanotic congenital heart disease (CCHD). Neurodevelopmental assessment was done using Trivandrum development screening chart (TDSC). Out of total 50 children in study population, 24 children had TDSC delay, distribution as 11 (22%) ACHD and 13 (26%) CCHD. Out of 24 children in the age group of 0-3 years, 13 (54.2%) were ACHD and 11 (45.8%) were CCHD. Out of 26 children in the age group of 3-6 years, 15 (57.7%) were ACHD and 11 (42.3%) were CCHD. Among different ACHD included in the study population (0-3 years) children with ventricular septal defect (VSD) were maximum (n = 5) next in the decreasing order was atrial septal defect (ASD) (n = 3). ACHD included in the study population (3-6 years) children with VSD was maximum (n = 6) next in the order was ASD (n = 4). Proportion of delay in children with ACHD was 22% as compared to 26% in children with CCHD. There is a high proportion of neurodevelopmental delay in children with CHD which can be detected using TDSC which is a simple screening tool and can be used by any health-care professional without training for the assessment of neurodevelopmental outcome in these children. Delay was more in children with CCHD than ACHD.


Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora.
The soy isoflavones, daidzein and genistein, and the lignans, matairesinol and secoisolariciresinol, are phytoestrogens metabolized extensively by the intestinal microflora. Considerable important evidence is already available that shows extensive interindividual variation in isoflavone metabolism, and we have investigated the extent of this variation in a crossover study of a soy-containing food low or high in isoflavones (each treatment period lasted for 17 days, and the 2 treatment periods were separated by a 25-day washout period) in 24 healthy subjects [19 women and 5 men, mean age 30 yr, range 19-40, mean body mass index 22.5 +/- 3.5 (SD) kg/m2]. There was a 16-fold variation in total isoflavonoid excretion in urine after the high-isoflavone treatment period. The variation in urinary equol excretion was greatest (664-fold), and subjects fell into two groups: poor equol excretors and good equol excretors (36%). A significant negative correlation was found between the proportion of energy from fat in the habitual diet and urinary equol excretion (r = -0.55; p = 0.012). Good equol excretors consumed less fat as percentage of energy than poor excretors (26 +/- 2.3% compared with 35 +/- 1.6%, p < 0.01) and more carbohydrate as percentage of energy than poor excretors (55 +/- 2.9% compared with 47 +/- 1.7%, p < 0.05). Interindividual variation in the urinary excretion of O-desmethyl-angolensin (O-DMA) was also apparent (76-fold after the high-isoflavone treatment period), but there was no relationship between equol excretion and O-DMA excretion. Enterolactone was the major lignan metabolite in urine and plasma but showed less interindividual variation than equol and O-DMA. It is suggested that the dietary fat intake decreases the capacity of gut microbial flora to synthesize equol.


Characterizing "blue blobs". Immunohistochemical staining and ultrastructural study.
To investigate the nature and origin of "blue blobs" (Bbs) in atrophic Pap smears in postmenopausal women and to study their clinical significance. A retrospective study of 412 atrophic Pap smears from postmenopausal women was done to detect the presence of Bbs. The smears from 24 cases showing Bbs were further studied to evaluate the nature of the Bbs with special stains, immunohistochemistry and electron microscopy. Bbs showed a heterogeneous morphology, with variable numbers and staining intensity. The diameter of Bbs was approximately equivalent to that of a parabasal/intermediate squamous cell. Special stains showed Bbs to be positive for periodic acid-Schiff and methyl green pyronin and negative for mucicarmine and calcium. Immunohistochemistry revealed Bbs to be positive for cytokeratin, epithelial membrane antigen and carcinoembryonic antigen and negative for vimentin and muscle-specific actin. Some Bbs had residual ghost nuclear shadows. Electron microscopy revealed cellular skeletons with residual tonofilaments enmeshed within a loose cytoskeleton matrix and nuclei with variable degrees of degeneration. Special stains, immunohistochemistry and electron microscopy indicated that Bbs represent parabasal/intermediate squamous cells exhibiting various degree of degeneration. In general, Bbs appear to be of no clinical significance except as a source of potential diagnostic error.


An adaptable implementation package targeting evidence-based indicators in primary care: A pragmatic cluster-randomised evaluation.
In primary care, multiple priorities and system pressures make closing the gap between evidence and practice challenging. Most implementation studies focus on single conditions, limiting generalisability. We compared an adaptable implementation package against an implementation control and assessed effects on adherence to four different evidence-based quality indicators. We undertook two parallel, pragmatic cluster-randomised trials using balanced incomplete block designs in general practices in West Yorkshire, England. We used 'opt-out' recruitment, and we randomly assigned practices that did not opt out to an implementation package targeting either diabetes control or risky prescribing (Trial 1); or blood pressure (BP) control or anticoagulation in atrial fibrillation (AF) (Trial 2). Within trials, each arm acted as the implementation control comparison for the other targeted indicator. For example, practices assigned to the diabetes control package acted as the comparison for practices assigned to the risky prescribing package. The implementation package embedded behaviour change techniques within audit and feedback, educational outreach, and computerised support, with content tailored to each indicator. Respective patient-level primary endpoints at 11 months comprised the following: achievement of all recommended levels of haemoglobin A1c (HbA1c), BP, and cholesterol; risky prescribing levels; achievement of recommended BP; and anticoagulation prescribing. Between February and March 2015, we recruited 144 general practices collectively serving over 1 million patients. We stratified computer-generated randomisation by area, list size, and pre-intervention outcome achievement. In April 2015, we randomised 80 practices to Trial 1 (40 per arm) and 64 to Trial 2 (32 per arm). Practices and trial personnel were not blind to allocation. Two practices were lost to follow-up but provided some outcome data. We analysed the intention-to-treat (ITT) population, adjusted for potential confounders at patient level (sex, age) and practice level (list size, locality, pre-intervention achievement against primary outcomes, total quality scores, and levels of patient co-morbidity), and analysed cost-effectiveness. The implementation package reduced risky prescribing (odds ratio [OR] 0.82; 97.5% confidence interval [CI] 0.67-0.99, p = 0.017) with an incremental cost-effectiveness ratio of £1,359 per quality-adjusted life year (QALY), but there was insufficient evidence of effect on other primary endpoints (diabetes control OR 1.03, 97.5% CI 0.89-1.18, p = 0.693; BP control OR 1.05, 97.5% CI 0.96-1.16, p = 0.215; anticoagulation prescribing OR 0.90, 97.5% CI 0.75-1.09, p = 0.214). No statistically significant effects were observed in any secondary outcome except for reduced co-prescription of aspirin and clopidogrel without gastro-protection in patients aged 65 and over (adjusted OR 0.62; 97.5% CI 0.39-0.99; p = 0.021). Main study limitations concern our inability to make any inferences about the relative effects of individual intervention components, given the multifaceted nature of the implementation package, and that the composite endpoint for diabetes control may have been too challenging to achieve. In this study, we observed that a multifaceted implementation package was clinically and cost-effective for targeting prescribing behaviours within the control of clinicians but not for more complex behaviours that also required patient engagement. The study is registered with the ISRCTN registry (ISRCTN91989345).


Dok-1 and Dok-2 are negative regulators of T cell receptor signaling.
Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein-tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCRzeta, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3(+)CD4(+) T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease.


Inhibition of the binding of 125I-labelled epidermal growth factor to mouse cells by a mitogen in goat mammary secretions.
Pre-colostrum and colostrum from goats cause a marked inhibition of the binding of 125I-labelled epidermal growth factor (125I-EGF) to Swiss 3T3 cells. The ability of these secretions to inhibit 125I-EGF binding is closely correlated with the ability to stimulate DNA synthesis in quiescent 3T3 cell cultures, suggesting that goat mammary secretions may contain an EGF-related mitogen. However, the material in colostrum which inhibits 125I-EGF binding to Swiss 3T3 cells is a basic protein with Mr greater than 20000 and is thus quite different from mouse and human EGF. Furthermore, the colostral-mediated inhibition of 125I-EGF binding, although rapid and apparently competitive, differs from the inhibition of binding induced by native, unlabelled EGF. Thus, the inhibitory effect of colostrum is markedly decreased when the assay temperature is shifted from 37 degrees C to 4 degrees C whereas unlabelled EGF is an effective competitive inhibitor at both 37 degrees C and 4 degrees C. Incubation of cells with EGF causes a reduction in cell surface EGF receptors whereas exposure to colostrum does not induce down-regulation of the EGF receptor. Our results suggest that the colostral factor does not bind directly to EGF receptors but inhibits 125I-EGF binding by an indirect mechanism which involves a temperature-sensitive step.


Motility-dependence of the heterogenous staining of culture cells by a monoclonal anti-tropomyosin antibody.
A monoclonal antibody (CG1) which recognizes tropomyosin isoforms 1 and 3 of chicken embryo fibroblasts was used to detect what is a motility-dependent change in the availability of the antigenic determinant in tropomyosin molecules along microfilaments. Immunofluorescence microscopy with this antibody revealed a heterogenous staining pattern among chicken embryo fibroblasts cells such that a population (17%) of cells showed only background staining. Stress fibers in about half the population of the cells stained weakly with this antibody, while the stress fibers in another population of cells (35%) showed very strong staining. After glycerination or cytochalasin B treatment, all of the cells became positive in reaction to CG1 antibody, suggesting that the antigenic determinant was present in every cell. On the other hand, all of the cells after brief nonionic detergent treatment became negative to CG1 antibody. The CG1 staining pattern was not significantly changed in cells at different stages after release from colcemid blockage, nor was a brief treatment of cells with buffer containing 2 M urea, mild trypsin, chymotrypsin, or V.8 protease effective in changing the reactivity. However, most of the cells with a morphology typical of movement, and all of the contracted, glycerinated cells were strongly positive to CG1 antibody. These results suggest that the unmasking of the CG1 determinant may be motility-dependent. Immunoblot analysis showed that forced modification on the cysteine residue of tropomyosin molecules, caused either by performic acid oxidation or by disulfide cross-linking with the chemical 5,5'-dithiobis (2-nitrobenzoate), results in drastic changes in the reactivity of the different isoforms to CG1 antibody. These results indicate that the cysteine residue is involved in the CG1 determinant. The motility-dependent unmasking of this determinant may suggest an important role for nonmuscle tropomyosin in regulating cell motility.


Does warming by open-top chambers induce change in the root-associated fungal community of the arctic dwarf shrub Cassiope tetragona (Ericaceae)?
Climate change may alter mycorrhizal communities, which impact ecosystem characteristics such as carbon sequestration processes. These impacts occur at a greater magnitude in Arctic ecosystems, where the climate is warming faster than in lower latitudes. Cassiope tetragona (L.) D. Don is an Arctic plant species in the Ericaceae family with a circumpolar range. C. tetragona has been reported to form ericoid mycorrhizal (ErM) as well as ectomycorrhizal (ECM) symbioses. In this study, the fungal taxa present within roots of C. tetragona plants collected from Svalbard were investigated using DNA metabarcoding. In light of ongoing climate change in the Arctic, the effects of artificial warming by open-top chambers (OTCs) on the fungal root community of C. tetragona were evaluated. We detected only a weak effect of warming by OTCs on the root-associated fungal communities that was masked by the spatial variation between sampling sites. The root fungal community of C. tetragona was dominated by fungal groups in the Basidiomycota traditionally classified as either saprotrophic or ECM symbionts, including the orders Sebacinales and Agaricales and the genera Clavaria, Cortinarius, and Mycena. Only a minor proportion of the operational taxonomic units (OTUs) could be annotated as ErM-forming fungi. This indicates that C. tetragona may be forming mycorrhizal symbioses with typically ECM-forming fungi, although no characteristic ECM root tips were observed. Previous studies have indicated that some saprophytic fungi may also be involved in biotrophic associations, but whether the saprotrophic fungi in the roots of C. tetragona are involved in biotrophic associations remains unclear. The need for more experimental and microscopy-based studies to reveal the nature of the fungal associations in C. tetragona roots is emphasized.


Beyond the Activity-Based Anorexia Model: Reinforcing Values of Exercise and Feeding Examined in Stressed Adolescent Male and Female Mice.
Anorexia nervosa (AN), mostly observed in female adolescents, is the most fatal mental illness. Its core is a motivational imbalance between exercise and feeding in favor of the former. The most privileged animal model of AN is the "activity-based anorexia" (ABA) model wherein partly starved rodents housed with running wheels exercise at the expense of feeding. However, the ABA model bears face and construct validity limits, including its inability to specifically assess running motivation and feeding motivation. As infant/adolescent trauma is a precipitating factor in AN, this study first analyzed post-weaning isolation rearing (PWIR) impacts on body weights and wheel-running performances in female mice exposed to an ABA protocol. Next, we studied through operant conditioning protocols i) whether food restriction affects in a sex-dependent manner running motivation before ii) investigating how PWIR and sex affect running and feeding drives under ad libitum fed conditions and food restriction. Besides amplifying ABA-elicited body weight reductions, PWIR stimulated wheel-running activities in anticipation of feeding in female mice, suggesting increased running motivation. To confirm this hypothesis, we used a cued-reward motivated instrumental task wherein wheel-running was conditioned by prior nose poke responses. It was first observed that food restriction increased running motivation in male, but not female, mice. When fed grouped and PWIR mice were tested for their running and palatable feeding drives, all mice, excepted PWIR males, displayed increased nose poke responses for running over feeding. This was true when rewards were proposed alone or within a concurrent test. The increased preference for running over feeding in fed females did not extend to running performances (time, distance) during each rewarded sequence, confirming that motivation for, and performance during, running are independent entities. With food restriction, mice displayed a sex-independent increase in their preference for feeding over running in both group-housed and PWIR conditions. This study shows that the ABA model does not specifically capture running and feeding drives, i.e. components known to be affected in AN.


Cyclodextrin nanosystems in oral drug delivery: A mini review.
Oral delivery of many therapeutic agents remains challenging due to gastric insolubility/poor dissolution, inefficient intestinal permeability and pre-systemic inactivation. These problems limit the advantages of convenience and increased compliance they provide in the therapy of many chronic diseases. Cyclodextrin nanosystems have emerged as promising platforms for drug-specific construction of the oral delivery nanosystems able to optimize the desired physicochemical properties and pharmacokinetic parameters; without a compromise on safety. This review focuses on some recent and encouraging advances in the application of cyclodextrin nanosystems for oral drug delivery. A general overview of cyclodextrins and pharmaceutical nanotechnology in oral delivery systems is provided. Some of the strategies being exploited for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal tract for optimal bioavailability and biodistribution are then illustrated. Perspectives for translating these nanosystems from laboratory efficient formulations to clinically useful medicines are also discussed.


Prevalence of coeliac disease in Turner syndrome.
This study was undertaken to investigate the prevalence of coeliac disease in children and adolescents with Turner syndrome. Eighty-seven children and adolescents with Turner syndrome were screened for IgA-antiendomysium antibodies (EMA) and IgA-antigliadin antibodies (AGA), 5% (4/87) being found to be EMA-positive, and 15% (13/87) to have AGA levels above normal. Of the 10 patients who were either AGA- or EMA-positive and further investigated with intestinal biopsy, four manifested villous atrophy (i.e. all three of the EMA-positive patients, but only one of the seven AGA-positive patients). The results suggest EMA-positivity to be a good immunological marker for use in screening for coeliac disease, and such screening to be justified in patients with Turner syndrome.