Psychological therapies delivered remotely for the management of chronic pain (excluding headache) in adults.
Chronic pain (pain lasting three months or more) is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Common types (excluding headache) include back pain, fibromyalgia, and neuropathic pain. Access to traditional face-to-face therapies can be restricted by healthcare resources, geography, and cost. Remote technology-based delivery of psychological therapies has the potential to overcome treatment barriers. However, their therapeutic effectiveness compared to traditional delivery methods requires further investigation. To determine the benefits and harms of remotely-delivered psychological therapies compared to active control, waiting list, or treatment as usual for the management of chronic pain in adults. We searched for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, Embase, and PsycINFO to 29 June 2022. We also searched clinical trials registers and reference lists. We conducted a citation search of included trials to identify any further eligible trials. We included RCTs in adults (≥ 18 years old) with chronic pain. Interventions included psychological therapies with recognisable psychotherapeutic content or based on psychological theory. Trials had to have delivered therapy remote from the therapist (e.g. Internet, smartphone application) and involve no more than 30% contact time with a clinician. Comparators included treatment as usual (including waiting-list controls) and active controls (e.g. education). We used standard Cochrane methodological procedures. We included 32 trials (4924 participants) in the analyses. Twenty-five studies delivered cognitive behavioural therapy (CBT) to participants, and seven delivered acceptance and commitment therapy (ACT). Participants had back pain, musculoskeletal pain, opioid-treated chronic pain, mixed chronic pain, hip or knee osteoarthritis, spinal cord injury, fibromyalgia, provoked vestibulodynia, or rheumatoid arthritis. We assessed 25 studies as having an unclear or high risk of bias for selective reporting. However, across studies overall, risk of bias was generally low. We downgraded evidence certainty for primary outcomes for inconsistency, imprecision, and study limitations. Certainty of evidence ranged from moderate to very low. Adverse events were inadequately reported or recorded across studies. We report results only for studies in CBT here. Cognitive behavioural therapy (CBT) versus treatment as usual (TAU) Pain intensity Immediately after treatment, CBT likely demonstrates a small beneficial effect compared to TAU (standardised mean difference (SMD) -0.28, 95% confidence interval (CI) -0.39 to -0.16; 20 studies, 3206 participants; moderate-certainty evidence). Participants receiving CBT are probably more likely to achieve a 30% improvement in pain intensity compared to TAU (23% versus 11%; risk ratio (RR) 2.15, 95% CI 1.62 to 2.85; 5 studies, 1347 participants; moderate-certainty evidence). They may also be more likely to achieve a 50% improvement in pain intensity (6% versus 2%; RR 2.31, 95% CI 1.14 to 4.66; 4 studies, 1229 participants), but the evidence is of low certainty. At follow-up, there is likely little to no difference in pain intensity between CBT and TAU (SMD -0.04, 95% CI -0.17 to 0.09; 8 studies, 959 participants; moderate-certainty evidence). The evidence comparing CBT to TAU on achieving a 30% improvement in pain is very uncertain (40% versus 24%; RR 1.70, 95% CI 0.82 to 3.53; 1 study, 69 participants). No evidence was available regarding a 50% improvement in pain. Functional disability Immediately after treatment, CBT may demonstrate a small beneficial improvement compared to TAU (SMD -0.38, 95% CI -0.53 to -0.22; 14 studies, 2672 participants; low-certainty evidence). At follow-up, there is likely little to no difference between treatments (SMD -0.05, 95% CI -0.23 to 0.14; 3 studies, 461 participants; moderate-certainty evidence). Quality of life Immediately after treatment, CBT may not have resulted in a beneficial effect on quality of life compared to TAU, but the evidence is very uncertain (SMD -0.16, 95% CI -0.43 to 0.11; 7 studies, 1423 participants). There is likely little to no difference between CBT and TAU on quality of life at follow-up (SMD -0.16, 95% CI -0.37 to 0.05; 3 studies, 352 participants; moderate-certainty evidence). Adverse events Immediately after treatment, evidence about the number of people experiencing adverse events is very uncertain (34% in TAU versus 6% in CBT; RR 6.00, 95% CI 2.2 to 16.40; 1 study, 140 participants). No evidence was available at follow-up. Cognitive behavioural therapy (CBT) versus active control Pain intensity Immediately after treatment, CBT likely demonstrates a small beneficial effect compared to active control (SMD -0.28, 95% CI -0.52 to -0.04; 3 studies, 261 participants; moderate-certainty evidence). The evidence at follow-up is very uncertain (mean difference (MD) 0.50, 95% CI -0.30 to 1.30; 1 study, 127 participants). No evidence was available for a 30% or 50% pain intensity improvement. Functional disability Immediately after treatment, there may be little to no difference between CBT and active control on functional disability (SMD -0.26, 95% CI -0.55 to 0.02; 2 studies, 189 participants; low-certainty evidence). The evidence at follow-up is very uncertain (MD 3.40, 95% CI -1.15 to 7.95; 1 study, 127 participants). Quality of life Immediately after treatment, there is likely little to no difference in CBT and active control (SMD -0.22, 95% CI -1.11 to 0.66; 3 studies, 261 participants; moderate-certainty evidence). The evidence at follow-up is very uncertain (MD 0.00, 95% CI -0.06 to 0.06; 1 study, 127 participants). Adverse events Immediately after treatment, the evidence comparing CBT to active control is very uncertain (2% versus 0%; RR 3.23, 95% CI 0.13 to 77.84; 1 study, 135 participants). No evidence was available at follow-up. Currently, evidence about remotely-delivered psychological therapies is largely limited to Internet-based delivery of CBT. We found evidence that remotely-delivered CBT has small benefits for pain intensity (moderate certainty) and functional disability (moderate to low certainty) in adults experiencing chronic pain. Benefits were not maintained at follow-up. Our appraisal of quality of life and adverse events outcomes post-treatment were limited by study numbers, evidence certainty, or both. We found limited research (mostly low to very low certainty) exploring other psychological therapies (i.e. ACT). More high-quality studies are needed to assess the broad translatability of psychological therapies to remote delivery, the different delivery technologies, treatment longevity, comparison with active control, and adverse events.


Host response to fungal infections - how immunology and host genetics could help to identify and treat patients at risk.
In spite of the ever-increasing incidence and poor outcome of invasive fungal infections in immune compromised patients, there is currently no reliable method to accurately predict the risk, to monitor the outcome and to treat these infections. Protective immunity against Candida and Aspergillus depends on a highly coordinated interaction between the innate and adaptive immune systems. Genetic and immunological defects in components of these networks result in increased risk of invasive fungal infections among patients undergoing chemotherapy or transplant recipients. We review the most important genetic and immunological factors that influence human susceptibility to Candida and Aspergillus infections and discuss the potential role of basic research to promote precision medicine for infectious diseases. We discuss how immunogenetic studies can help to provide tools for improved identification of high-risk patients and the development of tailored antifungal therapies.


Purification and catalytic activities of the two domains of the allene oxide synthase-lipoxygenase fusion protein of the coral Plexaura homomalla.
The conversion of fatty acid hydroperoxides to allene epoxides is catalyzed by a cytochrome P450 in plants and, in coral, by a 43-kDa catalase-related hemoprotein fused to the lipoxygenase that synthesizes the 8R-hydroperoxyeicosatetraenoic acid (8R-HPETE) substrate. We have expressed the separate lipoxygenase and allene oxide synthase (AOS) domains of the coral protein in Escherichia coli (BL21 cells) and purified the proteins; this system gives high expression (1.5 and 0.3 micromol/liter, respectively) of catalytically active enzymes. Both domains show fast reaction kinetics. Catalytic activity of the lipoxygenase domain is stimulated 5-fold by high concentrations of monovalent cations (500 mM Na(+), Li(+), or K(+)), and an additional 5-fold by 10 mM Ca(2+). The resulting rates of reaction are approximately 300 turnovers/s, 1-2 orders of magnitude faster than mammalian lipoxygenases. This makes the coral lipoxygenase well suited for partnership with the AOS domain, which shows maximum rates of approximately 1400 turnovers/s in the conversion of 8R-HPETE to the allene oxide. Some unusual catalytic activities of the two domains are described. The lipoxygenase domain converts 20.3omega6 partly to the bis-allylic hydroperoxide (10-hydroperoxyeicosa-8,11,14-trienoic acid). Metabolism of the preferred substrate of the AOS domain, 8R-HPETE, is inhibited by the enantiomer 8S-HPETE. Although the AOS domain has homology to catalase in primary structure, it is completely lacking in catalatic action on H(2)O(2); catalase itself, as expected from its preference for small hydroperoxides, is ineffective in allene oxide synthesis from 8R-HPETE.


Consensus statement on essential patient characteristics in systemic treatment trials for metastatic colorectal cancer: Supported by the ARCAD Group.
Patient characteristics and stratification factors are key features influencing trial outcomes. However, there is substantial heterogeneity in reporting of patient characteristics and use of stratification factors in phase 3 trials investigating systemic treatment of metastatic colorectal cancer (mCRC). We aimed to develop a minimum set of essential baseline characteristics and stratification factors to include in such trials. We performed a modified, two-round Delphi survey among international experts with wide experience in the conduct and methodology of phase 3 trials of systemic treatment of mCRC. Thirty mCRC experts from 15 different countries completed both consensus rounds. A total of 14 patient characteristics were included in the recommended set: age, performance status, primary tumour location, primary tumour resection, prior chemotherapy, number of metastatic sites, liver-only disease, liver involvement, surgical resection of metastases, synchronous versus metachronous metastases, (K)RAS and BRAF mutation status, microsatellite instability/mismatch repair status and number of prior treatment lines. A total of five patient characteristics were considered the most relevant stratification factors: RAS/BRAF mutation status, performance status, primary tumour sidedness and liver-only disease. This survey provides a minimum set of essential baseline patient characteristics and stratification factors to include in phase 3 trials of systemic treatment of mCRC. Inclusion of these patient characteristics and strata in study protocols and final study reports will improve interpretation of trial results and facilitate cross-study comparisons.


Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism.
The aim of this study was to identify a subgroup of pregnant women with asymptomatic hypercholanaemia of pregnancy (AHP), in which the relationship between alterations in the level and pattern of serum bile acids (BAs) and of progesterone plus progesterone metabolites could be investigated in the absence of overt impairment of hepatobiliary function. Cholanaemia and serum concentrations of progesterone were assayed by an enzymic technique and by ELISA respectively, while BA molecular species and progesterone metabolites were measured by GC-MS, in the serum of 411 healthy pregnant women. Samples were collected after an overnight fast in the final week of each trimester of gestation. Two pregnant women were excluded because of the suspicion of intrahepatic cholestasis of pregnancy (ICP). Cholanaemia was found to increase progressively throughout pregnancy, but with normal mean values lower than 3.0 microM. Thus in our series AHP was defined arbitrarily as the presence of serum total BA concentrations 2-fold higher than this value, i.e. 6 microM, in the absence of hepatobiliary disease or symptoms of ICP. The prevalence of this condition was observed to increase with gestational age. Changes in the pattern of serum BAs in AHP were also found. These were reflected in a marked increase in the proportion of cholic acid together with a decrease in that of deoxycholic acid, while the proportions of chenodeoxycholic acid and lithocholic acid changed only moderately. When groups at the same gestational age were compared, serum progesterone levels were always significantly lower, while those of progesterone metabolites were higher, in women with AHP. Our results suggest that AHP is a relatively common condition in our geographical location, where ICP is rarely diagnosed. Changes in the serum BA pattern in hypercholanaemia resemble these described in ICP. The simultaneous finding of lower serum total progesterone levels along with an increase in its metabolites supports the hypothesis that a primary defect in progesterone metabolism may be involved in the aetiology of ICP.


Use of Bone Marrow Concentrate to Treat Pain and Musculoskeletal Disorders: An Academic Delphi Investigation.
Acute and degenerative musculoskeletal disorders are among the most common etiologies of disability worldwide. Recently, there has been interest in the field of regenerative medicine to bridge the gap between conservative and surgical management of these conditions. Autologous bone marrow concentrate is one type of injectate that has increased in popularity over the last few decades. Though there is promising evidence supporting its efficacy, standard of care practice guidelines to govern the appropriate use and implementation of such technology are currently lacking. The aim of this article is to report findings from a survey administered using the Delphi technique to a group of physicians using bone marrow concentrate in practice to determine best practice consensus regarding optimization of patient safety and education. Delphi panel technique. The study was first announced at a national meeting and continued remotely across the United States via 4 rounds of online surveys. An initial panel of 30 expert members was convened and a 5-member steering committee was established. Four rounds of consensus questionnaires totaling 11 unique questions were distributed. Ten questions included a 5-point Likert scale from "Strongly Agree" to "Strongly Disagree," and one question had a selection of 5 options regarding minimum level of evidence required. The anonymized aggregate results of each round were shared with the group prior to voting in the subsequent round in accordance with the Delphi process. Consensus was defined as 80% agreement of the statements indicating either "Strongly Agree" or "Agree" for the 10 questions with the Likert Scale and 80% agreement among 2 of 5 choices in the question regarding levels of evidence. Three invited participants were excluded by the second round of questions due to lack of response in a timely manner, leaving 27 physicians queried. Nine of the 11 questions met criteria for > 80% consensus. Areas of agreement included importance of a treatment registry, candidacy grading, expanded informed consent, scientific accuracy in advertising, institutional review board approval for novel uses, performance of procedures by only licensed physicians or mid-level providers with direct physician oversight, use of image guidance for injections, data submission for publication in peer reviewed literature, and a minimum requirement of case-series level of evidence for use of bone marrow concentrate in musculoskeletal medicine. The 2 areas that did not meet criteria for consensus included online publishing of individual clinic data and standards around cell counting for dosing. The Delphi panel of experts was convened on a voluntary basis rather than a nomination process. Our panel of experts were all physicians who use bone marrow concentrate in practice, therefore it is possible that a different panel of experts within other disciplines would reach different conclusions. There is significant consensus among a panel of physicians performing bone marrow concentrate injections regarding best practice guidelines for musculoskeletal conditions.


Medication risk factors associated with healthcare-associated Clostridium difficile infection: a multilevel model case-control study among 64 US academic medical centres.
The main objective of this study was to determine patient- and hospital-level medication risk factors associated with Clostridium difficile infection (CDI) occurrence among patients clustered within hospitals using a multilevel model. Patients with healthcare-associated (HA)-CDI were identified from among 64 academic medical centres in 2009. A frequency match was conducted; for each case, up to two controls were selected, matched on similar pre-infection length of stay and clinical service line. Patient- and hospital-level medication use, including antibacterial and gastric acid-suppressant agents, was assessed using a two-level logistic regression model. A total of 5967 CDI cases and 8167 controls were included in the analysis. The odds of acquiring HA-CDI increased with the following medications [OR (95% CI)]: anti-methicillin-resistant Staphylococcus aureus agents [1.38 (1.22-1.56)]; third- or fourth-generation cephalosporins [1.75 (1.62-1.89)]; carbapenems [1.60 (1.44-1.79)]; β-lactam/β-lactamase inhibitor combinations [1.49 (1.36-1.64)]; vancomycin [1.73 (1.57-1.89)]; and proton pump inhibitors [1.43 (1.30-1.57)]. The odds of acquiring HA-CDI decreased with the following medications: clindamycin [0.74 (0.63-0.87)]; and macrolides [0.88 (0.77-0.99)]. Controlling for patient-level covariates, no hospital-level medication covariates that we analysed had statistically significant effects on HA-CDI. The odds of acquiring HA-CDI increased with the hospital proportion of patients aged ≥ 65 years [1.01 (1.00-1.02)]. We found several medications that were associated with the risk of patients developing HA-CDI, including β-lactam/β-lactamase inhibitor combinations, third- or fourth-generation cephalosporins, carbapenems, vancomycin, proton pump inhibitors and anti-methicillin-resistant S. aureus agents. There were no medication effects significant at the hospital level.


Nosocomial pseudo-outbreak of Mycobacterium gordonae associated with a hospital's water supply contamination: a case series of 135 patients.
Nontuberculous mycobacteria (NTM) are opportunistic pathogens found in natural and human-engineered waters. In 2009, a relative increase in the isolation of Mycobacterium gordonae from pulmonary samples originating from General Hospital Zabok was noted by the National Mycobacteria Reference Laboratory. An epidemiological survey revealed a contamination of the cold tap water with M. gordonae and guidelines regarding sputum sample taking were issued. In addition, all incident cases of respiratory infection due to NTM reported from 2007 to 2012 at General Hospital Zabok were included in a retrospective review. Out of 150 individual NTM isolates, M. gordonae was the most frequently isolated species (n = 135; 90%) and none of the cases met the criteria of the American Thoracic Society for pulmonary NTM disease. While concomitant Mycobacterium tuberculosis infection was confirmed in only 6 (4%) patients, anti-tuberculosis treatment was initiated for a significant portion of patients (n = 64; 42.6%) and unnecessary contact tracing was performed. This study points out the need to enhance the knowledge about NTM in our country and indicates the importance of faster NTM identification, as well as the importance of good communication between laboratory personnel and physicians when evaluating the significance of the isolated NTM.


Reduced number of circulating monocytes after institution of insulin therapy--relevance for development of atherosclerosis in diabetics?
Twelve patients with Type II diabetes mellitus, insufficiently controlled with oral hypoglycemic agents, were studied before, after 2 months, and after 4 months on insulin therapy. For comparison the same variables were also studied in 10 healthy subjects. From the start, in the diabetic group, the authors found alterations in the hemorheologic parameters indicated by increased values for whole blood viscosity, plasma viscosity, red cell transit time (RCTT), and decreased values for white cell initial relative filtration rate (IrFR). In hematologic parameters they found increased values for mean corpuscular volume (MCV), leukocyte count, counts of neutrophils and monocytes, and a decreased count of lymphocytes. They also found increased values in the lipid parameters P-triglycerides and Apo B/Apo A-I ratio, risk factors of coronary atherosclerosis. After 4 months of insulin treatment whole blood and plasma viscosity were still increased, but there was a partial improvement of lipoprotein abnormalities. Red and white cell filterability, however, tended to normalize. These results indicate that changes in blood cell filterability do not necessarily influence in vitro measurements of blood viscosity. The change in RCTT during the insulin treatment was associated with a decreased MCV and the change in white cell IrFR with a decrease in the number of monocytes. This change of white cell filterability during insulin therapy, probably due to a reduced number of monocytes, may be of interest in the study of atherosclerosis and circulatory disease in diabetics.


Green Synthesis of CuO Nanoparticles Using Agaricus bisporus Extract as a Highly Efficient Catalyst for the Suzuki Cross-Coupling Reaction.
Copper oxide nanoparticles (CuONPs) were synthesized using a rapid, eco-friendly, cost-effective, efficient, and biological method employing aqueous Agaricus bisporus extract as a capping and reducing agent. The formation of CuONPs was checked by UV-vis spectroscopy and was characterized by X-ray diffraction analysis (XRD), dynamic light scattering spectroscopy (DLS), transmission electron microscopy (TEM), and surface area and porosimetry analyzer. The characterization results showed that the synthesized nanoparticles had a spherical-like appearance and a crystal structure with 40-100 nm particle size. The green synthesized CuONPs were found to be an excellent and sustainable heterogeneous catalyst (TOF up to 29700 h-1 ) for the Suzuki C-C coupling of aryl halides with phenylboronic acid in a very short reaction time (10 minutes). Moreover, the easily recovered catalyst can be reused five times with just a negligible reduction in catalytic behavior.


Angiotensin type 2 receptors: potential importance in the regulation of blood pressure.
The angiotensin type 2 receptor is one of two major angiotensin II receptors that has been identified, cloned and sequenced. The other major receptor, the angiotensin type 1 receptor, is thought to mediate most of the biological responses to the peptide. The angiotensin type 2 receptor is expressed heavily in fetal tissues, but only at a low level in the adult. Documented angiotensin type 2 receptor expression sites in the adult include kidney, heart and mesenteric blood vessels. The function of the angiotensin type 2 receptor is just beginning to be explored. Most of the evidence suggests that the angiotensin type 2 receptor mediates a vasodilator signalling cascade that includes bradykinin, nitric oxide and cyclic guanosine 5-monophosphate. At least some of the beneficial actions of angiotensin type 1 receptor blockade, such as hypotension, are mediated by stimulation of the angiotensin type 2 receptor. Several recent papers suggest that angiotensin type 2 receptors, presumably located in systemic blood vessels, mediate vasodilation and hypotension. The angiotensin type 2 receptor may be a new therapeutic target and candidate gene for the pathophysiology of hypertension.


Should 15° of valgus coronal-plane deformity be the upper limit for a total ankle arthroplasty?
Preoperative talar valgus deformity ≥ 15° is considered a contraindication for total ankle arthroplasty (TAA). We compared operative procedures and clinical outcomes of TAA in patients with talar valgus deformity ≥ 15° and < 15°. A matched cohort of patients similar for demographics and components used but differing in preoperative coronal-plane tibiotalar valgus deformity ≥ 15° (valgus, n = 50; 52% male, mean age 65.8 years (SD 10.3), mean body mass index (BMI) 29.4 (SD 5.2)) or < 15° (control, n = 50; 58% male, mean age 65.6 years (SD 9.8), mean BMI 28.7 (SD 4.2)), underwent TAA by one surgeon. Preoperative and postoperative radiographs, Ankle Osteoarthritis Scale (AOS) pain and disability and 36-item Short Form Health Survey (SF-36) version 2 scores were collected prospectively. Ancillary procedures, secondary procedures, and complications were recorded. At mean 5.1 years follow-up (SD 2.6) (valgus) and 6.6 years (SD 3.3) (controls), mean AOS scores decreased and SF-36 scores increased significantly in both groups. Improvements in scores were similar for both groups - AOS pain: valgus, mean 26.2 points (SD 24.2), controls, mean 22.3 points (SD 26.4); AOS disability: valgus, mean 41.2 points (SD 25.6); controls, mean 34.6 points (SD 24.3); and SF-36 PCS: valgus, mean 9.1 points (SD 14.1), controls, mean 7.4 points (SD 9.8). Valgus ankles underwent more ancillary procedures during TAA (40 (80%) vs 13 (26%)) and more secondary procedures postoperatively (18 (36%) vs 7 (14%)) than controls. Tibiotalar deformity improved significantly (p < 0.001) towards a normal weightbearing axis in valgus ankles. Three valgus and four control ankles required subsequent fusion, including two for deep infections (one in each group). Satisfactory mid-term results were achieved in patients with preoperative valgus malalignment ≥ 15°, but they required more adjunctive procedures during and after TAA. Valgus coronal-plane deformity ≥ 15° is not an absolute contraindication for TAA if associated deformities are addressed. Cite this article: Bone Joint J 2020;102-B(12):1689-1696.


Carbon cycling and storage in mangrove forests.
Mangroves are ecologically and economically important forests of the tropics. They are highly productive ecosystems with rates of primary production equal to those of tropical humid evergreen forests and coral reefs. Although mangroves occupy only 0.5% of the global coastal area, they contribute 10-15% (24 Tg C y(-1)) to coastal sediment carbon storage and export 10-11% of the particulate terrestrial carbon to the ocean. Their disproportionate contribution to carbon sequestration is now perceived as a means for conservation and restoration and a way to help ameliorate greenhouse gas emissions. Of immediate concern are potential carbon losses to deforestation (90-970 Tg C y(-1)) that are greater than these ecosystems' rates of carbon storage. Large reservoirs of dissolved inorganic carbon in deep soils, pumped via subsurface pathways to adjacent waterways, are a large loss of carbon, at a potential rate up to 40% of annual primary production. Patterns of carbon allocation and rates of carbon flux in mangrove forests are nearly identical to those of other tropical forests.


Steroidal Alkaloids from Food Waste of Tomato Processing Inhibit Neuroblastoma Cell Viability.
Nowadays, there is considerable attention toward the use of food waste from food processing as possible sources of compounds with health properties, such as anticancer activity. An example is tomato processing, which is responsible for generating a remarkable amount of waste (leaves, peel, seeds). Therefore, our goal was to evaluate the potential anticancer property of tomato extracts, in particular "Datterino" tomato (DT) and "Piccadilly" tomato (PT), and to study their phytochemical composition. Liquid chromatography with tandem mass spectrometry (LC/MS-MS) results showed that these extracts are rich in alkaloids, flavonoids, fatty acids, lipids, and terpenes. Furthermore, their potential anticancer activity was evaluated in vitro by MTT assay. In particular, the percentage of cell viability was assessed in olfactory ensheathing cells (OECs), a particular glial cell type of the olfactory system, and in SH-SY5Y, a neuroblastoma cell line. All extracts (aqueous and ethanolic) did not lead to any significant change in the percentage of cell viability on OECs when compared with the control. Instead, in SH-SY5Y we observed a significant decrease in the percentage of cell viability, confirming their potential anticancer activity; this was more evident for the ethanolic extracts. In conclusion, tomato leaves extracts could be regarded as a valuable source of bioactive compounds, suitable for various applications in the food, nutraceutical, and pharmaceutical fields.


Status-Based Identity.
Psychological research on socioeconomic status (SES) has grown significantly over the past decade. In this article, we build upon and integrate existing approaches to direct greater attention toward investigating the subjective meaning and value that people attach to understanding their own SES as an identity. We use the term status-based identity to organize relevant research and examine how people understand and make meaning of their SES from moment to moment in real time. Drawing from multiple areas of research on identity, we suggest that even temporary shifts in how people construe their status-based identities predict changes in thought, affect, motivation, and behavior. This novel focus is positioned to examine the psychological effects of status transitions (e.g., upward or downward mobility). Further, in initial empirical work, we introduce a new measure to assess uncertainty regarding one's SES (i.e., status-based identity uncertainty) and offer evidence that greater uncertainty regarding one's status-based identity is associated with lower individual well-being. In sum, we argue that insight from the literature on identity will both expand and serve to organize the burgeoning literature on the psychology of SES and, in so doing, reveal promising new directions for research.


The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA.
The Elav-like proteins are specific mRNA binding proteins which are required for cellular differentiation. They contain three characteristic RNP2/RNP1-type RNA binding motifs. Previously we have shown that the first and second RNA binding domains bind to AU-rich elements in the 3'-UTR of mRNA. In this paper we show that the Elav-like proteins exhibit poly(A) binding activity. This activity is distinct from poly(A) binding activities that have been previously described. The Elav-like proteins specifically bind to long chain poly(A) tails. We have shown that the third RNA binding domain encompasses this poly(A) binding activity. Using poly(A)-Sepharose beads in a 'sandwich' assay we have shown that the Elav-like proteins can bind simultaneously to the AU-rich element and to the poly(A) tail.


Strategies for heart regeneration: approaches ranging from induced pluripotent stem cells to direct cardiac reprogramming.
Cardiovascular disease remains a leading cause of death for which current therapeutic regimens are limited. Following myocardial injury, endogenous cardiac fibroblasts, which account for more than half of the cells in the heart, proliferate and synthesize extracellular matrix, leading to fibrosis and heart failure. As terminally differentiated cardiomyocytes have little regenerative capacity following injury, development of cardiac regenerative therapy is highly desired. Embryonic stem (ES) and induced pluripotent stem (iPS) cells are promising tools for regenerative medicine; however, these stem cells demonstrate variable cardiac differentiation efficiency and tumorigenicity, which should be solved for clinical applications. Up until the last decade, it was an established theory that cardiomyocytes could only be produced from fibroblasts mediating through stem cells. However, in 2010, we reported for the first time a novel method of the direct reprogramming of fibroblasts into cardiomyocytes, demonstrating various reprogramming pathways exist. This review summarizes the latest trends in stem cell and regenerative research, touching upon iPS cells, partial reprogramming strategy, and direct cardiac reprogramming. Specifically, we examine the many recent advances in both in vitro and in vivo direct cardiac reprogramming, and explore the application of these methods to cardiovascular regenerative medicine.


Fibrinogen receptors in platelet adhesion to surfaces of extracorporeal circuit.
The role of platelet fibrinogen receptors and platelet-protein interaction in platelet consumption during simulated cardiopulmonary bypass was investigated. In five recirculation experiments, with whole blood, the platelet count fell to 13% of initial values and in two experiments, with blood from patients with Bernard-Soulier syndrome, to 3% of normal values. However, in three experiments with blood from the patients with Glanzmann's thrombasthenia, the platelet count decreased to 69% of initial values. The extent of platelet consumption in normal blood was diminished to only 72% by addition of 0.5 microM prostaglandin E1 (PGE1) (5 experiments) and to 80% by precoating surfaces of the circuit with 2.5% human albumin (5 experiments). beta-Thromboglobulin antigen (beta TG) loss from platelets was associated with thrombocytopenia. The extent of beta TG loss was significantly reduced by the addition of PGE1 to blood or precoating surfaces with albumin. Proteins adsorbed on the surface of the circuit exposed to normal blood were removed with 0.5% Triton X-100. Some of these proteins were identified to be glycoprotein IIIa (GPIIIa) (3.4-4.3 micrograms/ml), beta TG (1.0-1.6 micrograms/ml), and fibrinogen (1.9-3.7 micrograms/ml). The amount of GPIIIa recovered in the Triton X-100 eluates correlated with the number of platelets lost during recirculation. These studies indicate that exposure of fibrinogen receptors associated with GPIIb-GPIIIa complex contributes to platelet consumption during cardiopulmonary bypass.


Treating the common cold during pregnancy.
Many of my pregnant patients inquire as to what medication they can use when they experience symptoms of the common cold, such as cough, congestion, sneezing, and fever. I am hesitant to recommend over-the-counter cold remedies because I have heard conflicting information regarding the safety of these products. What is known about the safety of cold medications during pregnancy? Although there are many over-the-counter brands of cold medications, most products are quite similar, with some containing up to 5 medicinal ingredients. The evidence-based information for all these ingredients suggests no increased risk with short-term use. However, pregnant women should read labels carefully and, when necessary, consult with pharmacists to ensure they are not taking medicine they do not require.


[Towards an accreditation system for the Dutch hospitals].
The development of the Netherlands system for accreditation of hospitals started in 1989 in the Pilotproject Accreditation (PACE). This resulted in the establishment of the Netherlands Institute for Accreditation of Hospitals (NAIH) early 1999, by the Dutch Association of Hospitals, the Dutch Association of University Hospitals, the Dutch Organisation of Medical Specialists and the PACE foundation. Dutch hospitals may request (voluntary) for an accredition for their whole organisation or for parts of it, independent of the used quality system. An accreditation assesses whether organizational requirements are available for quality assurance. Accreditation is not primarily aimed to account for organizational quality, but rather to find points for improvement. The survey is carried out by peers: experts from other Dutch hospitals. The frame of reference used in accreditation is composed of 35 departmentwise standards and a hospitalwide standard 'Quality system'. All standards are developed by people in Dutch hospitals. NIAH can accept certificates for parts of the hospital (e.g. laboratoria) issues by organisations. The system is complementary to the 'visitities' which are organized by the medical specialist societies in the Netherlands. From 1996-1998 trial accreditations were carried out in 19 Dutch hospitals. These showed that the accreditation system has an added value for Dutch hospitals.


Thiobaca trueperi gen. nov., sp. nov., a phototrophic purple sulfur bacterium isolated from freshwater lake sediment.
Two strains of a novel species of phototrophic micro-organism were isolated from the sediments of a shallow, freshwater, eutrophic lake. Both strains grew photolithoheterotrophically with sulfide as an electron donor, transiently accumulating intracellular sulfur globules. Photolithoautotrophic growth was not observed. One strain was designated BCH(T) (the type strain) and was studied in most detail. Cells contained bacteriochlorophyll a, and the dominant carotenoid was lycopene. Cell suspensions were brown. The photosynthetic membranes had a vesicular arrangement. Acetate, propionate, pyruvate, succinate and fumarate were each used as electron donors and carbon sources in the presence of sulfide and bicarbonate. In the presence of light, growth did not occur with hydrogen, thiosulfate or iron(II). The optimum temperature for growth was between 25 and 30 degrees C, the maximum being 36 degrees C. The G+C content of the genomic DNA of strain BCH(T) was 63 mol%. Analysis of the 16S RNA genes showed that both strains belonged to the gamma-subclass of the Proteobacteria but were phylogenetically distinct from any described phototrophic organisms within the Chromatiaceae. On the basis of phylogenetic and physiological differences from other phototrophic microorganisms, strain BCH(T) is described as a novel species of a new genus, Thiobaca trueperi gen. nov., sp. nov.


Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10.
Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid fever and vary in their effector repertoire. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector that induces production of the anti-inflammatory cytokine IL-10. RNA-seq of cells infected with either ΔsarA or wild-type S. Typhimurium revealed that SarA activates STAT3 transcriptional targets. Consistent with this, SarA is necessary and sufficient for STAT3 phosphorylation, STAT3 inhibition blocks IL-10 production, and SarA and STAT3 interact by co-immunoprecipitation. These effects of SarA contribute to intracellular replication in vitro and bacterial load at systemic sites in mice. Our results demonstrate the power of using comparative genomics for identifying effectors and that Salmonella has evolved mechanisms for activating an important anti-inflammatory pathway.


MiR-34a-3p suppresses pulmonary vascular proliferation in acute pulmonary embolism rat by targeting DUSP1.
Acute pulmonary embolism (APE) is a prevalent reason of cardiovascular morbidity and mortality. Recent studies have underscored the positive effects of microRNAs (miRNAs) on many diseases. The present study aimed to identify the critical miRNA with differential expressions and explore its role in APE. The critical miRNA with its target gene was screened by bioinformatics analysis. Their binding relationship was analyzed by TargetScan, Dual-luciferase reporter and RNA pull-down assays. A rat model of APE was established by self-blood coagulum. Human pulmonary artery smooth muscle cells (PASMCs) were exposed to platelet-derived growth factor (PDGF-BB) for excessive proliferation, and transfected with miR-34a-3p mimic. Mean pulmonary arterial pressure (mPAP) of rat was measured, and the pulmonary tissues were used for the pathological observation by Hematoxylin-Eosin (H&E) staining. Cell viability and proliferation were detected by Cell Counting Kit-8 (CCK-8) and EdU assays. The expressions of miR-34a-3p with its target genes (including dual-specificity phosphatase-1 (DUSP1)), neuron-derived orphan receptor-1 (NOR-1) and proliferating cell nuclear antigen (PCNA) were determined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) or/and Western blot. MiR-34a-3p expression was down-regulated in APE patients, which attenuated the increment of mPAP and thickening of the pulmonary arterial walls in APE rats, accompanied with regulation of NOR-1 and PCNA levels. MiR-34a-3p suppressed DUSP1 expression by directly binding to its 3'-untranslated region (UTR), and attenuated cell viability, proliferation, and the expressions of NOR-1 and PCNA in PDGF-BB-induced PASMCs by inhibiting DUSP1 expression. Up-regulated miR-34a-3p negatively regulates DUSP1 expression to inhibit PASMC proliferation, which, thus, may act on APE treatment by negatively regulating pulmonary vascular proliferation.


Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples.
Genome sequencing has become a powerful tool for studying emerging infectious diseases; however, genome sequencing directly from clinical samples (i.e., without isolation and culture) remains challenging for viruses such as Zika, for which metagenomic sequencing methods may generate insufficient numbers of viral reads. Here we present a protocol for generating coding-sequence-complete genomes, comprising an online primer design tool, a novel multiplex PCR enrichment protocol, optimized library preparation methods for the portable MinION sequencer (Oxford Nanopore Technologies) and the Illumina range of instruments, and a bioinformatics pipeline for generating consensus sequences. The MinION protocol does not require an Internet connection for analysis, making it suitable for field applications with limited connectivity. Our method relies on multiplex PCR for targeted enrichment of viral genomes from samples containing as few as 50 genome copies per reaction. Viral consensus sequences can be achieved in 1-2 d by starting with clinical samples and following a simple laboratory workflow. This method has been successfully used by several groups studying Zika virus evolution and is facilitating an understanding of the spread of the virus in the Americas. The protocol can be used to sequence other viral genomes using the online Primal Scheme primer designer software. It is suitable for sequencing either RNA or DNA viruses in the field during outbreaks or as an inexpensive, convenient method for use in the lab.


Storage and release of mechanical energy by active muscle: a non-elastic mechanism?
In frog muscle fibres, tetanically stimulated at a sarcomere length of about 2 micron, stretched at a velocity of 1 lengths-1 and released against a force equal to the maximum isometric, P0, a phase of rapid isotonic shortening takes place after release. As the amplitude of the stretch is increased from 1.5 to 9% of the initial length: (1) the amount of rapid isotonic shortening increases up to 9-10 nm per half sarcomere and (2) the stiffness of the fibre (an indication of the number of bridges attached) decreases to a value about equal to that measured during an isometric contraction. If a 5-10 ms delay is left between the end of stretch and release, the amount of rapid isotonic shortening increases to about 12 nm hs-1. A 300-500 ms delay, however, results in a decrease in rapid isotonic shortening to about 5 nm hs-1 and also results in a velocity transients against P0 that are similar to those described during release from a state of isometric contraction. It is concluded that the force attained after large, fast stretches is due to a greater force developed by each bridge and not to a greater number of bridges. After the elastic recoil (when the force is suddenly reduced to P0), these strained bridges are able to shorten by about 12 nm hs-1, suggesting that, during and immediately after stretching, they are charged to levels of potential energy greater than those attained in an isometric contraction.


Underexpressed coactivators PGC1alpha and SRC1 impair hepatocyte nuclear factor 4 alpha function and promote dedifferentiation in human hepatoma cells.
Hepatocyte nuclear factor 4alpha (HNF4alpha) plays critical roles during liver development and in the transcriptional regulation of many hepatic genes in adult liver. Here we have demonstrated that in human hepatoma HepG2 cells, HNF4alpha is expressed at levels as high as in human liver but its activity on target genes is very low or absent. We have discovered that the low expression of key coactivators (PGC1alpha, SRC1, SRC2, and PCAF) might account for the lack of function of HNF4alpha in HepG2 cells. Among them, PGC1alpha and SRC1 are the two most important HNF4alpha coactivators as revealed by reporter assays with an Apo-CIII promoter construct. Moreover, the expression of these two coactivators was found to be down-regulated in all human hepatomas investigated. Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. The positive effect of PGC1alpha was seen to be dependent on HNF4alpha. Finally, insulin treatment of human hepatocytes and HepG2 cells caused repression of PGC1alpha and a concomitant down-regulation of ApoCIII, PEPCK, AldoB, and OTC. Altogether, our results suggest that SRC1, and notably PGC1alpha, are key coactivators for the proper function of HNF4alpha in human liver and for an integrative control of multiple hepatic genes involved in metabolism and homeostasis. The down-regulation of key HNF4alpha coactivators could be a determinant factor for the dedifferentiation of human hepatomas.


Cellular pathophysiology of hepatitis.
This paper represents an analysis of the subcellular events that occur in the human liver in viral hepatitis. They involve both hepatocytes and sinusoidal lining cells, including Kupffer cells. We present a new hypothesis concerning the sequence of events that occurs in hepatic parenchymal cells. These events begin with a virus-hepatocyte interaction that involves primary damage to the cell membrane. This is assumed to trigger a complex sequence of events that results in the characteristic hepatocellular impairment of this disease. These events center around ionic shifts resulting from an altered plasma membrane, leading to interactive events in hepatocyte organelles, mostly reversible, but resulting in the characteristic hepatocellular impairment.


The promise of genetic screens in human in vitro brain models.
Advances of in vitro culture models have allowed unprecedented insights into human neurobiology. At the same time genetic screening has matured into a robust and accessible experimental strategy allowing for the simultaneous study of many genes in parallel. The combination of both technologies is a newly emerging tool for neuroscientists, opening the door to identifying causal cell- and tissue-specific developmental and disease mechanisms. However, with complex experimental genetic screening set-ups new challenges in data interpretation and experimental scope arise that require a deep understanding of the benefits and challenges of individual approaches. In this review, we summarize the literature that applies genetic screening to in vitro brain models, compare experimental strengths and weaknesses and point towards future directions of these promising approaches.


Is an absolute level of cortical beta suppression required for proper movement? Magnetoencephalographic evidence from healthy aging.
Previous research has connected a specific pattern of beta oscillatory activity to proper motor execution, but no study to date has directly examined how resting beta levels affect motor-related beta oscillatory activity in the motor cortex. Understanding this relationship is imperative to determining the basic mechanisms of motor control, as well as the impact of pathological beta oscillations on movement execution. In the current study, we used magnetoencephalography (MEG) and a complex movement paradigm to quantify resting beta activity and movement-related beta oscillations in the context of healthy aging. We chose healthy aging as a model because preliminary evidence suggests that beta activity is elevated in older adults, and thus by examining older and younger adults we were able to naturally vary resting beta levels. To this end, healthy younger and older participants were recorded during motor performance and at rest. Using beamforming, we imaged the peri-movement beta event-related desynchronization (ERD) and extracted virtual sensors from the peak voxels, which enabled absolute and relative beta power to be assessed. Interestingly, absolute beta power during the pre-movement baseline was much stronger in older relative to younger adults, and older adults also exhibited proportionally large beta desynchronization (ERD) responses during motor planning and execution compared to younger adults. Crucially, we found a significant relationship between spontaneous (resting) beta power and beta ERD magnitude in both primary motor cortices, above and beyond the effects of age. A similar link was found between beta ERD magnitude and movement duration. These findings suggest a direct linkage between beta reduction during movement and spontaneous activity in the motor cortex, such that as spontaneous beta power increases, a greater reduction in beta activity is required to execute movement. We propose that, on an individual level, the primary motor cortices have an absolute threshold of beta power that must be reached in order to move, and that an inability to suppress beta power to this threshold results in an increase in movement duration.


A Lagrangian network for kinematic control of redundant robot manipulators.
A recurrent neural network, called the Lagrangian network, is presented for the kinematic control of redundant robot manipulators. The optimal redundancy resolution is determined by the Lagrangian network through real-time solution to the inverse kinematics problem formulated as a quadratic optimization problem. While the signal for a desired velocity of the end-effector is fed into the inputs of the Lagrangian network, it generates the joint velocity vector of the manipulator in its outputs along with the associated Lagrange multipliers. The proposed Lagrangian network is shown to be capable of asymptotic tracking for the motion control of kinematically redundant manipulators.


Chelativorans intermedius sp. nov. and proposal to reclassify Thermovum composti as Chelativorans composti comb. nov.
Two Gram-stain-negative, non-endospore-forming, rod-shaped bacteria, strains CC-MHSW-5(T) and A1392, were isolated from water of coastal hot springs located in Taiwan and China, respectively, and investigated for their taxonomic position. The two strains shared identical 16S rRNA gene sequences, a DNA-DNA hybridization value >80% and similar genomic DNA G+C contents (64.3 and 64.6 mol%), but showed different genomic fingerprint patterns generated by BOX-PCR and three random amplification polymorphic DNA PCRs. The strains shared highest 16S rRNA gene sequence similarities with the type strains of Chelativorans multitrophicus (96.7 and 96.1%), Thermovum composti (96.2 and 96.1%) and Chelativorans oligotrophicus (96.1 and 95.8%). Phylogenetic trees (based on 16S rRNA and recA gene sequence comparisons) showed a distinct clustering of both strains with the type strains of species of the genus Chelativorans and T. composti Nis3(T). The quinone systems of strains CC-MHSW-5(T) and Nis3(T) contained ubiquinone Q-10 as the major component. The major polyamine in both strains was sym-homospermidine. Putrescine, spermidine and, for strain CC-MHSW-5(T), spermine were found in minor concentrations. Their polar lipid profiles consisted of phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and diphosphatidylglycerol. The fatty acid profile contained major amounts of C18 : 1ω7c and C19 : 0 cyclo ω8c. On the basis of these results, the two strains are considered to represent a novel species of the genus Chelativorans , for which the name Chelativorans intermedius sp. nov. is proposed. The type strain is CC-MHSW-5(T) ( =CCM 8543(T) =LMG 28482(T) =DSM 29391(T) =CIP 110825(T)). Based on both genotypic and phenotypic characters, it is proposed that T. composti be reclassified within the genus Chelativorans as Chelativorans composti comb. nov.


Birth weight for gestational age norms for a large cohort of infants born to HIV-negative women in Botswana compared with norms for U.S.-born black infants.
Standard values for birth weight by gestational age are not available for sub-Saharan Africa, but are needed to evaluate incidence and risk factors for intrauterine growth retardation in settings where HIV, antiretrovirals, and other in utero exposures may impact birth outcomes. Birth weight data were collected from six hospitals in Botswana. Infants born to HIV-negative women between 26-44 weeks gestation were analyzed to construct birth weight for gestational age charts. These data were compared with published norms for black infants in the United States. During a 29 month period from 2007-2010, birth records were reviewed in real-time from 6 hospitals and clinics in Botswana. Of these, 11,753 live infants born to HIV-negative women were included in the analysis. The median gestational age at birth was 39 weeks (1st quartile 38, 3rd quartile 40 weeks), and the median birth weight was 3100 grams (1st quartile 2800, 3rd quartile 3400 grams). We constructed estimated percentile curves for birth weight by gestational age which demonstrate increasing slope during the third trimester and leveling off beyond 40 weeks. Compared with black infants in the United States, Botswana-born infants had lower median birth weight for gestational age from weeks 37 through 42 (p < .02). We present birth weight for gestational age norms for Botswana, which are lower at term than norms for black infants in the United States. These findings suggest the importance of regional birth weight norms to identify and define risk factors for higher risk births. These data serve as a reference for Botswana, may apply to southern Africa, and may help to identify infants at risk for perinatal complications and inform comparisons among infants exposed to HIV and antiretrovirals in utero.


On the olfactory anatomy in an archaic whale (Protocetidae, Cetacea) and the minke whale Balaenoptera acutorostrata (Balaenopteridae, Cetacea).
The structure of the olfactory apparatus is not well known in both archaic and extant whales; the result of poor preservation in most fossils and locational isolation deep within the skulls in both fossil and Recent taxa. Several specimens now shed additional light on the subject. A partial skull of an archaic cetacean is reported from the Pamunkey River, Virginia, USA. The specimen probably derives from the upper middle Eocene (Piney Point Formation) and is tentatively assigned to the Protocetidae. Uncrushed cranial cavities associated with the olfactory apparatus were devoid of sediment. CT scans clearly reveal the dorsal nasal meatus, ethmoturbinates within the olfactory recess, the cribriform plate, the area occupied by the olfactory bulbs, and the olfactory nerve tract. Several sectioned skulls of the minke whale (Balaenoptera acutorostrata) were also examined, and olfactory structures are remarkably similar to those observed in the fossil skull from the Pamunkey River. One important difference between the two is that the fossil specimen has an elongate olfactory nerve tract. The more forward position of the external nares in extant balaenopterids when compared with those of extant odontocetes is interpreted to be the result of the need to retain a functional olfactory apparatus and the forward position of the supraoccipital/cranial vertex. An increase in the distance between the occipital condyles and the vertex in balaenopterids enhances the mechanical advantage of the epaxial musculature that inserts on the occiput, a specialization that likely stabilizes the head of these enormous mammals during lunge feeding.


Symposium on 'The challenge of translating nutrition research into public health nutrition'. Session 2: Personalised nutrition. Genetic variation and disease risk: new advances.
Variations in human DNA, most frequently single-nucleotide polymorphisms (SNPs), can have functional consequences ranging from severe to none. Variations in outcome (phenotype) can be compared, from cystic fibrosis through haemochromatosis to general familial risks in, for example, colo-rectal cancer (CRC). Cystic fibrosis and haemochromatosis have severe phenotypes with high penetrance, with signs and symptoms always or mostly present; thus, they have been easy to identify from family studies. However, the familial risks that are known to contribute markedly to CRC are unknown. The sequencing of the human genome has now made possible the identification of these and other disease variants. Knowing the DNA sequence in an idealised individual adds little unless variants that increase (or decrease) disease risk from the norm can be identified. Such variants can be expected to be very common in the general population, but have low penetrance and only change risk to a limited extent. Many patients will not have the risk variant and many 'normal' patients will have the risk variant. Thus, very large case-control cohorts are essential. These case-control cohorts can be analysed at three different levels: (1) individual SNPs; (2) individual genes; (3) genome-wide analysis (GWA). Level 1 looks for case-control differences for specific SNPs. Alternatively, new technology can be applied to examine a range of SNPs within a gene to track differences in its regulation as well as in function. Finally, the whole genome with >or=0.5x10(6) SNPs could be marked. The first two approaches involve selecting 'candidate' SNPs or genes, while GWA looks for any variation in the genome that is enriched in the cases. All three approaches carry the certainty that significant associations will be found by statistical chance, for which correction must be made. This latter issue is helped by large numbers and by independent replication cohorts.


Expression of AtMHX, an Arabidopsis vacuolar metal transporter, is repressed by the 5' untranslated region of its gene.
AtMHX is an Arabidopsis tonoplast transporter that can exchange protons with Mg2+ and Zn2+ ions. This transporter, which may play a role in ion homeostasis of plants, is encoded by a single gene in Arabidopsis. The molecular mechanisms that regulate the expression of this transporter are practically unknown. While AtMHX transcript can be easily visualized, expression of the corresponding protein is apparently low. To understand whether AtMHX expression is repressed at the translational level, the 5' untranslated region (5' UTR) of this gene was fused to reporter genes. In vitro analyses showed that the 5' UTR of AtMHX can repress the translation of downstream coding sequences. The major cause of the repression was efficient initiation at an upstream open-reading-frame (uORF) included in the 5' UTR. Although the sequence context of the upstream AUG (uAUG) codon was highly unfavourable, it was recognized by over 90% of the scanning ribosomes both in vitro and in vivo. The inhibitory effect of the uORF was mediated by imposing the need for reinitiation and not by ribosome stalling, as the inhibition was not dependent on the amino-acid sequence of the uORF peptide. The efficiency of reinitiation was low. The in vivo studies, carried out with transiently transformed tobacco plants, indicated that alternations in the Mg2+ or Zn2+ levels did not affect the rate of translation. These data suggest that AtMHX expression is repressed by the 5' UTR of its gene.


Usage and Acceptability of the iBobbly App: Pilot Trial for Suicide Prevention in Aboriginal and Torres Strait Islander Youth.
The proliferation of mental health apps purporting to target and improve psychological wellbeing is ever-growing and also concerning: Few apps have been rigorously evaluated, and, indeed, the safety of the vast majority of them has not been determined. Over 10,000 self-help apps exist but most are not used much after being downloaded. Gathering and analyzing usage data and the acceptability of apps are critical to inform consumers, researchers, and app developers. This paper presents pilot usage and acceptability data from the iBobbly suicide prevention app, an app distributed through a randomized controlled trial. Aboriginal and Torres Strait Islander participants from the Kimberley region of Western Australia completed a survey measuring their technology use in general (n=13), and data on their experiences with and views of the iBobbly app were also collected in semistructured interviews (n=13) and thematically analyzed. Finally, engagement with the app, such as the number of sessions completed and time spent on various acceptance-based therapeutic activities, was analyzed (n=18). Both groups were participants in the iBobbly app pilot randomized controlled trial (n=61) completed in 2015. Regression analysis indicated that app use improved psychological outcomes, although only minimally, and effects were not significant. However, results of the thematic analysis indicated that the iBobbly app was deemed effective, acceptable, and culturally appropriate by those interviewed. There is a scarcity of randomized controlled trials and eHealth interventions in Indigenous communities, while extremely high rates of psychological distress and suicide persist. In this environment, studies that can add evidence from mixed-methods approaches are important. While the regression analysis in this study did not indicate a significant effect of app use on psychological wellbeing, this was predictable considering the small sample size (n=18) and typically brief app use. The results on engagement with the iBobbly app were however positive. This study showed that Indigenous youth are early and frequent users of technology in general, and they regarded the iBobbly app to be culturally safe and of therapeutic value. Qualitative analyses demonstrated that iBobbly app use was associated with self-reported improvements in psychological wellbeing, mental health literacy, and reductions in shame. Importantly, participants reported that they would recommend other similar apps if available to their peers.


[Various physico-chemical properties of the amylolytic complex from Bacillus mesentericus].
Some physico-chemical properties of the Bacillus mesentericus amylolytic complex were studied, and optimal conditions of starch hydrolysis (pH 7.5-8.0; 45 degrees C) were found. The half-life of amylases at 50 degrees was 75 min. The heat stability of the enzymes increased in the presence of Ca2+ ions. Amylase was stable at pH 7-9 and readily inactivated at pH below 6.0. By physical and chemical characteristics the complex was close to analogous preparations from Bacillus alkalophilic strains. Isoelectrofocusing revealed that the complex consisted at least of two amylolytic enzymes.


Carbon Dioxide Dimer Radical Anion as Surface Intermediate of Photoinduced CO2 Reduction at Aqueous Cu and CdSe Nanoparticle Catalysts by Rapid-Scan FT-IR Spectroscopy.
Monitoring of visible light sensitized reduction of CO2 at Cu nanoparticles in aqueous solution by rapid-scan ATR FT-IR spectroscopy on the time scale of seconds allowed structural identification of a one-electron intermediate and demonstrated its kinetic relevancy for the first time. Isotopic labeling (12C: 1632, 1358, 1346 cm-1; 13C: 1588, 1326, 1316 cm-1) revealed a species of carbon dioxide dimer radical anion structure, most likely bound to the catalyst surface through carbon. Intermediacy of Cu-C(═O)OCO2- surface species is in agreement with a recently proposed mechanism for electrocatalytic CO2 reduction at Cu metal nanoparticles based on Tafel slope analysis. Spontaneous decrease of the intermediate after termination of the photosensitization pulse (Sn porphyrin excited at 405 nm) was accompanied by the growth of HCO3-. CO was produced as well, but sensitive detection required photolysis for tens of minutes. A direct kinetic link between a C2O4- surface intermediate and the CO product was also demonstrated for photocatalyzed CO2 reduction at aqueous CdSe nanoparticles, where first order growth of a Cd-C(═O)OCO2- species was accompanied by rise of CO (monitored by a fast Ni complex trap) and HCO3- showing a distinct induction period. The detection of the one-electron surface intermediate and confirmation of its catalytic relevancy was enabled by the delivery of electrons one-by-one by the photosensitization method. The observation of carbon dioxide dimer radical anion points to approaches for rate enhancements of heterogeneous CO2 reduction by creating catalytic environments that favor formation of this intermediate.


Individualistic and social motives for justice judgments.
Justice judgments are subjective by nature, and are influenced substantially by motivational processes. In the present contribution, two motives underlying justice judgments are examined: individualistic motives to evaluate solutions to social problems that benefit the self in material or immaterial ways as fair versus social motives to conceptualize justice in terms of the well-being of others, such as a desire for equality, adherence to in-group norms, and a concern for the collective interest. A review of relevant research reveals evidence for both motivations when people make evaluations of justice. Moreover, which motive is most dominant in the justice judgment process depends on perceptual salience: whereas individualistic motives are activated when a perceiver's own needs and goals are perceptually salient, social motives are activated when others' needs and goals are perceptually salient. It is concluded that both individualistic and social motives contribute in predictable ways to justice judgments.


MHC Class I Related Chain A (MICA) Antibodies - A Potential Cause of Renal Allograft Rejection.
MHC class I related chain A (MICA) antibodies, especially those directed against the donor in absence of donor-specific anti-HLA antibodies have been reported to be possibly associated with renal allograft rejection in sensitized recipients. We are the first ones to present a case series of five patients who underwent primary live related donor renal transplantation in non-sensitized recipients either in the presence of donor-specific MICA antibodies (MICA-DSA) or developed de novo. Four of them presented characteristics of either accelerated, acute or chronic antibody-mediated rejection (AMR) attributable to the presence of MICA DSA. This case series emphasizes that AMR due to MICA-DSA is amenable to treatment with conventional regimens for treatment of AMR and there is a need for screening of MICA antibodies especially those directed against the donor on case to case basis.


[Technical aspects of breast sonography. Experience with an immersion scanner (Octoson) (author's transl)].
The experience with the sonographic examination of 80 patients with an Octoson body unit is described. It was found that with the present technique immersion of the breast in most cases is less satisfactory than compression of the breast. The compound scan improves the information as compared with a single scan up to a point. Immersion sonography, like all other types of ultrasound examination, is at present not satisfactory as the sole method for examining the breast. As an addition to mammography and palpation, sonography is, however, already an important complementary method.


Quantitative evaluation of tongue protrusion force.
The tongue plays an important role in the functions of speech, mastication, swallowing, and breathing. The tongue helps in the maintenance of proper dental alignment and arch stability. Adequate strength is essential for the tongue to perform these tasks. Recently the Biomechanical Engineering Group from Universidade Federal de Minas Gerais, Brazil, developed a device to improve tongue strength evaluation. The purpose of this study is to describe and compare the main results obtained in tongue protrusion force measurements in different age groups using this new device. Fifteen healthy subjects were given a qualitative evaluation and determined to have normal tongue strength. They were separated by age in three groups: children, adults and elderly. They were then given a quantitative evaluation. Maximum and average forces were analyzed. The time taken to reach maximum force was also assessed. Higher values of maximum and average tongue force were obtained in the adult group, followed by the elderly group and the group of children. Older subjects had greater tongue force when compared to children. However, there were statistically significant differences in the average force and in the maximum force only between children and adults. Time taken to reach maximal isometric force was longer in the elderly group and shorter in the group of children than in the group of adults although no statistically significant difference was found between groups.


[Reproductive biology of Artibeus lituratus (Olfers, 1818) (Chiroptera: Phyllostomidae)].
The reproductive biology of the bat Artibeus lituratus was studied. Females were collected monthly at the Estação Florestal de Experimentação Engenheiro Agrônomo Mário Xavier, Itaguaí, R.J. The reproductive status of each female was assessed by the histological examination of the reproductive organs. The results suggest that A. lituratus is polioestrous since lactant females were found to be also pregnant. There are two birth peaks in the year that coincide with the rainy season.


Insomnia and incident depression: role of objective sleep duration and natural history.
Longitudinal studies that have examined the association of insomnia with incident depression using objective sleep measures are very limited. The aim of this study was to examine the predictive role of the severity of insomnia for incident depression in a general population sample using psychometric and polysomnographic data. From a random, general population sample of 1741 individuals of the Penn State Adult Cohort, 1137 adults without depression were followed up with a structured telephone interview after 7.5 years. All subjects completed a full medical evaluation, 1-night polysomnogram and Multiphasic Minnesota Personality Inventory at baseline. The incidence of depression was 15%. Poor sleep (odds ratio = 1.5, P = 0.001) and insomnia (odds ratio = 1.9, P = 0.031) were significantly associated with incident depression. The odds of incident depression were highest (odds ratio = 2.2, P = 0.019) in insomnia with objective short sleep duration and independent of Multiphasic Minnesota Personality Inventory Ego Strength scores, an index of poor coping resources. The persistence of insomnia and worsening of poor sleep into insomnia significantly increased the odds of incident depression (odds ratios ranged from 1.8 to 6.3), whereas their full remission did not (odds ratio ranged from 1.2 to 1.8). Insomnia with short sleep duration is associated with incident depression independent of poor coping resources, whereas the association of insomnia with normal sleep duration with incident depression was mediated by poor coping resources. Persistence and worsening of poor sleep or insomnia, but not their full remission, are significant predictors of incident depression. These data suggest that there is a significant relationship between the severity of insomnia and incident depression.


Genome-wide association study of anogenital distance and its (co)variances with fertility in growing and lactating Holstein-Friesian dairy cattle.
Anogenital distance (AGD) is a moderately heritable trait that can be measured at a young age that may provide an opportunity to indirectly select for improved fertility in dairy cattle. In this study, we characterized AGD and its genetic and phenotypic relationships with a range of body stature and fertility traits. We measured AGD, shoulder height, body length, and body weight in a population of 5,010 Holstein-Friesian and Holstein-Friesian × Jersey crossbred heifers at approximately 11 mo of age (AGD1). These animals were born in 2018 across 54 seasonal calving, pasture-based dairy herds. A second measure of AGD was collected in a subset of herds (n = 17; 1,956 animals) when the animals averaged 29 mo of age (AGD2). Fertility measures included age at puberty (AGEP), then time of calving, breeding, and pregnancy during the first and second lactations. We constructed binary traits reflecting the animal's ability to calve during the first 42 d of their herd's seasonal calving period (CR42), be presented for breeding during the first 21 d of the seasonal breeding period (PB21) and become pregnant during the first 42 d of the seasonal breeding period (PR42). The posterior mean of sampled heritabilities for AGD1 was 0.23, with 90% of samples falling within a credibility interval (90% CRI) of 0.20 to 0.26, whereas the heritability of AGD2 was 0.29 (90% CRI 0.24 to 0.34). The relationship between AGD1 and AGD2 was highly positive, with a genetic correlation of 0.89 (90% CRI 0.82 to 0.94). Using a GWAS analysis of 2,460 genomic windows based on 50k genotype data, we detected a region on chromosome 20 that was highly associated with variation in AGD1, and a second region on chromosome 13 that was moderately associated with variation in AGD1. We did not detect any genomic regions associated with AGD2 which was measured in fewer animals. The genetic correlation between AGD1 and AGEP was 0.10 (90% CRI 0.00 to 0.19), whereas the genetic correlation between AGD2 and AGEP was 0.30 (90% CRI 0.15 to 0.44). The timing of calving, breeding, and pregnancy (CR42, PB21, and PR42) during first or second lactations exhibited moderate genetic relationships with AGD1 (0.19 to 0.52) and AGD2 (0.46 to 0.63). Genetic correlations between AGD and body stature traits were weak (≤0.16). We conclude that AGD is a moderately heritable trait, which may have value as an early-in-life genetic predictor for reproductive success during lactation.


Isolation and characterization of RNA ligase from wheat germ.
A RNA ligase from wheat germ has been extensively purified. In the presence of ATP these enzyme preparations catalyze the covalent linkage of 5'-phosphate and 2',3'-cyclic phosphate termini of RNA chains. Concomitant with the formation of a 3',5'-phosphodiester linkage, the 2',3'-cyclic phosphate is converted to a 2'-phosphate ester, in accord with the findings of Konarska et al. [Konarska, M., Filipowicz, W. & Gross, H. J. (1982) Proc. Natl. Acad. Sci. USA 79, 1474-1478]. The action of the purified enzyme is totally dependent on ATP and on RNA substrates containing a 5'-phosphate terminus at one end and either a 2',3'-cyclic phosphate or a 2'-phosphate terminus at the other end. In the latter case, the reaction is about 30% as active as with the cyclic derivative. In contrast, RNA chains containing 3'-phosphate ends are less than 5% as active as those with the cyclic ends. Purified preparations of RNA ligase have an intrinsic ability to hydrolyze 2',3'-cyclic phosphate termini to 2'-phosphate termini. This reaction is readily detectable in the absence of ATP.


Identification of xylan arabinosyl 2-O-xylosyltransferases catalyzing the addition of 2-O-xylosyl residue onto arabinosyl side chains of xylan in grass species.
Grass xylan, the major hemicellulose in both primary and secondary cell walls, is heavily decorated with α-1,3-linked arabinofuranosyl (Araf) residues that may be further substituted at O-2 with xylosyl (Xyl) or Araf residues. Although xylan 3-O-arabinosyltransferases (XATs) catalyzing 3-O-Araf addition onto xylan have been characterized, glycosyltransferases responsible for the transfer of 2-O-Xyl or 2-O-Araf onto 3-O-Araf residues of xylan to produce the Xyl-Araf and Araf-Araf disaccharide side chains remain to be identified. In this report, we showed that a rice GT61 member, named OsXAXT1 (xylan arabinosyl 2-O-xylosyltransferase 1) herein, was able to mediate the addition of Xyl-Araf disaccharide side chains onto xylan when heterologously co-expressed with OsXAT2 in the Arabidopsis gux1/2/3 (glucuronic acid substitution of xylan 1/2/3) triple mutant that lacks any glycosyl substitutions. Recombinant OsXAXT1 protein expressed in human embryonic kidney 293 cells exhibited a xylosyltransferase activity catalyzing the addition of Xyl from UDP-Xyl onto arabinosylated xylooligomers. Consistent with its function as a xylan arabinosyl 2-O-xylosyltransferase, CRISPR-Cas9-mediated mutations of the OsXAXT1 gene in transgenic rice plants resulted in a reduction in the level of Xyl-Araf disaccharide side chains in xylan. Furthermore, we revealed that XAXT1 close homologs from several other grass species, including switchgrass, maize, and Brachypodium, possessed the same functions as OsXAXT1, indicating functional conservation of XAXTs in grass species. Together, our findings establish that grass XAXTs are xylosyltransferases catalyzing Xyl transfer onto O-2 of Araf residues of xylan to form the Xyl-Araf disaccharide side chains, which furthers our understanding of genes involved in xylan biosynthesis.


How special is social looking in ASD: a review.
This review is primarily concerned with the view that individuals with autism spectrum disorder (ASD) look less at the eyes and more at the mouth compared to typically developing (TD) individuals. Such performance in ASD could reflect that the eyes are not meaningful or that they are perceived as threatening, two ideas that may seem intuitively appealing. However, our review shows that despite the fact that the excess mouth/diminished eye gaze hypothesis fits with clinical common sense and initial data from adults, it does not-as a generalization across ages and contexts-fit with the emerging pattern of eye-tracking data. In adolescents and adults, there is only partial support for the excess mouth/diminished eye gaze hypothesis, and regarding children, most studies do not support this hypothesis. In particular, independent studies have found longer looking durations on the mouth in TD children than in children with ASD, and no difference for the eye area. We describe recent evidence that mouth fixations are functional responses related to (early) stages of normative language development. We conclude that although individuals with ASD often give less preferential attention to social objects and events (faces, people, and social actions) than TD individuals, the excess mouth/diminished eye gaze hypothesis of ASD is not generally supported. Therefore, this hypothesis needs to be reevaluated, as do related theories of social perception in ASD.


SMARCB1/INI1 Loss in Epithelioid Schwannoma: A Clinicopathologic and Immunohistochemical Study of 65 Cases.
The epithelioid variant of schwannoma is rare, and loss of SMARCB1/INI1 expression has been observed in a subset of cases. Our aim was to further define the clinicopathologic features and to evaluate SMARCB1/INI1 deficiency in a large cohort of 65 epithelioid schwannomas diagnosed between 2002 and 2015, which consisted of 32 men and 33 women with median age at diagnosis of 45 years (range, 13 to 75 y). Most tumors arose in the extremities (upper, 20, lower, 15) and trunk (17); 9 were visceral (8 gastrointestinal). Most somatic tumors were in dermis/subcutis (53/54) and encapsulated (53/54) with an epithelial membrane antigen-positive perineurial capsule in 46 cases; visceral tumors were unencapsulated. No patients were reported to have any neurocristopathy. Three patients had multiple lesions (2 each). Tumor size range was 0.4 to 22.7 cm (median, 1.2 cm). Tumors showed multilobulated growth of uniform epithelioid cells in sheets and nests or singly dispersed within a frequently myxoid or hyalinized stroma. Tumor cells had round vesicular nuclei and abundant palely eosinophilic cytoplasm, usually lacking significant pleomorphism or hyperchromasia. Some tumors showed foci resembling conventional schwannoma (spindled morphology, 29; Antoni B foci or Verocay bodies, 8; hyalinized thick-walled vessels, 16). Mitoses ranged from 0 to 9 per 10 high-power fields (median count, 1). No tumor had necrosis. Twenty-three cases showed degenerative nuclear atypia. Focally striking cytologic atypia was present in 7 tumors, 3 of which showed transformation to epithelioid malignant peripheral nerve sheath tumor. All tumors showed diffuse positivity for S-100 protein and consistent positivity for SOX10 (50/50), while INI1 expression was lost in 24 of 57. Other positive immunohistochemical results were: glial fibrillary acidic protein (15/37) and focal keratin (2/40); epithelial membrane antigen (0/53) and melanocytic markers were negative (Mart-1 0/29; HMB-45 0/23). Most patients underwent local excision (13 complete; 47 marginal/positive margins). Follow-up data available for 31 patients (range, 1 to 108 mo; median, 37) indicated that no patient had developed metastatic disease, including 3 cases with cytologic atypia, one of which showed malignant transformation. One tumor without atypia developed local recurrence 48 months after marginal excision; all other patients were alive with no evidence of disease. Epithelioid schwannoma most commonly occurs as a superficial tumor on the extremities or trunk in adults. Loss of SMARCB1/INI1 expression is seen in 42% of tumors. Tumors follow a generally benign clinical course, although recurrence and malignant transformation are infrequent. Some tumors are characterized by notable cytologic atypia, the significance of which is uncertain but which may indicate a morphologic continuum with low-grade epithelioid malignant peripheral nerve sheath tumor.


Radiological and clinical comparison of kinematically versus mechanically aligned total knee arthroplasty.
The aim of this study was to compare the post-operative radiographic and clinical outcomes between kinematically and mechanically aligned total knee arthroplasties (TKAs). A total of 60 TKAs (30 kinematically and 30 mechanically aligned) were performed in 60 patients with varus osteoarthritis of the knee using a navigation system. The angles of orientation of the joint line in relation to the floor, the conventional and true mechanical axis (tMA) (the line from the centre of the hip to the lowest point of the calcaneus) were compared, one year post-operatively, on single-leg and double-leg standing long leg radiographs between the groups. The range of movement and 2011 Knee Society Scores were also compared between the groups at that time. The angles of orientation of the joint line in the kinematic group changed from slight varus on double-leg standing to slight valgus with single-leg standing. The mechanical axes in the kinematic group passed through a neutral position of the knee in the true condition when the calcaneus was considered. The post-operative angles of flexion and functional activity scores were significantly better in the kinematic than in the mechanical group (p < 0.003 and 0.03, respectively). A kinematically aligned TKA results in a joint line which has a more parallel orientation in relation to the floor during single- and double-leg standing, and more neutral weight-bearing in tMA than a mechanically aligned TKA. Cite this article: Bone Joint J 2017;99-B:640-6.


Systemic sclerosis-associated interstitial lung disease.
Systemic sclerosis is an autoimmune connective tissue disease, which is characterised by immune dysregulation and progressive fibrosis that typically affects the skin, with variable internal organ involvement. It is a rare condition that affects mostly young and middle-aged women, resulting in disproportionate morbidity and mortality. Currently, interstitial lung disease is the most common cause of death among patients with systemic sclerosis, with a prevalence of up to 30% and a 10-year mortality of up to 40%. Interstitial lung disease is more common among African Americans and in people with the diffuse cutaneous form of systemic sclerosis or anti-topoisomerase 1 antibodies. Systemic sclerosis-associated interstitial lung disease most commonly presents with dyspnoea, cough, and a non-specific interstitial pneumonia pattern on CT scan, with a minority of cases fulfilling the criteria for usual interstitial pneumonia. The standard therapy has traditionally been combinations of immunosuppressants, particularly mycophenolate mofetil or cyclophosphamide. These immunosuppressants can be supplemented by targeted biological and antifibrotic therapies, whereas autologous haematopoietic stem-cell transplantation and lung transplantation are reserved for refractory cases.


More Accurate Transcript Assembly via Parameter Advising.
Computational tools used for genomic analyses are becoming more accurate but also increasingly sophisticated and complex. This introduces a new problem in that these pieces of software have a large number of tunable parameters that often have a large influence on the results that are reported. We quantify the impact of parameter choice on transcript assembly and take some first steps toward generating a truly automated genomic analysis pipeline by developing a method for automatically choosing input-specific parameter values for reference-based transcript assembly using the Scallop tool. By choosing parameter values for each input, the area under the receiver operator characteristic curve (AUC) when comparing assembled transcripts to a reference transcriptome is increased by an average of 28.9% over using only the default parameter choices on 1595 RNA-Seq samples in the Sequence Read Archive. This approach is general, and when applied to StringTie, it increases the AUC by an average of 13.1% on a set of 65 RNA-Seq experiments from ENCODE. Parameter advisors for both Scallop and StringTie are available on Github.


Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis.
Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.


A biotechnological approach to improving the nutritive value of alfalfa.
The postruminal supply of the sulfur-containing amino acids, methionine and cysteine, has been reported to be a major limitation to wool growth in sheep. We aim to improve the protein quality of forage for ruminants by introducing into alfalfa chimeric genes encoding a ruminally stable, sulfur amino acid-rich protein from sunflower seeds. Four gene constructs were transferred to Australian commercial cultivars of alfalfa using Agrobacterium tumefaciens-mediated transformation and selection with phosphinothricin (PPT). Modification of the sunflower seed albumin protein-coding region by addition of the coding information for an endoplasmic reticulum (ER) retention signal was found to greatly increase the level to which the sulfur amino acid-rich protein accumulated in the leaves of transgenic alfalfa plants. The Cauliflower Mosaic Virus (CaMV) 35S promoter and two light-regulated plant gene promoter regions were compared for their ability to direct high-level expression of the introduced genes in alfalfa leaves. The highest expression of sunflower seed albumin was found in transformants bearing a gene incorporating the promoter from the Arabidopsis thaliana ats1A gene, which encodes the ribulose bisphosphate carboxylase small subunit. The highest level of sunflower seed albumin found in transgenic alfalfa leaves was estimated to constitute .1% of soluble leaf protein. This level of accumulation of the foreign protein would be predicted to supply an extra 40 mg of sulfur amino acids daily to sheep fed the modified forage. Published studies in which wool growth rates were significantly increased employed supplementation of approximately 1 to 2 g of sulfur amino acids daily.


A model for studying cutaneous wound healing and resilience to aging: Ear punch biopsy in old mice.
Resilience to aging is a biological event that precedes age-related decline in physiological function and is defined as an organism's ability to respond to physical stress with increasing age. There is a need to identify factors that may predict resilience for enhancing and maintaining healthy aging. Older people often experience delayed wound healing beause of compromised tissue repair and immune response. Therefore preclincal models may be of value to investigate the relationship between cutaneous wound healing and resilience to aging. This brief report descibes an ear punch biopsy model of cutaneous wound healing in aging mice and shows that mice with biopsy ear wounds that heal more quickly have better cognition, increased strength and better running endurance later in life.


Effects of combination therapy of docetaxel with selenium on the human breast cancer cell lines MDA-MB-231 and MCF-7.
The anticancer property and cytoprotective role of selenium in chemotherapy have been reported. However, the combination effects of selenium on chemotherapy for advanced breast cancer have not yet been clearly defined. The purpose of this study was to investigate the combined effects of selenium on chemotherapy using docetaxel on breast cancer cell lines. Under adherent culture conditions, two breast cancer cell lines, MDA-MB-231 and MCF-7, were treated with docetaxel at 500pM and selenium at 100nM, 1µM, or 10µM. Changes in cell growth, cell cycle duration, and degree of apoptosis after 72 hours in each treated group were evaluated. In the MDA-MB-231 cells, the combination therapy group (docetaxel at 500pM plus selenium at 10µM) showed a significantly decreased percentage of cell growth (15% vs. 28%; P = 0.004), a significantly increased percentage of late apoptosis (63% vs. 26%; P = 0.001), and an increased cell cycle arrest in the G2/M phase (P = 0.001) compared with the solitary docetaxel therapy group. Isobologram analysis demonstrated the synergistic effect of the combination therapy in the MDA-MB-231 cells. However, in the MCF-7 cells, no significant differences in the percentage of cell growth apoptosis, the percentage of apoptosis, and the pattern of cell cycle arrest were noted between the combination therapy groups and the solitary docetaxel therapy group. Our in vitro study indicated that the combination of selenium with docetaxel inhibits cell proliferation through apoptosis and cell arrest in the G2/M phase in MDA-MB-231 breast cancer cells.


High-resolution solid-state NMR structure of an anticancer agent.
We demonstrate that solid-state NMR methods can be used to rapidly determine the high-resolution 3D structure of Epothilone B in the polycrystalline state. The solid-state NMR structures exhibit an average heavy atom RMSD to the mean structure of 0.14 A. The 3D-structural analysis leads to stereospecific assignments and provides insight into the influence of intermolecular interactions upon ssNMR chemical-shift parameters. Our results pave the way to the study of ligand-microtubule interactions in a noncrystalline and insoluble environment at atomic level.


Treatment of Setleis syndrome. Case report.
Setleis syndrome is characterised by a leonine appearance. We have treated an 8-year-old boy with the syndrome and describe the plastic surgical procedures done and the histological findings.


Transmission dynamics and control of COVID-19 in Chile, March-October, 2020.
Since the detection of the first case of COVID-19 in Chile on March 3rd, 2020, a total of 513,188 cases, including ~14,302 deaths have been reported in Chile as of November 2nd, 2020. Here, we estimate the reproduction number throughout the epidemic in Chile and study the effectiveness of control interventions especially the effectiveness of lockdowns by conducting short-term forecasts based on the early transmission dynamics of COVID-19. Chile's incidence curve displays early sub-exponential growth dynamics with the deceleration of growth parameter, p, estimated at 0.8 (95% CI: 0.7, 0.8) and the reproduction number, R, estimated at 1.8 (95% CI: 1.6, 1.9). Our findings indicate that the control measures at the start of the epidemic significantly slowed down the spread of the virus. However, the relaxation of restrictions and spread of the virus in low-income neighborhoods in May led to a new surge of infections, followed by the reimposition of lockdowns in Greater Santiago and other municipalities. These measures have decelerated the virus spread with R estimated at ~0.96 (95% CI: 0.95, 0.98) as of November 2nd, 2020. The early sub-exponential growth trend (p ~0.8) of the COVID-19 epidemic transformed into a linear growth trend (p ~0.5) as of July 7th, 2020, after the reimposition of lockdowns. While the broad scale social distancing interventions have slowed the virus spread, the number of new COVID-19 cases continue to accrue, underscoring the need for persistent social distancing and active case detection and isolation efforts to maintain the epidemic under control.


Late salvage of failed open reduction and internal fixation of posterior wall fractures of the acetabulum.
The purpose of this study was to review the outcome of late revision surgery in a series of patients with posterior wall fractures having recurrent hip instability after failed initial open reduction and internal fixation. Retrospective analysis of consecutive patients. Level 1 trauma center. A retrospective analysis of consecutive acetabulum patients treated by a single surgeon between 1989 and 2005 identified 4 patients referred for recurrent hip instability subsequently treated by revision open reduction and internal fixation performed 3 weeks or more (range 3 weeks to 9 months) after the original injury. Revision open reduction and internal fixation through a Kocher-Langenbeck approach. Final radiographic appearance and modified Merle d'Aubigne Score. Three of the 4 patients eventually required total hip arthroplasty. Two of these 3 patients required total hip arthroplasty within 18 months of revision surgery. Both, older than 50 years, had experienced catastrophic early hip redislocation associated with femoral head pathology after the original surgery. Despite progression of traumatic arthrosis, 1 patient continues to ambulate without assistance or pain on her native hip, 18 years after the revision open reduction and internal fixation surgery. Patients are likely to experience poor clinical outcome, ultimately requiring total hip arthroplasty, when salvage procedures are delayed by more than 3 weeks. In older patients, failure occurs rapidly; in younger patients, total hip replacement surgery may be delayed. Therefore, in older patients, particularly if there is concomitant damage to the femoral head, late revision fracture fixation surgery is ill advised and total hip arthroplasty seems to be the most appropriate secondary surgery. However, late revision fracture fixation surgery may provide young, active patients a limited number of years of satisfactory function before total hip arthroplasty is required.