Effect of competition on the production and activity of secondary metabolites in Aspergillus species.
Secondary metabolites are of intense interest to humans due to their pharmaceutical and/or toxic properties. Also, these metabolites are clinically relevant because of their importance in fungal pathogenesis. Aspergillus species secrete secondary metabolites when grown individually and in the presence of other fungal species. However, it is not known whether secreted secondary metabolites provide a competitive advantage over other fungal species, or whether competition has any effect on the production of those metabolites. Here, we have performed co-cultivation competition assays among different species of Aspergillus to determine relative species fitness in culture, and to analyze the presence of possible antifungal activity of secondary metabolites in extracts. The results show that, for the most part, at 30 degrees C only one species is able to survive direct competition with a second species. In contrast, survival of both competitors was often observed at 37 degrees C. Consistent with these observations, antifungal activity of extracts from cultures grown at 30 degrees C was greater than that of extract from cultures at 37 degrees C. Interestingly, culture extracts from all species studied had some degree of antifungal activity, but in general, the extracts had greater antifungal activity when species were grown in the presence of a competitor. Using gas chromatography it was determined that the composition of extracts changed due to competition and a shift in temperature. These findings indicate that co-cultivation could be a very promising method for inducing and characterizing novel antifungal compounds produced by species of Aspergillus.


A versatile and robust Agrobacterium-based gene stacking system generates high-quality transgenic Arabidopsis plants.
Biotechnology provides a means for the rapid genetic improvement of plants. Although single genes have been important in engineering herbicide and pest tolerance traits in crops, future improvements of complex traits like yield and nutritional quality will likely require the introduction of multiple genes. This research reports a system (GAANTRY; Gene Assembly in Agrobacterium by Nucleic acid Transfer using Recombinase technologY) for the flexible, in vivo stacking of multiple genes within an Agrobacterium virulence plasmid Transfer-DNA (T-DNA). The GAANTRY system utilizes in vivo transient expression of unidirectional site-specific recombinases and an alternating selection scheme to sequentially assemble multiple genes into a single transformation construct. To demonstrate GAANTRY's capabilities, 10 cargo sequences were sequentially stacked together to produce a 28.5-kbp T-DNA, which was used to generate hundreds of transgenic events. Approximately 90% of the events identified using a dual antibiotic selection screen exhibited all of the introduced traits. A total of 68% of the tested lines carried a single copy of the selection marker transgene located near the T-DNA left border, and only 8% contained sequence from outside the T-DNA. The GAANTRY system can be modified to easily accommodate any method of DNA assembly and generate high-quality transgenic plants, making it a powerful, yet simple to use tool for plant genetic engineering.


So depression is an inflammatory disease, but where does the inflammation come from?
We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is 'what is the source of this chronic low-grade inflammation?' This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency. The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.


The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe): a protocol of a prospective, cohort study of causes of mortality among preterm births and stillbirths.
In South Asia, where most stillbirths and neonatal deaths occur, much remains unknown about the causes of these deaths. About one-third of neonatal deaths are attributed to prematurity, yet the specific conditions which cause these deaths are often unclear as is the etiology of stillbirths. In low-resource settings, most women are not routinely tested for infections and autopsy is rare. This prospective, cohort study will be conducted in hospitals in Davengere, India and Karachi, Pakistan. All women who deliver either a stillbirth or a preterm birth at one of the hospitals will be eligible for enrollment. With consent, the participant and, when applicable, her offspring, will be followed to 28-days post-delivery. A series of research tests will be conducted to determine infection and presence of other conditions which may contribute to the death. In addition, all routine clinical investigations will be documented. For both stillbirths and preterm neonates who die ≤ 28 days, with consent, a standard autopsy as well as minimally invasive tissue sampling will be conducted. Finally, an expert panel will review all available data for stillbirths and neonatal deaths to determine the primary and contributing causes of death using pre-specified guidance. This will be among the first studies to prospectively obtain detailed information on causes of stillbirth and preterm neonatal death in low-resource settings in Asia. Determining the primary causes of death will be important to inform strategies most likely to reduce the high mortality rates in South Asia. Clinicaltrials.gov ( NCT03438110 ) Clinical Trial Registry of India ( CTRI/2018/03/012281 ).


Modelling Ebola virus dynamics: Implications for therapy.
Ebola virus (EBOV) causes a severe, often fatal Ebola virus disease (EVD), for which no approved antivirals exist. Recently, some promising anti-EBOV drugs, which are experimentally potent in animal models, have been developed. However, because the quantitative dynamics of EBOV replication in humans is uncertain, it remains unclear how much antiviral suppression of viral replication affects EVD outcome in patients. Here, we developed a novel mathematical model to quantitatively analyse human viral load data obtained during the 2000/01 Uganda EBOV outbreak and evaluated the effects of different antivirals. We found that nucleoside analogue- and siRNA-based therapies are effective if a therapy with a >50% inhibition rate is initiated within a few days post-symptom-onset. In contrast, antibody-based therapy requires not only a higher inhibition rate but also an earlier administration, especially for otherwise fatal cases. Our results demonstrate that an appropriate choice of EBOV-specific drugs is required for effective EVD treatment.


Homeopathic and conventional treatment for acute respiratory and ear complaints: a comparative study on outcome in the primary care setting.
The aim of this study was to assess the effectiveness of homeopathy compared to conventional treatment in acute respiratory and ear complaints in a primary care setting. The study was designed as an international, multi-centre, comparative cohort study of non-randomised design. Patients, presenting themselves with at least one chief complaint: acute (< or = 7 days) runny nose, sore throat, ear pain, sinus pain or cough, were recruited at 57 primary care practices in Austria (8), Germany (8), the Netherlands (7), Russia (6), Spain (6), Ukraine (4), United Kingdom (10) and the USA (8) and given either homeopathic or conventional treatment. Therapy outcome was measured by using the response rate, defined as the proportion of patients experiencing 'complete recovery' or 'major improvement' in each treatment group. The primary outcome criterion was the response rate after 14 days of therapy. Data of 1,577 patients were evaluated in the full analysis set of which 857 received homeopathic (H) and 720 conventional (C) treatment. The majority of patients in both groups reported their outcome after 14 days of treatment as complete recovery or major improvement (H: 86.9%; C: 86.0%; p = 0.0003 for non-inferiority testing). In the per-protocol set (H: 576 and C: 540 patients) similar results were obtained (H: 87.7%; C: 86.9%; p = 0.0019). Further subgroup analysis of the full analysis set showed no differences of response rates after 14 days in children (H: 88.5%; C: 84.5%) and adults (H: 85.6%; C: 86.6%). The unadjusted odds ratio (OR) of the primary outcome criterion was 1.40 (0.89-2.22) in children and 0.92 (0.63-1.34) in adults. Adjustments for demographic differences at baseline did not significantly alter the OR. The response rates after 7 and 28 days also showed no significant differences between both treatment groups. However, onset of improvement within the first 7 days after treatment was significantly faster upon homeopathic treatment both in children (p = 0.0488) and adults (p = 0.0001). Adverse drug reactions occurred more frequently in adults of the conventional group than in the homeopathic group (C: 7.6%; H: 3.1%, p = 0.0032), whereas in children the occurrence of adverse drug reactions was not significantly different (H: 2.0%; C: 2.4%, p = 0.7838). In primary care, homeopathic treatment for acute respiratory and ear complaints was not inferior to conventional treatment.


A 39-Amino-Acid C-Terminal Truncation of GDV1 Disrupts Sexual Commitment in Plasmodium falciparum.
Malaria is a mosquito-borne disease caused by apicomplexan parasites of the genus Plasmodium. Completion of the parasite's life cycle depends on the transmission of sexual stages, the gametocytes, from an infected human host to the mosquito vector. Sexual commitment occurs in only a small fraction of asexual blood-stage parasites and is initiated by external cues. The gametocyte development protein 1 (GDV1) has been described as a key facilitator to trigger sexual commitment. GDV1 interacts with the silencing factor heterochromatin protein 1 (HP1), leading to its dissociation from heterochromatic DNA at the genomic locus encoding AP2-G, the master transcription factor of gametocytogenesis. How this process is regulated is not known. In this study, we have addressed the role of protein kinases implicated in gametocyte development. From a pool of available protein kinase knockout (KO) lines, we identified two kinase knockout lines which fail to produce gametocytes. However, independent genetic verification revealed that both kinases are not required for gametocytogenesis but that both lines harbor the same mutation that leads to a truncation in the extreme C terminus of GDV1. Introduction of the identified nonsense mutation into the genome of wild-type parasite lines replicates the observed phenotype. Using a GDV1 overexpression line, we show that the truncation in the GDV1 C terminus does not interfere with the nuclear import of GDV1 or its interaction with HP1 in vitro but appears to be important to sustain GDV1 protein levels and thereby sexual commitment.IMPORTANCE Transmission of malaria-causing Plasmodium species by mosquitos requires the parasite to change from a continuously growing asexual parasite form growing in the blood to a sexually differentiated form, the gametocyte. Only a small subset of asexual parasites differentiates into gametocytes that are taken up by the mosquito. Transmission represents a bottleneck in the life cycle of the parasite, so a molecular understanding of the events that lead to stage conversion may identify novel intervention points. Here, we screened a subset of kinases we hypothesized to play a role in this process. While we did not identify kinases required for sexual conversion, we identified a mutation in the C terminus of the gametocyte development 1 protein (GDV1), which abrogates sexual development. The mutation destabilizes the protein but not its interaction with its cognate binding partner HP1. This suggests an important role for the GDV1 C terminus beyond trafficking and protein stability.


Loss of caveolin-3 induces a lactogenic microenvironment that is protective against mammary tumor formation.
Here, we show that functional loss of a single gene is sufficient to confer constitutive milk protein production and protection against mammary tumor formation. Caveolin-3 (Cav-3), a muscle-specific caveolin-related gene, is highly expressed in muscle cells. We demonstrate that Cav-3 is also expressed in myoepithelial cells within the mammary gland. To determine whether genetic ablation of Cav-3 expression affects adult mammary gland development, we studied the phenotype(s) of Cav-3(-/-)-null mice. Interestingly, Cav-3(-/-) virgin mammary glands developed lobulo-alveolar hyperplasia, akin to the changes normally observed during pregnancy and lactation. Genome-wide expression profiling revealed up-regulation of gene transcripts associated with pregnancy/lactation, mammary stem cells, and human breast cancers, consistent with a constitutive lactogenic phenotype. Expression levels of three key transcriptional regulators of lactation, namely Elf5, Stat5a, and c-Myc, were also significantly elevated. Experiments with pregnant mice directly showed that Cav-3(-/-) mice underwent precocious lactation. Finally, using orthotopic tumor cell implantation, we demonstrated that virgin Cav-3(-/-) mice were dramatically protected against mammary tumor formation. Thus, Cav-3(-/-) mice are a novel preclinical model to study the protective effects of a lactogenic microenvironment on mammary tumor onset and progression. Our current studies have broad implications for using the lactogenic microenvironment as a paradigm to discover new therapies for the prevention and/or treatment of human breast cancers.


Pressure-induced unfolding of the molten globule of all-Ala alpha-lactalbumin.
Pressure-induced unfolding of a molten globule (MG) was studied in a residue-specific manner with (1)H-(15)N two-dimensional NMR spectroscopy using a variant of human alpha-lactalbumin (alpha-LA), in which all eight cysteines had been replaced with alanines (all-Ala alpha-LA). The NMR spectrum underwent a series of changes from 30 to 2000 bar at 20 degrees C and from -18 degrees C to 36 degrees C at 2000 bar, showing a highly heterogeneous unfolding pattern according to the secondary structural elements of the native structure. Unfolding began in the loop part of the beta-domain, and then extended to the remainder of the beta-domain, after which the alpha-domain began to unfold. Within the alpha-domain, the pressure stability decreased in the order: D-helix approximately 3(10)-helix > C-helix approximately B-helix > A-helix. The D-helix, C-terminal 3(10)-helix and a large part of B- and C-helices did not unfold at 2000 bar, even at 36 degrees C or at -18 degrees C. The results verify that the MG state consists of a mixture of variously unfolded conformers from the mostly folded to the nearly totally unfolded that differ in stability and partial molar volume. Not only heat but also cold denaturation was observed, supporting the view that the MG state is stabilized by hydrophobic interactions.


All-Cause Mortality and Incidence of Major Adverse Cardiac Events in Sickle Cell Nephropathy: A Comparative Study.
Background Sickle cell disease (SCD) is an autosomal recessive disease resulting in hemolytic anemia and recurrent vaso-occlusive events. Consequently, it can result in a broad range of functional and structural renal and cardiac alterations. Chronic kidney disease (CKD), in SCD, is associated with proteinuria, microalbuminuria, and hemoglobinuria. Cardiac complications in SCD include pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, and sudden death. In patients with advancing age, cardio-renal dysfunction can have substantial effects on morbidity and mortality. Our primary aim was to compare the incidence of major adverse cardiac events (MACE) and all-cause mortality in sickle cell nephropathy (SCN). Methods In this retrospective study, we used International Classification of Diseases (ICD)-10 codes to identify admissions in 2019 with a diagnosis of MACE with a prior diagnosis of SCD and/or SCN. Our search of the HCA Healthcare Enterprise Data Warehouse for adult patients >18 years yielded 6,693 patients with SCD, of which 658 patients (9.8%) had SCN. Primary endpoints were incidence of MACE and all-cause mortality. Patients with MACE encompassed those with nonfatal stroke, nonfatal myocardial infarction, and congestive heart failure (CHF) exacerbations. A secondary endpoint was length of stay (LOS). Logistic regression analysis was used for MACE and all-cause mortality. LOS was analyzed using multiple linear regression analysis. Results were considered statistically significant for analyses showing p <0.05. All outcomes were adjusted for demographic variables and comorbidities. Results Logistic regression, after adjustment for comorbidities, demonstrated that SCN patients had significantly higher odds of all-cause mortality (odds ratio [OR] 2.343, p = 0.035, 95% confidence interval [CI] 1.063-5.166) compared to patients without SCN. Compared to those without SCN, those with SCN did not have a higher odds of MACE (OR 1.281, p = 0.265, 95% CI 0.828-1.982). Linear regression for LOS did not reveal a significant association with SCN (p = 0.169, 95% CI 0.157-0.899). Conclusion Based on the analysis of 6,693 patients with SCD, SCN was associated with significantly higher odds of all-cause mortality. SCN was not associated with significantly higher odds of MACE or prolonged LOS.


Differential timing of antibody-mediated phagocytosis and cell-free killing of invasive African Salmonella allows immune evasion.
Nontyphoidal Salmonellae commonly cause fatal bacteraemia in African children lacking anti-Salmonella antibodies. These are facultative intracellular bacteria capable of cell-free and intracellular survival within macrophages. To better understand the relationship between extracellular and intracellular infection in blood and general mechanisms of Ab-related protection against Salmonella, we used human blood and sera to measure kinetics of Ab and complement deposition, serum-mediated bactericidal killing and phagocytosis of invasive African Salmonella enterica serovar Typhimurium D23580. Binding of antibodies peaked by 30 s, but C3 deposition lagged behind, peaking after 2-4 min. C5b-9 deposition was undetectable until between 2 and 6 min and peaked after 10 min, after which time an increase in serum-mediated killing occurred. In contrast, intracellular, opsonized Salmonellae were readily detectable within 5 min. By 10 min, around half of monocytes and most neutrophils contained bacteria. The same kinetics of serum-mediated killing and phagocytosis were observed with S. enterica Typhimurium laboratory strain SL1344, and the S. enterica Enteritidis African invasive isolate D24954 and laboratory strain PT4. The differential kinetics between cell-free killing and phagocytosis of invasive nontyphoidal Salmonella allows these bacteria to escape the blood and establish intracellular infection before they are killed by the membrane attack complex.


Multi-domain models of risk factors for depression and anxiety symptoms in preschoolers: evidence for common and specific factors.
Relatively few studies have examined multiple pathways by which risk factors from different domains are related to symptoms of anxiety and depression in young children; even fewer have assessed risks for these symptoms specifically, rather than for internalizing symptoms in general. We examined a theoretically- and empirically-based model of variables associated with these symptom types in a diverse community sample of 796 4-year-olds (391 boys, 405 girls) that included factors from the following domains: contextual (SES, stress and family conflict); parent characteristics (parental depression); parenting (support/engagement, hostility and scaffolding); and child characteristics including negative affect (NA) effortful control (EC) sensory regulation (SR), inhibitory control (IC) and attachment. We also compared the models to determine which variables contribute to a common correlates of symptoms of anxiety or depression, and which correlates differentiate between those symptom types. In the best-fitting model for these symptom types (a) SES, stress and conflict had indirect effects on both symptom types via long-chain paths; (b) caregiver depression had direct effects and indirect ones (mediated through parenting and child effortful control) on both symptom types; (c) parenting had direct and indirect effects (via temperament and SR); and temperament had direct effects on both symptom types. These data provide evidence of common risk factors, as well as indicate some specific pathways/mediators for the different symptom types. EC was related to anxiety, but not depression symptoms, suggesting that strategies to improve child EC may be particularly effective for treatment of anxiety symptoms in young children.


Surface microhardness of three thicknesses of mineral trioxide aggregate in different setting conditions.
This study aimed to compare the surface microhardness of mineral trioxide aggregate (MTA) samples having different thicknesses and exposed to human blood from one side and with or without a moist cotton pellet on the other side. Ninety cylindrical molds with three heights of 2, 4, and 6 mm were fabricated. In group 1 (dry condition), molds with heights of 2, 4, and 6 mm (10 molds of each) were filled with ProRoot MTA (Dentsply Tulsa Dental), and the upper surface of the material was not exposed to any additional moisture. In groups 2 and 3, a distilled water- or phosphate-buffered saline (PBS)-moistened cotton pellet was placed on the upper side of MTA, respectively. The lower side of the molds in all the groups was in contact with human blood-wetted foams. After 4 day, the Vickers microhardness of the upper surface of MTA was measured. In the dry condition, the 4 and 6 mm-thick MTA samples showed significantly lower microhardness than the 2 mm-thick samples (p = 0.003 and p = 0.001, respectively). However, when a distilled water- or PBS-moistened cotton pellet was placed over the MTA, no significant difference was found between the surface microhardness of samples having the abovementioned three thicknesses of the material (p = 0.210 and p = 0.112, respectively). It could be concluded that a moist cotton pellet must be placed over the 4 to 6 mm-thick MTA for better hydration of the material. However, this might not be necessary when 2 mm-thick MTA is used.


Observation of Proton Transfer Coupled Spin Transition and Trapping of Photoinduced Metastable Proton Transfer State in an Fe(II) Complex.
An important technique to realize novel electron- and/or proton-based functionalities is to use a proton-electron coupling mechanism. When either a proton or electron is excited, the other one is modulated, producing synergistic functions. However, although compounds with proton-coupled electron transfer have been synthesized, crystalline molecular compounds that exhibit proton-transfer-coupled spin-transition (PCST) behavior have not been reported. Here, we report the first example of a PCST Fe(II) complex, wherein the proton lies on the N of hydrazone and pyridine moieties in the ligand at high-spin and low-spin Fe(II), respectively. When the Fe(II) complex is irradiated with light, intramolecular proton transfer occurs from pyridine to hydrazone in conjunction with the photoinduced spin transition via the PCST mechanism. Because the light-induced excited high-spin state is trapped at low temperatures in the Fe(II) complex-a phenomenon known as the light-induced excited-spin-state trapping effect-the light-induced proton-transfer state, wherein the proton lies on the N of hydrazone, is also trapped as a metastable state. The proton transfer was accomplished within 50 ps at 190 K. The bistable nature of the proton position, where the position can be switched by light irradiation, is useful for modulating proton-based functionalities in molecular devices.


Arabidopsis proteome and the mass spectral assay library.
Arabidopsis is an important model organism and the first plant with its genome completely sequenced. Knowledge from studying this species has either direct or indirect applications for agriculture and human health. Quantitative proteomics by data-independent acquisition mass spectrometry (SWATH/DIA-MS) was recently developed and is considered as a high-throughput, massively parallel targeted approach for accurate proteome quantification. In this approach, a high-quality and comprehensive spectral library is a prerequisite. Here, we generated an expression atlas of 10 organs of Arabidopsis and created a library consisting of 15,514 protein groups, 187,265 unique peptide sequences, and 278,278 precursors. The identified protein groups correspond to ~56.5% of the predicted proteome. Further proteogenomics analysis identified 28 novel proteins. We applied DIA-MS using this library to quantify the effect of abscisic acid on Arabidopsis. We were able to recover 8,793 protein groups of which 1,787 were differentially expressed. MS data are available via ProteomeXchange with identifier PXD012708 and PXD012710 for data-dependent acquisition and PXD014032 for DIA analyses.


A 3D printed PCL/hydrogel construct with zone-specific biochemical composition mimicking that of the meniscus.
Engineering the meniscus is challenging due to its bizonal structure; the tissue is cartilaginous at the inner portion and fibrous at the outer portion. Here, we constructed an artificial meniscus mimicking the biochemical organization of the native tissue by 3D printing a meniscus shaped PCL scaffold and then impregnating it with agarose (Ag) and gelatin methacrylate (GelMA) hydrogels in the inner and outer regions, respectively. After incubating the constructs loaded with porcine fibrochondrocytes for 8 weeks, we demonstrated that presence of Ag enhanced glycosaminoglycan (GAG) production by about 4 fold (p < 0.001), while GelMA enhanced collagen production by about 50 fold (p < 0.001). In order to mimic the physiological loading environment, meniscus shaped PCL/hydrogel constructs were dynamically stimulated at strain levels gradually increasing from the outer region (2% of initial thickness) towards the inner region (10%). Incorporation of hydrogels protected the cells from the mechanical damage caused by dynamic stress. Dynamic stimulation resulted in increased ratio of collagen type II (COL 2) in the Ag-impregnated inner region (from 50% to 60% of total collagen), and increased ratio of collagen type I (COL 1) in the GelMA-impregnated outer region (from 60% to 70%). We were able to engineer a meniscus, which is cartilage-like at the inner portion and fibrocartilage-like at the outer portion. Our construct has a potential for use as a substitute for total meniscus replacement.


Fertility among female hairdressers.
The study investigated whether working as a hairdresser has a negative impact on fertility, measured as time to pregnancy and miscarriage risk. Self-administered questionnaires were sent to 5289 Swedish hairdressers (response rate 50%) and to 5299 age-matched women from the general Swedish population (response rate 54%). Information was collected on time to pregnancy or trying time for women who had tried, but failed, to conceive at the time of the study. The outcome of the pregnancy was determined and categorized as either miscarriage or stillbirth or live birth. The hairdressers were compared with the referents with respect to these two outcomes. Within the hairdresser cohort, the effects of hair treatments, as well as physical workload and stress were investigated. The hairdressers were less successful than the reference cohort in conceiving (fecundability ratio 0.91, 95% confidence interval 0.83-0.99). The effect was reduced after first-month conceptions were excluded, the indication being that the effect may be the result of birth control bias. Within the hairdresser cohort, a self-perceived stressful work situation seemed to prolong the time to pregnancy. No effects were found for the different chemical hair treatments. There was no cohort difference with respect to miscarriage risk (odds ratio 1.12, 95% confidence interval 0.88-1.42), but miscarriage risks were increased for most of the hair treatments and for self-perceived stressful work situations. However, none of these effects were statistically significant. The present study indicates a negative impact on time to pregnancy and miscarriage risk for working as a hairdresser".


Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy.
Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]). A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045). The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study.


Hsp27 protects mitochondria of thermotolerant cells against apoptotic stimuli.
Enhanced cell survival and resistance to apoptosis during thermotolerance correlates with an increased expression of heat shock proteins (Hsps). Here we present additional evidence in support of the hypothesis that the induction of Hsp27 and Hsp72 during acquired thermotolerance in Jurkat T-lymphocytes prevents apoptosis. In thermotolerant cells, Hsp27 was shown to associate with the mitochondrial fraction, and inhibition of Hsp27 induction during thermotolerance in cells transfected with hsp27 antisense potentiated mitochondrial cytochrome c release after exposure to various apoptotic stimuli, despite the presence of elevated levels of Hsp72. Caspase activation and apoptosis were inhibited under these conditions. In vitro studies revealed that recombinant Hsp72 more efficiently blocked cytochrome c-mediated caspase activation than did recombinant Hsp27. A model is presented for the inhibition of apoptosis during thermotolerance in which Hsp27 preferentially blocks mitochondrial cytochrome c release, whereas Hsp72 interferes with apoptosomal caspase activation.


Are orthodontic systematic reviews registered a priori in PROSPERO?
Aim of this study was to assess the registration of orthodontic systematic reviews in PROSPERO. Seven databases were searched for orthodontic systematic reviews published in 2012-2016. After duplicate study selection and data extraction, descriptive statistics, followed by chi-square/Fisher exact tests were calculated. Finally, bivariable/multivariable regression with relative risks (RR) and 95% confidence intervals (CIs) was used. A total of 182 orthodontic systematic reviews were identified, 37 (20.3%) of which were registered in PROSPERO, with registration rates ranging from 4.3% in 2012 to 37.0% in 2016. Differences in review registration were found according to publication year, geographic origin, multicentre status, funding, and journal category. After controlling for confounders, each additional year was associated with increased registration probability (RR = 1.51; 95% CI = 1.19-1.93). Reviews from South America were more likely to be registered than reviews from Europe (RR = 1.49; 95% CI = 1.06-2.11). Finally, reviews published in orthodontic specialty journals were more likely to be registered than reviews in general dentistry journals (RR = 1.87; 95% CI = 1.02-3.49). A small percentage of orthodontic systematic reviews was registered a priori, although improvement signs have been seen since the initiation of PROSPERO.


Decreased fluidity of polymorphonuclear leukocyte membrane in streptozocin-induced diabetic rats.
Using flow cytometry with the excimer-forming lipid technique with pyrenedecanoic acid, we measured membrane fluidity of polymorphonuclear leukocytes (PMNs) from 20 streptozocin (STZ)-induced diabetic rats. Diabetes mellitus was induced in male Sprague-Dawley rats (body wt 243 +/- 11 g) with an injection of 25 mg/kg i.v. STZ. Membrane fluidity of PMNs was significantly lower at 2 wk after the STZ injection when serum glucose reached the plateau (31.1 +/- 5.8 mM), and after 3 wk, membrane fluidity remained unchanged. In 7 STZ-resistant rats for which serum glucose was less than 10 mM at 2 wk after the STZ injection, gradual normalization in membrane fluidity was observed. PMN membrane fluidity at each week correlated inversely with respective serum glucose levels 1 wk previously (r = -0.76) but not with serum lipid levels. Cross-incubation studies ascribed this observation to factors in the diabetic rat serum. Glycosylated protein, which was separated from diabetic rat serum, decreased membrane fluidity of control rat PMNs. Human diabetic subjects have an increased risk for infection, which may be due partly to altered membrane fluidity of their PMNs.


Playfulness in children with and without disability: measurement and intervention.
The differences in playfulness between young children with cerebral palsy and developmental delays and children who are typically developing, and the comparative effects of two interventions (one focused on improving mother-child interaction patterns, the other a neurodevelopmental treatment [NDT] session) on children's playfulness were examined in this study. Reliability and validity of the Test of Playfulness (ToP) also were examined. Three trained raters used the ToP to score 38 children, half with cerebral palsy and developmental delays and half typically developing, as they played with their mothers. Mental ages of the children ranged from 3 to 18 months. The mother-child dyads in which the children had cerebral palsy and developmental delays were then randomly assigned to an intervention group. After a 1-hr intervention to improve mother-child interaction, the children were rescored on the ToP. After examination of ToP reliability and validity, children with cerebral palsy and developmental delays were found to score significantly lower on the ToP than their peers who were typically developing. In addition, children whose mothers received an intervention to improve mother-child interactions scored significantly higher on the ToP after intervention than before intervention. However, the gain scores of children whose mothers received the intervention were not significantly higher than those of children who received direct NDT. The results suggested that when the shared goal of parents and therapists is to enable children to express their inherent playfulness, intervention to improve parent-child interactions may be more potent than intervention directed at improving the child's developmental skills.


Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro.
1. We tested the hypothesis that nitric oxide (NO) augments vagal neurotransmission and bradycardia via phosphorylation of presynaptic calcium channels to increase vesicular release of acetylcholine. 2. The effects of enzyme inhibitors and calcium channel blockers on the actions of the NO donor sodium nitroprusside (SNP) were evaluated in isolated guinea-pig atrial-right vagal nerve preparations. 3. SNP (10 microM) augmented the heart rate response to vagal nerve stimulation but not to the acetylcholine analogue carbamylcholine (100 nM). SNP also increased the release of [3H]acetylcholine in response to field stimulation. No effect of SNP was observed on either the release of [3H] acetylcholine or the HR response to vagal nerve stimulation in the presence of the guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 microM). 4. The phosphodiesterase 3 (PDE 3) inhibitor milrinone (1 microM) increased the release of [3H] acetylcholine and the vagal bradycardia and prevented any further increase by SNP. SNP was still able to augment the vagal bradycardia in the presence of the protein kinase G inhibitor KT5823 (1 microM) but not after protein kinase A (PKA) inhibition with H-89 (0.5 microM) or KT5720 (1 microM) had reduced the HR response to vagal nerve stimulation. Neither milrinone nor H-89 changed the HR response to carbamylcholine. 5. SNP had no effect on the magnitude of the vagal bradycardia after inhibition of N-type calcium channels with omega-conotoxin GVIA (100 nM). 6. These results suggests that NO acts presynaptically to facilitate vagal neurotransmission via a cGMP-PDE 3-dependent pathway leading to an increase in cAMP-PKA-dependent phosphorylation of presynaptic N-type calcium channels. This pathway may augment the HR response to vagal nerve stimulation by increasing presynaptic calcium influx and vesicular release of acetylcholine.


[Pasteurized milk as a factor in the transmission of the causative agents of yersiniosis].
From 43 (35.8%) out of 120 samples of pasteurized milk used by volunteers 182 cultures of five Yersinia species--Y. enterocolitica, biovar 1 (70.3%), Y. intermedia (18.1%), Y. frederiksenii (7.7%), Y. kristensenii (3.3%) and Y. aldovae (0.5%)--were isolated in the course of bacteriological studies carried out in 1987-1990. The isolated Yersinia cultures belonged to nonpathogenic pyraminidaze-positive serovars. Yersinia pathogenic bio/serovars (4/O3, 2/O9, 1B/O8) were not detected. No deviations from the normal state were registered in the volunteers drinking pasteurized milk, and Yersinia could be isolated from their feces only during the first 3 days following milk consumption. In 390 patients examined for the presence of Yersinia infections the isolation rate of Yersinia of biovar 1 (99.6% of the cultures) varied between 4.4% and 21.3% and correlated with the increase of the isolation rate from milk (13.6% to 53.9%). The results of the study suggest that unboiled pasteurized milk contributes to the spread of Yersinia carriership among the population.


Btbd7 is essential for region-specific epithelial cell dynamics and branching morphogenesis in vivo.
Branching morphogenesis of developing organs requires coordinated but poorly understood changes in epithelial cell-cell adhesion and cell motility. We report that Btbd7 is a crucial regulator of branching morphogenesis in vivo. Btbd7 levels are elevated in peripheral cells of branching epithelial end buds, where it enhances cell motility and cell-cell adhesion dynamics. Genetic ablation of Btbd7 in mice disrupts branching morphogenesis of salivary gland, lung and kidney. Btbd7 knockout results in more tightly packed outer bud cells, which display stronger E-cadherin localization, reduced cell motility and decreased dynamics of transient cell separations associated with cleft formation; inner bud cells remain unaffected. Mechanistic analyses using in vitro MDCK cells to mimic outer bud cell behavior establish that Btbd7 promotes loss of E-cadherin from cell-cell adhesions with enhanced migration and transient cell separation. Btbd7 can enhance E-cadherin ubiquitination, internalization, and degradation in MDCK and peripheral bud cells for regulating cell dynamics. These studies show how a specific regulatory molecule, Btbd7, can function at a local region of developing organs to regulate dynamics of cell adhesion and motility during epithelial branching morphogenesis.


Sensitivity of resonance frequency analysis for detecting early implant failure: a case-control study.
The aim of this study was to test the sensitivity of the resonance frequency analysis for detecting early implant failure. In all, 3,786 implants placed from June 2007 to January 2013 were retrospectively evaluated. A total of 20 implants (in 20 patients) placed in pristine bone were found to have failed before loading. The implant stability quotient (ISQ) values were extracted from these 20 implants at baseline (immediate) and 4 months after placement (delayed). Simple linear regression, logistic regression, and two-way contingency tables were used to test for the relationships between ISQ values and early implant failure. Immediate ISQ values were significantly related to failure (odds ratio [OR] = 4.27). Furthermore, the results of the second regression showed a significant relationship between ISQ at delayed measurement and implant failure (OR = 9.20). For immediate ISQ, it seems that the 73.7% correct classifications were obtained at the cost of an incorrect classification of 55% of the implant failures. However, for the delayed ISQ, 86.2% correct classifications were obtained at the cost of assuming that all implants will survive. The present study showed that ISQ values are not reliable in predicting early implant failure. In addition, the real cutoff ISQ value to differentiate between success and early implant failure remains to be determined.


Does this patient have delirium?: value of bedside instruments.
Delirium occurs in many hospitalized older patients and has serious consequences including increased risk for death and admission to long-term care. Despite its importance, health care clinicians often fail to recognize delirium. Simple bedside instruments may lead to improved identification. To systematically review the evidence on the accuracy of bedside instruments in diagnosing the presence of delirium in adults. Search of MEDLINE (from 1950 to May 2010), EMBASE (from 1980 to May 2010), and references of retrieved articles to identify studies of delirium among inpatients. Prospective studies of diagnostic accuracy that compared at least 1 delirium bedside instrument to the Diagnostic and Statistical Manual of Mental Disorders-based diagnosis made by a geriatrician, psychiatrist, or neurologist. There were 6570 unique citations identified with 25 prospectively conducted studies (N = 3027 patients) meeting inclusion criteria and describing use of 11 instruments. Positive results that suggested delirium with likelihood ratios (LRs) greater than 5.0 were present for the Global Attentiveness Rating (GAR), Memorial Delirium Assessment Scale (MDAS), Confusion Assessment Method (CAM), Delirium Rating Scale Revised-98 (DRS-R-98), Clinical Assessment of Confusion (CAC), and Delirium Observation Screening Scale (DOSS). Normal results that decreased the likelihood of delirium with LRs less than 0.2 were calculated for the GAR, MDAS, CAM, DRS-R-98, Delirium Rating Scale (DRS), DOSS, Nursing Delirium Screening Scale (Nu-DESC), and Mini-Mental State Examination (MMSE). The Digit Span test and Vigilance "A" test in isolation have limited utility in diagnosing delirium. Considering the instrument's ease of use, test performance, and clinical importance of the heterogeneity in the confidence intervals (CIs) of the LRs, the CAM has the best available supportive data as a bedside delirium instrument (summary-positive LR, 9.6; 95% CI, 5.8-16.0; summary-negative LR, 0.16; 95% CI, 0.09-0.29). Of all scales, the MMSE (score <24) was the least useful for identifying a patient with delirium (LR, 1.6; 95% CI, 1.2-2.0). The choice of instrument may be dictated by the amount of time available and the discipline of the examiner; however, the best evidence supports use of the CAM, which takes 5 minutes to administer.


Elucidating the role of surface passivating ligand structural parameters in hole wave function delocalization in semiconductor cluster molecules.
This article describes the mechanisms underlying electronic interactions between surface passivating ligands and (CdSe)34 semiconductor cluster molecules (SCMs) that facilitate band-gap engineering through the delocalization of hole wave functions without altering their inorganic core. We show here both experimentally and through density functional theory calculations that the expansion of the hole wave function beyond the SCM boundary into the ligand monolayer depends not only on the pre-binding energetic alignment of interfacial orbitals between the SCM and surface passivating ligands but is also strongly influenced by definable ligand structural parameters such as the extent of their π-conjugation [π-delocalization energy; pyrene (Py), anthracene (Anth), naphthalene (Naph), and phenyl (Ph)], binding mode [dithiocarbamate (DTC, -NH-CS2-), carboxylate (-COO-), and amine (-NH2)], and binding head group [-SH, -SeH, and -TeH]. We observe an unprecedentedly large ∼650 meV red-shift in the lowest energy optical absorption band of (CdSe)34 SCMs upon passivating their surface with Py-DTC ligands and the trend is found to be Ph- < Naph- < Anth- < Py-DTC. This shift is reversible upon removal of Py-DTC by triethylphosphine gold(i) chloride treatment at room temperature. Furthermore, we performed temperature-dependent (80-300 K) photoluminescence lifetime measurements, which show longer lifetime at lower temperature, suggesting a strong influence of hole wave function delocalization rather than carrier trapping and/or phonon-mediated relaxation. Taken together, knowledge of how ligands electronically interact with the SCM surface is crucial to semiconductor nanomaterial research in general because it allows the tuning of electronic properties of nanomaterials for better charge separation and enhanced charge transfer, which in turn will increase optoelectronic device and photocatalytic efficiencies.


Is hydroxylamine-induced cytotoxicity a valid marker for hypersensitivity reactions to sulfamethoxazole in human immunodeficiency virus-infected individuals?
Hypersensitivity (HS) reactions to sulfonamides and sulfones continue to limit their use in human immunodeficiency virus (HIV)-infected individuals. In vitro cytotoxicity of hydroxylamine metabolites toward peripheral blood mononuclear cells (PBMCs) has been proposed as a marker for these HS reactions. To test the validity of this in vitro system, we determined the selective susceptibility of PBMCs from HIV-infected patients to the cytotoxic effects of hydroxylamine metabolites of sulfamethoxazole (SMX) and dapsone (DDS). Concentration-cytotoxic response data were collected using PBMCs from 12 sulfa-HS (10 SMX-HS and 2 SMX/DDS-HS) and 10 sulfa-tolerant HIV-infected individuals. Although sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) both caused concentration-dependent increases in cell death, DDS-NOH was significantly more potent in each subject (P <.0001). A comparison of a variety of mean data for sulfa-HS and -tolerant patient populations failed to demonstrate the increased susceptibility of PBMCs from HS patients, noted by others, to either SMX-NOH or DDS-NOH. Moreover, any trend toward an increased susceptibility of PBMCs from HS patients was eliminated when adjusted for control cell death. PBMCs from sulfa-HS patients showed significantly greater susceptibility to the stress of short term in vitro incubation (P <. 02). Mean (S.D.) vehicle control cell death values were 24.1% (7.6%) for HS patients and 17.1% (4.4%) for tolerant patients. No significant correlation was observed between hydroxylamine-induced or control cell death and any of the recorded clinical parameters. Although several potential reasons are proposed to explain the disparity with past investigations, the data suggest that in vitro cytotoxicity is not a valid marker for HS reactions in HIV-infected individuals using currently accepted experimental procedures.


Compact static Fourier transform imaging spectropolarimeter based on channeled polarimetry.
The theoretical operation and experimental demonstration of a Fourier transform imaging spectropolarimeter for real time measurement of the polarization state of light are presented. The spectropolarimeter uses a Wollaston prism as a birefringent interferometer and two high-order retarders to incorporate channeled polarimetry. Compared with previous instruments, the most significant advantage of the described model is that the complete wavelength-dependent polarization is acquired simultaneously along a one-dimensional spatial image by a single snapshot. Also, we show that, in this configuration, we can benefit from the advantages of the model: it is compact and robust, and the birefringent interferometer has a high throughput.


Dysregulation of working memory and default-mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study.
Deficits in working memory (WM) are a consistent neurocognitive marker for schizophrenia. Previous studies have suggested that WM is the product of coordinated activity in distributed functionally connected brain regions. Independent component analysis (ICA) is a data-driven approach that can identify temporally coherent networks that underlie fMRI activity. We applied ICA to an fMRI dataset for 115 patients with chronic schizophrenia and 130 healthy controls by performing the Sternberg Item Recognition Paradigm. Here, we describe the first results using ICA to identify differences in the function of WM networks in schizophrenia compared to controls. ICA revealed six networks that showed significant differences between patients with schizophrenia and healthy controls. Four of these networks were negatively task-correlated and showed deactivation across the posterior cingulate, precuneus, medial prefrontal cortex, anterior cingulate, inferior parietal lobules, and parahippocampus. These networks comprise brain regions known as the default-mode network (DMN), a well-characterized set of regions shown to be active during internal modes of cognition and implicated in schizophrenia. Two networks were positively task-correlated, with one network engaging WM regions such as bilateral DLPFC and inferior parietal lobules while the other network engaged primarily the cerebellum. Our results suggest that DLPFC dysfunction in schizophrenia might be lateralized to the left and intrinsically tied to other regions such as the inferior parietal lobule and cingulate gyrus. Furthermore, we found that DMN dysfunction in schizophrenia exists across multiple subnetworks of the DMN and that these subnetworks are individually relevant to the pathophysiology of schizophrenia. In summary, this large multisite study identified multiple temporally coherent networks, which are aberrant in schizophrenia versus healthy controls and suggests that both task-correlated and task-anticorrelated networks may serve as potential biomarkers.


Augmented high-dose regimen of cyclophosphamide, carmustine, and etoposide with autologous hematopoietic stem cell transplantation for relapsed and refractory aggressive non-Hodgkin's lymphoma.
Progressive disease is the major cause of treatment failure after autologous hematopoietic stem cell transplantation for relapsed or refractory non-Hodgkin's lymphoma. An augmented high-dose regimen of cyclophosphamide 7,200 mg/m2, carmustine 300 - 400 mg/m2, and etoposide 2,400 mg/m2 (CBV) was developed in an attempt to improve disease control post-transplant. Sixty-seven adult patients received augmented CBV followed by infusion of unpurged autologous peripheral blood stem cells. Thirty seven patients had relapsed after standard chemotherapy, 28 patients had primary refractory disease, and 2 patients had transformed lymphoma in first partial response. Treatment-related mortality was 4%. Actuarial four year overall survival and progression-free survival were 46+/-8% and 36+/-6%, respectively. Risk factors for disease progression were histologic involvement of marrow by lymphoma and infusion of increased numbers of CD34 + cells per kg in the stem cell autograft. The outcome for patients with relatively chemorefractory disease (defined as 25 - 49% reduction in tumor volume after salvage chemotherapy) was no different than that for patients with chemosensitive disease. Compared to standard high-dose CBV regimens, augmented CBV does not appear to have substantially improved disease control. Prospective study of the association between inferior progression-free survival and infusion of higher CD34 + cell doses in stem cell autografts is warranted.


Literature Review and Meta-Analysis of Transcutaneous Electrical Nerve Stimulation in Treating Chronic Back Pain.
This study is a meta-analysis of randomized controlled trials comparing the efficacy of transcutaneous electrical nerve stimulation (TENS) to a control and to other nerve stimulation therapies (NSTs) for the treatment of chronic back pain. Citations were identified in MEDLINE, the Cochrane Library, Google Scholar, and ClinicalTrials.gov through June 2014 using the following keywords: nerve stimulation therapy, transcutaneous electrical nerve stimulation, back pain, chronic pain. Control treatments included sham, placebo, or medication only. Other NSTs included electroacupuncture, percutaneous electrical nerve stimulation, and percutaneous neuromodulation therapy. Twelve randomized controlled trials including 700 patients were included in the analysis. The efficacy of TENS was similar to that of control treatment for providing pain relief (standardized difference in means [SDM] = -0.20; 95% confidence interval [CI], -0.58 to 0.18; P = 0.293). Other types of NSTs were more effective than TENS in providing pain relief (SDM = 0.86; 95% CI, 0.15-1.57; P = 0.017). Transcutaneous electrical nerve stimulation was more effective than control treatment in improving functional disability only in patients with follow-up of less than 6 weeks (SDM = -1.24; 95% CI, -1.83 to -0.65; P < 0.001). There was no difference in functional disability outcomes between TENS and other NSTs. These results suggest that TENS does not improve symptoms of lower back pain, but may offer short-term improvement of functional disability.


Linearly polarized emission from random lasers with anisotropically amplifying media.
Simulations on three-dimensional random lasers were performed by finite-difference time-domain integration of Maxwell's equations combined with rate-equations providing gain. We investigated the frequency-dependent emission polarization of random lasers in the far-field of the sample and characterized the influence of anisotropic pumping in orthogonal polarizations. Under weak scattering, the polarization states of random lasing modes were random for isotropic pumping and linear under anisotropic pumping. These findings are in accordance with recent experimental observations. A crossover was observed towards very strong scattering, in which the scattering destroys the pump-induced polarization-anisotropy of the random lasing modes and randomizes (scrambles) the mode-polarization.


Perioperative predictors of colonic ischemia after ruptured abdominal aortic aneurysm.
Colonic ischemia and colonic resection occur frequently after ruptured abdominal aortic aneurysm (rAAA). The purpose of this study was to identify the perioperative risk factors that might help to determine earlier in the postoperative period which patients are at risk for colonic ischemia and colonic resection. The medical records of the 43 patients who underwent repair of rAAA from January 1989 to November 1997 were reviewed. The data were reviewed for the following factors: acidosis, pressor agents, lactate levels, guaiac status, cardiac index, coagulopathy, early postoperative bowel movement, the lowest intraoperative pH level, the temperature at the conclusion of the case, the location and duration of aortic cross clamping, the amount of fluid boluses administered after surgery, the amount of packed red blood cells administered during the case, and the average systolic blood pressure at admission and during surgery. Univariate analysis was performed with Fisher exact test, chi2 test, and Student t test. Multivariate analyses also were performed with the variables that were found to be significant on the univariate analysis. Thirteen of the 43 patients (30. 2%) had colonic ischemia, and seven of the 13 underwent colonic resection (53.8%). The overall mortality rate was 51.2% (22/43) five of the deaths were intraoperative and excluded from the study. In a comparison of the patients who had colonic ischemia with those who did not, statistically significant differences were found in the following variables: average systolic blood pressure at admission 90 mm Hg or less, hypotension of more than 30 minutes' duration, temperature less than 35 degreesC, pH less than 7.3, fluid boluses administered after surgery 5 L or more, and packed red blood cells 6 units or more. Multivariate analysis indicated that the number of these variables present correlated significantly with the positive predicted probability of colonic ischemia occurring. No patient with two factors or fewer had an ischemic bowel, and the positive predictive probability of colonic ischemia for those patients with six factors was 80%. The results of this study show that: (1) colonic ischemia after rAAA may be predicted with the presence of two or more specific perioperative factors, (2) the lack of a guaiac-positive bowel movement may be misleading for the early diagnosis of colonic ischemia, and (3) more than 50% of the patients with colonic ischemia will require a colonic resection. We recommend that any patient with rAAA with more than two perioperative factors undergo sigmoidoscopy every 12 hours after surgery for 48 hours to rule out colonic ischemia without waiting for early or guaiac-positive bowel movement.


Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.
The Sydney System for the classification of gastritis emphasized the importance of combining topographical, morphological, and etiological information into a schema that would help to generate reproducible and clinically useful diagnoses. To reappraise the Sydney System 4 years after its introduction, a group of gastrointestinal pathologists from various parts of the world met in Houston, Texas, in September 1994. The aims of the workshop were (a) to establish an agreed terminology of gastritis; (b) to identify, define, and attempt to resolve some of the problems associated with the Sydney System. This article introduces the Sydney System as it was revised at the Houston Gastritis Workshop and represents the consensus of the participants. Overall, the principles and grading of the Sydney System were only slightly modified, the grading being aided by the provision of a visual analogue scale. The terminology of the final classification has been improved to emphasize the distinction between the atrophic and nonatrophic stomach; the names used for each entity were selected because they are generally acceptable to both pathologists and gastroenterologists. In addition to the main categories and atrophic and nonatrophic gastritis, the special or distinctive forms are described and their respective diagnostic criteria are provided. The article includes practical guidelines for optimal biopsy sampling of the stomach, for the use of the visual analogue scales for grading the histopathologic features, and for the formulation of a comprehensive standardized diagnosis. A glossary of gastritis-related terms as used in this article is provided.


Critical involvement of Tcf-1 in expansion of thymocytes.
T cell maturation in Tcf-1(-/-) mice deteriorates progressively and halts completely around 6 mo of age. During fetal development thymocyte subpopulations seem normal, although total cell numbers are lower. By 4 to 6 wk of age, obvious blockades in the differentiation of CD4- 8- thymocytes are observed at two distinct stages (CD44+ 25+ and CD44- 25-), both of which are normally characterized by extensive proliferation. This lack of thymocyte expansion and/or differentiation was also observed when Tcf-1(-/-) progenitor cells from the aorta-gonad-mesonephros region (embryonic day 11.5), fetal liver (embryonic day 12.5/14.5), and fetal bone marrow (embryonic day 18.5) were allowed to differentiate in normal thymic lobes (fetal thymic organ cultures) or were injected intrathymically into normal recipients. Despite these apparent defects in thymocyte differentiation and expansion, adult Tcf-1(-/-) mice are immunocompetent, as they generate virus neutralizing Abs at normal titers. Furthermore, their peripheral T cells have an activated phenotype (increased CD44 and decreased CD62L expression) and proliferate normally in response to Ag or mitogen, suggesting that these cells may have arisen from the early wave of development during embryogenesis and are either long lived or have subsequently been maintained by peripheral expansion. As Tcf-1 is a critical component in the Wnt/beta-catenin signaling pathway, these data suggest that Wnt-like factors play a role in the expansion of double-negative thymocytes.


Dietary outcomes of a community based intervention for mothers of young children: a randomised controlled trial.
Unhealthy dietary behaviours are one of the key risk factors for many lifestyle-related diseases worldwide. This randomised controlled trial aimed to increase the level of fruit, vegetable and fibre intake and decrease the fat and sugar consumption of mothers with young children (0-5 years) via the playgroup setting. Playgroups located in 60 neighbourhoods in Perth, Western Australia were randomly assigned to an intervention (n = 249) or control group (n = 272). Those in the intervention group received a 6-month multi-strategy primarily home-based physical activity and nutrition program (data is only presented on dietary behaviours). Data on dietary consumption was collected via the Fat and Fibre Barometer and frequency of serves of fruit and vegetable and cups of soft drink, flavoured drink and fruit juice. The effects of the intervention on continuous outcome measures were assessed using analysis of variance (ANOVA), after adjusting for mother's age and the corresponding variables. The outcomes of the intervention were positive with the intervention group showing statistically significant improvements, when compared to the control group in the overall consumption of fat and fibre (p < 0.0005); of fibre (p < 0.0005) - fruit and vegetables (p < 0.0005), wholegrain (p = 0.002): and fat (p = 0.005) - dairy products (p = 0.006) and lean meat and chicken (p = 0.041). There were no significant changes in the consumption of sweet drinks. This intervention was successful in improving dietary intake in the intervention group participants. The moderate positive outcomes indicate that playgroups potentially provide quite a viable setting to recruit, engage and retain this hard to reach group of mothers of young children in programs that support the adoption of health-enhancing behaviours. This adds valuable information to this under researched area. Australian and New Zealand Clinical Trials Registry ACTRN12609000718246.


Development of an RNA interference tool, characterization of its target, and an ecological test of caste differentiation in the eusocial wasp polistes.
Recent advancements in genomics provide new tools for evolutionary ecological research. The paper wasp genus Polistes is a model for social insect evolution and behavioral ecology. We developed RNA interference (RNAi)-mediated gene silencing to explore proposed connections between expression of hexameric storage proteins and worker vs. gyne (potential future foundress) castes in naturally-founded colonies of P. metricus. We extended four fragments of putative hexamerin-encoding P. metricus transcripts acquired from a previous study and fully sequenced a gene that encodes Hexamerin 2, one of two proposed hexameric storage proteins of P. metricus. MALDI-TOF/TOF, LC-MSMS, deglycosylation, and detection of phosphorylation assays showed that the two putative hexamerins diverge in peptide sequence and biochemistry. We targeted the hexamerin 2 gene in 5(th) (last)-instar larvae by feeding RNAi-inducing double-stranded hexamerin 2 RNA directly to larvae in naturally-founded colonies in the field. Larval development and adult traits were not significantly altered in hexamerin 2 knockdowns, but there were suggestive trends toward increased developmental time and less developed ovaries, which are gyne characteristics. By demonstrating how data acquisition from 454/Roche pyrosequencing can be combined with biochemical and proteomics assays and how RNAi can be deployed successfully in field experiments on Polistes, our results pave the way for functional genomic research that can contribute significantly to learning the interactions of environment, development, and the roles they play in paper wasp evolution and behavioral ecology.


Development of a High-Sensitivity Wireless Accelerometer for Structural Health Monitoring.
Structural health monitoring (SHM) is playing an increasingly important role in ensuring the safety of structures. A shift of SHM research away from traditional wired methods toward the use of wireless smart sensors (WSS) has been motivated by the attractive features of wireless smart sensor networks (WSSN). The progress achieved in Micro Electro-Mechanical System (MEMS) technologies and wireless data transmission, has extended the effectiveness and range of applicability of WSSNs. One of the most common sensors employed in SHM strategies is the accelerometer; however, most accelerometers in WSS nodes have inadequate resolution for measurement of the typical accelerations found in many SHM applications. In this study, a high-resolution and low-noise tri-axial digital MEMS accelerometer is incorporated in a next-generation WSS platform, the Xnode. In addition to meeting the acceleration sensing demands of large-scale civil infrastructure applications, this new WSS node provides powerful hardware and a robust software framework to enable edge computing that can deliver actionable information. Hardware and software integration challenges are presented, and the associate resolutions are discussed. The performance of the wireless accelerometer is demonstrated experimentally through comparison with high-sensitivity wired accelerometers. This new high-sensitivity wireless accelerometer will extend the use of WSSN to a broader class of SHM applications.


Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline.
Many nonpharmacologic therapies are available for treatment of low back pain. To assess benefits and harms of acupuncture, back schools, psychological therapies, exercise therapy, functional restoration, interdisciplinary therapy, massage, physical therapies (interferential therapy, low-level laser therapy, lumbar supports, shortwave diathermy, superficial heat, traction, transcutaneous electrical nerve stimulation, and ultrasonography), spinal manipulation, and yoga for acute or chronic low back pain (with or without leg pain). English-language studies were identified through searches of MEDLINE (through November 2006) and the Cochrane Database of Systematic Reviews (2006, Issue 4). These electronic searches were supplemented by hand searching of reference lists and additional citations suggested by experts. Systematic reviews and randomized trials of 1 or more of the preceding therapies for acute or chronic low back pain (with or without leg pain) that reported pain outcomes, back-specific function, general health status, work disability, or patient satisfaction. We abstracted information about study design, population characteristics, interventions, outcomes, and adverse events. To grade methodological quality, we used the Oxman criteria for systematic reviews and the Cochrane Back Review Group criteria for individual trials. We found good evidence that cognitive-behavioral therapy, exercise, spinal manipulation, and interdisciplinary rehabilitation are all moderately effective for chronic or subacute (>4 weeks' duration) low back pain. Benefits over placebo, sham therapy, or no treatment averaged 10 to 20 points on a 100-point visual analogue pain scale, 2 to 4 points on the Roland-Morris Disability Questionnaire, or a standardized mean difference of 0.5 to 0.8. We found fair evidence that acupuncture, massage, yoga (Viniyoga), and functional restoration are also effective for chronic low back pain. For acute low back pain (<4 weeks' duration), the only nonpharmacologic therapies with evidence of efficacy are superficial heat (good evidence for moderate benefits) and spinal manipulation (fair evidence for small to moderate benefits). Although serious harms seemed to be rare, data on harms were poorly reported. No trials addressed optimal sequencing of therapies, and methods for tailoring therapy to individual patients are still in early stages of development. Evidence is insufficient to evaluate the efficacy of therapies for sciatica. Our primary source of data was systematic reviews. We included non-English-language trials only if they were included in English-language systematic reviews. Therapies with good evidence of moderate efficacy for chronic or subacute low back pain are cognitive-behavioral therapy, exercise, spinal manipulation, and interdisciplinary rehabilitation. For acute low back pain, the only therapy with good evidence of efficacy is superficial heat.


The effect of metronidazole on wound healing in rats.
Metronidazole is gaining increasing acceptance as a perioperative antimicrobial agent. We studied the effect of metronidazole on wound healing in Sprague-Dawley rats, which received seven daily intraperitoneal injections of either metronidazole, 20 mg/kg/day, (simulating a therapeutic course) or equivalent volumes of physiologic saline solution. On the second day of treatment 25 treated rats and 20 control rats had full-thickness circular skin defects created on the back and standardized midline celiotomy incisions. The fascial incisions were closed with staples, and the abdominal skin was closed with silk sutures. On the seventh postoperative day all rats were put to death. The breaking strength of 1 cm wide segments of skin and fascial celiotomy wounds was measured, and the contraction of the open back wounds was computed. There was no significant difference in wound contraction or skin wound breaking strength, but fascial wound breaking strength was lower in treated rats than in control rats (283 versus 548 gm mean; 2 p less than 0.001). To determine whether metronidazole permanently altered or only temporarily delayed fascial wound healing, 39 additional rats treated with metronidazole and 40 control rats underwent celiotomies as described above on the second day of a 7-day course of treatment. Fascial wound breaking strength was measured 2, 3, and 5 weeks after operation. The wound breaking strength in rats treated with metronidazole remained significantly lower than that of control rats at 2 and 3 weeks (860 versus 1005 gm at 2 weeks and 1071 versus 1369 gm at 3 weeks; both 2 p less than 0.05), but at 5 weeks there was no significant difference between treated and control groups (1358 versus 1399 gm). Metronidazole apparently interferes with early fascial wound healing, but the wounds of treated rats ultimately attain the same strength as untreated controls.


Three difficult cases: the challenge of autoimmunity, immunodeficiency and recurrent infections in patients with Good syndrome.
Good syndrome (GS) is a rare, adult-acquired primary combined immunodeficiency syndrome arising in the context of previous or current thymoma. Patients with GS frequently develop recurrent sinopulmonary infections and are also at high risk of autoimmune manifestations, including skin conditions such as lichen planus. We report three middle-aged patients with GS complicated by multiple autoimmune and infectious manifestations. The combination of immunodeficiency, autoimmunity and recurrent infections seen in patients with GS continues to present a management challenge, particularly in patients with oral mucosal disease and recurrent candidiasis. Clinicians should be prompted to investigate an underlying immunodeficiency in patients with multiple autoimmune conditions and recurrent sinopulmonary infections.


ICF linking rules: an update based on lessons learned.
Outcome research seeks to understand the end results of health services. Researchers use a wide variety of outcome measures including technical, clinical and patient-oriented measures. The International Classification of Functioning, Disability and Health (ICF) as a common reference framework for functioning may contribute to improved outcome research. The objective of this paper is to provide an updated version of the linking rules published in 2002 and illustrate how these rules are applied to link technical and clinical measures, health-status measures and interventions to the ICF. Three specific linking rules have been established to link health-status measures to the ICF and one specific linking rule has been created to link technical and clinical measures and interventions. A total of 8 linking rules have been established for use with all different outcome measures and with interventions. The newly updated linking rules will allow researchers systematically to link and compare meaningful concepts contained in them. This should prove extremely useful in selecting the most appropriate outcome measures among a number of candidate measures for the applied interventions. Further possible applications are the operationalization of concrete ICF categories using specific measures or the creation of ICF category-based item bankings.


Continuing episodes of pain in recurrent acute pancreatitis: Prospective follow up on a standardised protocol with drugs and pancreatic endotherapy.
To assess the outcomes of drug therapy (DT) followed by pancreatic endotherapy for continuing painful episodes in recurrent acute pancreatitis. DT comprised of pancreatic enzymes and anti-oxidants failing which, endotherapy (ET; pancreatic sphincterotomy and stent placement) was done. The frequency of pain, its visual analogue score (VAS), quality of life (QoL), serum C peptide and faecal elastase were compared between baseline and after 1 year of follow up in all patients and in the two subgroups on DT and ET. Response was defined as at least 50% reduction in the severity of pain to below a score of 5. Of the thirty nine patients analysed, 21 (53.9%) responded to DT and 18 (46.1%) underwent ET. The VAS for pain (7.0 ± 2.0 vs 1.3 ± 2.5, P < 0.001) and the number of days with pain per month decreased [1.0 (1.0, 2.0) vs 1.0 (0.0, 1.0), P < 0.001], and the QoL scores [55.0 (44.0, 66.0) vs 38.0 (32.00, 51.00), P < 0.01] improved significantly during follow up. Similar significant improvements were seen in patients in the subgroups of DT and ET except for QoL in ET. The serum C-peptide (P = 0.001) and FE (P < 0.001) levels improved significantly in the entire group and in the two subgroups of patients except for the C peptide levels in patients on DT. A standardised protocol of DT, followed by ET decreased the intensity and frequency of pain in recurrent acute pancreatitis, enhanced QoL and improved pancreatic function.


Role of the frontal eye field in human pupil and saccade orienting responses.
The appearance of a salient stimulus evokes a series of orienting responses including saccades and pupil size to prepare the body for appropriate action. The midbrain superior colliculus (SC) that receives critical control signals from the frontal eye field (FEF) is hypothesized to coordinate all components of orienting. It has shown recently that the FEF, together with the SC, is also importantly involved in the control of pupil size, in addition to its well-documented role in eye movements. Although the role of the FEF in pupil size is demonstrated in monkeys, its role in human pupil responses and the coordination between pupil size and saccades remains to be established. Through applying continuous theta-burst stimulation over the right FEF and vertex, we investigated the role of the FEF in human pupil and saccade responses evoked by a salient stimulus, and the coordination between pupil size and saccades. Our results showed that neither saccade reaction times (SRT) nor pupil responses evoked by salient stimuli were modulated by FEF stimulation. In contrast, the correlation between pupil size and SRTs in the contralateral stimulus condition was diminished with FEF stimulation, but intact with vertex stimulation. Moreover, FEF stimulation effects between saccade and pupil responses associated with salient stimuli correlated across participants. This is the first transcranial magnetic stimulation (TMS) study on the pupil orienting response, and our findings suggest that human FEF was involved in coordinating pupil size and saccades, but not involved in the control of pupil orienting responses.


Intentional pesticide poisoning and pesticide suicides in Nepal.
Intentional pesticide poisoning is a major clinical and public health problem in agricultural communities in low and middle income countries like Nepal. Bans of highly hazardous pesticides (HHP) reduce the number of suicides. We aimed to identify these pesticides by reviewing data from major hospitals across the country and from forensic toxicology laboratories. We retrospectively reviewed medical records of 10 hospitals for pesticide poisoned patients and two forensic laboratories of Nepal from April 2017 to February 2020. The poison was identified from the history, referral note, and clinical toxidrome in the hospitals and from gas chromatography analysis in the laboratories. Data on demographics, poison, and patient outcome were recorded on a data collection sheet. Simple descriptive analysis was performed. Among hospital cases (n = 4148), the commonest form of poisoning was self-poisoning (95.8%) while occupation poisoning was rare (0.03%). Case fatality was 5.3% (n = 62). Aluminum phosphide (n = 38/62, 61.3%) was the most commonly identified lethal pesticide for deaths. Forensic toxicology laboratories reported 2535 deaths positive for pesticides, with the compounds most commonly identified being organophosphorus (OP) insecticides (n = 1463/2535; 57.7%), phosphine gas (n = 653/2535; 25.7%; both aluminum [11.8%] and zinc [0.4%] phosphide) and organochlorine insecticides (n = 241/2535; 9.5%). The OP insecticide most commonly identified was dichlorvos (n = 273/450, 60.6%). The data held in the routine hospital medical records were incomplete but suggested that case fatality in hospitals was relatively low. The pesticides identified as causing most deaths were dichlorvos and aluminum phosphide. Since this study was completed, dichlorvos has been banned and the most toxic formulation of aluminum phosphide removed from sale. Improving the medical record system and working with forensic toxicology laboratories will allow problematic HHPs to be identified and the effects of the bans in reducing deaths monitored.


Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene.
We have used transgenic mice that carry an activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV) promoter to assess the stepwise progression of carcinogenesis in mammary epithelium. Unlike the stochastic occurrence of solitary mammary tumors in transgenic mice bearing the MMTV/c-myc or the MMTV/v-Ha-ras oncogenes, transgenic mice uniformly expressing the MMTV/c-neu gene develop mammary adenocarcinomas that involve the entire epithelium in each gland. Because these tumors arise synchronously and are polyclonal in origin, expression of the activated c-neu oncogene appears to be sufficient to induce malignant transformation in this tissue in a single step. In contrast, expression of the c-neu transgene in the parotid gland or epididymis leads to benign, bilateral epithelial hypertrophy and hyperplasia which does not progress to full malignant transformation during the observation period. These results indicate that the combination of activated oncogene and tissue context are major determinants of malignant progression and that expression of the activated form of c-neu in the mammary epithelium has particularly deleterious consequences.


Graf regulates hematopoiesis through GEEC endocytosis of EGFR.
GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation.


Resilience and Stress among Hopi Female Caregivers.
Resilience and stress are important factors in the caregiving experience, but research has yet to examine their association among American Indian (AI) caregivers. This study examines resilience and stress in a group of Hopi female caregivers. Data came from the Hopi Adult Caregiver Survey (2017), which conducted interviews with 44 Hopi women who were providing care without remuneration to an adult family member. Measures included the abbreviated Connor-Davidson Resilience Scale (CD-RISC-10), the Perceived Stress Scale (PSS-10), and questions about caregiver characteristics, care recipient characteristics, social support/ community support, and cultural factors. Stress and resilience were looked at above the median (higher stress or higher resilience) and below the median (lower stress or lower resilience). Caregivers who reported relatively lower resilience were more likely to report that they lived separately from their care recipients and that all Hopis are expected to be caregivers. Caregivers who reported relatively higher stress reported a higher total number of caregiver difficulties, a poorer self-perception of their own health, use of a traditional healer in the past 5 years, and that females are expected to be caregivers. A regression analysis adjusting for age, education, and employment status indicated that higher resilience among the caregivers was significantly associated with lower stress. In light of these findings, programs working with AI caregivers may wish to explore whether supporting the resilience of these caregivers is a means towards limiting their stress.


Association of loblolly pine xylem development gene expression with single-nucleotide polymorphisms.
Variation in the expression of genes with putative roles in wood development was associated with single-nucleotide polymorphisms (SNPs) using a population of loblolly pine (Pinus taeda L.) that included individuals from much of the native range. Association studies were performed using 3938 SNPs and expression data obtained using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) for 106 xylem development genes in 400 clonally replicated loblolly pine individuals. A general linear model (GLM) approach, which takes the underlying population structure into consideration, was used to discover significant associations. After adjustment for multiple testing using a false discovery rate correction, 88 statistically significant associations (Q<0.05) were observed for 80 SNPs with the expression data of 33 xylem development genes. Thirty SNPs caused nonsynonymous mutations, 18 resulted in synonymous mutations, 11 were in 3' untranslated regions (UTRs), 1 was in a 5' UTR and 20 were in introns. Using AraNet, we found that Arabidopsis genes with high similarity to the loblolly pine genes involved in 21 of the 88 statistically significant associations are connected in functional gene networks. Comparisons of gene expression values revealed that in most cases the average expression in plants homozygous for the rare SNP allele was lower than that of plants that were heterozygous or homozygous for the abundant allele. Although there are association studies of SNPs and expression profiles for humans, Arabidopsis and white spruce, to the best of our knowledge, this is the first example of such an association genetic study in pines. Functional validation of these associations will lead to a deeper understanding of the molecular basis of phenotypic differences in wood development among individuals in conifer populations.


Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia.
Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.


Threshold of Energy Deficit and Lower-Body Performance Declines in Military Personnel: A Meta-Regression.
Negative energy balance (EB) is common during military operations, diminishing body mass and physical performance. However, the magnitude of negative EB where performance would still be maintained is not well defined. Our objective was to explore relationships between EB and physical performance during military operations and define an acceptable negative EB threshold where performance may be maintained. A systematic search was performed for studies that measured EB and physical performance during military training. A total of 632 articles and technical reports were screened. Lower-body power and strength were the most common performance tests across investigations and were used as physical performance outcomes. Data were extracted from nine eligible studies containing 15 independent subgroups. Meta-regression assessed changes in performance in relation to study duration (days), average daily EB, and total EB (daily EB × duration). Changes in physical performance were not associated with average daily EB or training duration. Total EB was associated with changes in lower-body power (r2 = 0.764, P < 0.001) and strength (r2 = 0.836, P < 0.001) independently and combined (r2 = 0.454, P = 0.002). Predictive equations generated from the meta-regression indicated that, for a zero to small (2%) decline in performance, total EB should be limited to - 5686 to - 19,109 kcal, for an entire operation, whereas total EB of - 39,243 to - 59,377 kcal will result in moderate (7%) to large (10%) declines in performance. These data demonstrated that greater total negative EB is associated with declines in lower-body performance during military operations.


Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.


Prospective and longitudinal patient self-assessment of health-related quality of life following radical perineal prostatectomy.
We provide a comprehensive, longitudinal assessment of health related quality of life (HRQOL) following radical perineal prostatectomy (RPP). We report the results of a prospective cohort study of 109 patients with at least 3 months of followup who underwent RPP between January 2001 and July 2003. A validated patient self-assessment questionnaire, the Expanded Prostate Cancer Index Composite, was administered preoperatively, and 1, 3, 6, 9, 12 and 18 months postoperatively. Mean domain specific HRQOL scores were calculated as well as the proportion of patients achieving an individual baseline by each interval. The Cox proportional hazards model was used to identify predictors of a successful return to baseline of disease specific HRQOL scores. HRQOL scores were lowest 1 month postoperatively and they increased with time. By 6 months a majority of patients had recovered baseline summary scores in urinary (65.1%), bowel (93.6%) and hormonal (91.7%) domains at a median of 5.8 (95% CI 3.6 to 6.2), 1.3 (95% CI 1.1 to 1.5) and 1.3 (95% CI 1.2 to 1.8) months, respectively. One in 4 patients recovered the sexual summary score by 18 months. Significant independent predictors for the recovery of domain summary scores were younger age in urinary (p = 0.001), individual surgeon in bowel (p = 0.022), and older age (p = 0.017) and absent medical comorbidities (p = 0.012) in hormonal domains. A majority of patients undergoing RRP experience an early recovery of individual urinary, bowel and hormonal HRQOL. Future studies should establish the benefit of bilateral nerve sparing RPP on the recovery of sexual domain HRQOL.


Brain electrical activities of dancers and fast ball sports athletes are different.
Exercise training has been shown not only to influence physical fitness positively but also cognition in healthy and impaired populations. However, some particular exercise types, even though comparable based on physical efforts, have distinct cognitive and sensorimotor features. In this study, the effects of different types of exercise, such as fast ball sports and dance training, on brain electrical activity were investigated. Electroencephalography (EEG) scans were recorded in professional dancer, professional fast ball sports athlete (FBSA) and healthy control volunteer groups consisting of twelve subjects each. In FBSA, power of delta and theta frequency activities of EEG was significantly higher than those of the dancers and the controls. Conversely, dancers had significantly higher amplitudes in alpha and beta bands compared to FBSA and significantly higher amplitudes in the alpha band in comparison with controls. The results suggest that cognitive features of physical training can be reflected in resting brain electrical oscillations. The differences in resting brain electrical oscillations between the dancers and the FBSA can be the result of innate network differences determining the talents and/or plastic changes induced by physical training.


Development and validation of a simple algorithm for initiation of CPAP in neonates with respiratory distress in Malawi.
Low-cost bubble continuous positive airway pressure (bCPAP) systems have been shown to improve survival in neonates with respiratory distress, in developing countries including Malawi. District hospitals in Malawi implementing CPAP requested simple and reliable guidelines to enable healthcare workers with basic skills and minimal training to determine when treatment with CPAP is necessary. We developed and validated TRY (T: Tone is good, R: Respiratory Distress and Y=Yes) CPAP, a simple algorithm to identify neonates with respiratory distress who would benefit from CPAP. To validate the TRY CPAP algorithm for neonates with respiratory distress in a low-resource setting. We constructed an algorithm using a combination of vital signs, tone and birth weight to determine the need for CPAP in neonates with respiratory distress. Neonates admitted to the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi, were assessed in a prospective, cross-sectional study. Nurses and paediatricians-in-training assessed neonates to determine whether they required CPAP using the TRY CPAP algorithm. To establish the accuracy of the TRY CPAP algorithm in evaluating the need for CPAP, their assessment was compared with the decision of a neonatologist blinded to the TRY CPAP algorithm findings. 325 neonates were evaluated over a 2-month period; 13% were deemed to require CPAP by the neonatologist. The inter-rater reliability with the algorithm was 0.90 for nurses and 0.97 for paediatricians-in-training using the neonatologist's assessment as the reference standard. The TRY CPAP algorithm has the potential to be a simple and reliable tool to assist nurses and clinicians in identifying neonates who require treatment with CPAP in low-resource settings.


Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention: A Scientific Statement From the American Heart Association.
Cardiovascular disease (CVD) is the leading cause of death in women, who have a notable increase in the risk for this disease after menopause and typically develop coronary heart disease several years later than men. This observation led to the hypothesis that the menopause transition (MT) contributes to the increase in coronary heart disease risk. Over the past 20 years, longitudinal studies of women traversing menopause have contributed significantly to our understanding of the relationship between the MT and CVD risk. By following women over this period, researchers have been able to disentangle chronological and ovarian aging with respect to CVD risk. These studies have documented distinct patterns of sex hormone changes, as well as adverse alterations in body composition, lipids and lipoproteins, and measures of vascular health over the MT, which can increase a woman's risk of developing CVD postmenopausally. The reported findings underline the significance of the MT as a time of accelerating CVD risk, thereby emphasizing the importance of monitoring women's health during midlife, a critical window for implementing early intervention strategies to reduce CVD risk. Notably, the 2011 American Heart Association guidelines for CVD prevention in women (the latest sex-specific guidelines to date) did not include information now available about the contribution of the MT to increased CVD in women. Therefore, there is a crucial need to discuss the contemporary literature on menopause and CVD risk with the intent of increasing awareness of the significant adverse cardiometabolic health-related changes accompanying midlife and the MT. This scientific statement provides an up-to-date synthesis of the existing data on the MT and how it relates to CVD.