[What factors affect choice of hospital in cases of trauma? A study of conditions in the county of Ringkøbing].
The aim of the study was to investigate the behaviour of trauma patients in choosing between different hospitals in an area where there were no restrictions in choice. The design of the study was a combination of a questionnaire (600 persons) and an analysis of hospital data concerning all admissions of trauma patients to five different hospitals in the county of Ringkøbing in the period 1.1. to 31.12. 1990. The study showed that most trauma patients chose to be treated at the nearest hospital regardless of hospital size and specialization, and that only a very minor proportion of the trauma patients in a special subarea chose to be treated at a larger and more distant hospital. For inhabitants in border areas between hospitals the quality of treatment, service, former experience and the ease of getting to the hospital (e.g. by public transportation for visitors) were the main factors determining choice between the different hospitals.


Gestural coupling and social cognition: Möbius Syndrome as a case study.
Social cognition researchers have become increasingly interested in the ways that behavioral, physiological, and neural coupling facilitate social interaction and interpersonal understanding. We distinguish two ways of conceptualizing the role of such coupling processes in social cognition: strong and moderate interactionism. According to strong interactionism (SI), low-level coupling processes are alternatives to higher-level individual cognitive processes; the former at least sometimes render the latter superfluous. Moderate interactionism (MI) on the other hand, is an integrative approach. Its guiding assumption is that higher-level cognitive processes are likely to have been shaped by the need to coordinate, modulate, and extract information from low-level coupling processes. In this paper, we present a case study on Möbius Syndrome (MS) in order to contrast SI and MI. We show how MS-a form of congenital bilateral facial paralysis-can be a fruitful source of insight for research exploring the relation between high-level cognition and low-level coupling. Lacking a capacity for facial expression, individuals with MS are deprived of a primary channel for gestural coupling. According to SI, they lack an essential enabling feature for social interaction and interpersonal understanding more generally and thus ought to exhibit severe deficits in these areas. We challenge SI's prediction and show how MS cases offer compelling reasons for instead adopting MI's pluralistic model of social interaction and interpersonal understanding. We conclude that investigations of coupling processes within social interaction should inform rather than marginalize or eliminate investigation of higher-level individual cognition.


Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL.
Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; hazard ratio [HR], 0.71 [95% CI, 0.59-0.85]; P=0.0002) and key secondary composite end point (16.8% versus 22.5%; HR 0.71 [95% CI, 0.57-0.88]; P=0.001). The numeric reduction in cardiovascular death was greatest in the eGFR <60 mL·min-1·1.73 m-2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR, 0.70 [95% CI, 0.51-0.95]; P=0.02). Although patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the highest numeric rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42 [95% CI, 0.86-2.32]; P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR, 1.40 [95% CI, 0.90-2.18]; P=0.13), HRs for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter=0.92; P-interaction for serious bleeding=0.76). In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.


A bibliometric study of publications by Indian ophthalmologists and vision researchers, 2001-06.
The objective was to conduct a bibliometric analysis of Indian ophthalmic papers published from 2001 to 2006 in the peer-reviewed journals, to assess productivity, trends in journal choice, publication types, research funding, and collaborative research. We searched PubMed for articles indicating both vision-related content and author affiliation with an Indian research center. We identified research collaborations and funding from indexing for research support, and classified articles as reporting basic science, clinical science, or clinically descriptive research. Impact factors were determined from Journal Citation Reports for 2006. The total number of published articles that were retrieved for the years 2001 to 2006 was 2163. During the six-year period studied, the annual output of research articles has nearly doubled, from 284 in 2001 to 460 in 2006. Two-thirds of these were published in international journals; 41% in vision-related journals with 2006 impact factors; and 3% in impact factor journals which were not vision-related. Fifty percent of the publications came from nine major eye hospitals. Clinical science articles were most frequently published whereas basic science the least. Publications resulting from international collaborations increased from 3% in 2001 to 8% in 2006. The focus of the journal with the highest number of publications corresponds to the most common cause of bilateral blindness in India, cataract. This bibliometric study of publications of research from India in the field of ophthalmic and vision research shows that research productivity, as measured in both the number of publications in peer-reviewed journals and qualitative measures of those journals, has increased during the period of this study.


Neuropareidolia: diagnostic clues apropos of visual illusions.
Diagnosis in neuroimaging involves the recognition of specific patterns indicative of particular diseases. Pareidolia, the misperception of vague or obscure stimuli being perceived as something clear and distinct, is somewhat beneficial for the physician in the pursuit of diagnostic strategies. Animals may be pareidolically recognized in neuroimages according to the presence of specific diseases. By associating a given radiological aspect with an animal, doctors improve their diagnostic skills and reinforce mnemonic strategies in radiology practice. The most important pareidolical perceptions of animals in neuroimaging are the hummingbird sign in progressive supranuclear palsy, the panda sign in Wilson's disease, the panda sign in sarcoidosis, the butterfly sign in glioblastomas, the butterfly sign in progressive scoliosis and horizontal gaze palsy, the elephant sign in Alzheimer's disease and the eye-of-the-tiger sign in pantothenate kinase-associated neurodegenerative disease.


Mariner 6: origin of Mars ionized carbon dioxide ultraviolet spectrum.
The predicted intensities of the ionized carbon dioxide (CO(2)+) emission feature at 2890 angstroms and the Fox-Duffendack-Barker bands are 5.2 and 19.9 kilorayleighs, respectively, for a vertical column. Direct photoionization of carbon dioxide by solar radiation contributes 3.5 and 4.1 kilorayleighs, respectively, and fluorescent scattering by C0(2)+, 1.6 and 15.3 kilorayleighs, respectively. Photoelectron impacts are less important.


Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study.
Infections caused by Klebsiella pneumoniae (Kp) carbapenemase (KPC)-producing strains of Kp have become a significant threat in recent years. To assess their outcomes and identify risk factors for 14 day mortality, we conducted a 4 year (2010-13) retrospective cohort study in five large Italian teaching hospitals. The cohort included 661 adults with bloodstream infections (BSIs; n = 447) or non-bacteraemic infections (lower respiratory tract, intra-abdominal structure, urinary tract or other sites) caused by a KPC-Kp isolate. All had received ≥48 h of therapy (empirical and/or non-empirical) with at least one drug to which the isolate was susceptible. Most deaths occurred within 2 weeks of infection onset (14 day mortality: 225/661, 34.1%). Logistic regression analysis identified BSI (OR, 2.09; 95% CI, 1.34-3.29), presentation with septic shock (OR, 2.45; 95% CI, 1.47-4.08), inadequate empirical antimicrobial therapy (OR, 1.48; 95% CI, 1.01-2.18), chronic renal failure (OR, 2.27; 95% CI, 1.44-3.58), high APACHE III score (OR, 1.05; 95% CI, 1.04-1.07) and colistin-resistant isolates (OR, 2.18; 95% CI, 1.37-3.46) as independent predictors of 14 day mortality. Combination therapy with at least two drugs displaying in vitro activity against the isolate was associated with lower mortality (OR, 0.52; 95% CI, 0.35-0.77), in particular in patients with BSIs, lung infections or high APACHE III scores and/or septic shock at infection onset. Combinations that included meropenem were associated with significantly higher survival rates when the KPC-Kp isolate had a meropenem MIC of ≤8 mg/L. KPC-Kp infections are associated with high mortality. Treatment with two or more drugs displaying activity against the isolate improves survival, mainly in patients who are critically ill.


Modified Design of Anterolateral Thigh Flap for Total Pharyngolaryngectomy Reconstruction: A Single-Center Experience.
Defects after total pharyngolaryngectomy for hypopharyngeal cancer often require reconstruction via free tissue transfer. Recently, anterolateral thigh (ALT) flap has become the gold standard in many centers because of its advantages with respect to versatility, minimal donor-site morbidity, good speech quality, and relatively low fistula and anastomotic leakage rates. Moreover, ALT allows 2 surgical teams to work simultaneously. However, the height of the parallelogram in the ALT design for neoesophagus reconstruction is usually set at a minimum of 9.4 cm (circumference, 2πr) for smooth food passage. Because this height exceeds 8 cm, the donor site may not be closed primarily, which highly depends on the patient's body habitus and the skin tone or quality and requires other methods, such as local flap or skin graft for wound closure, which subsequently increase operating time and donor-site complication rate. Thus, we aimed to construct a simple and modified ALT design that will not only include the advantages described earlier but also provide adequate donor-site primary closure without jeopardizing complication rates. Ten patients with hypopharyngeal cancer underwent reconstructive surgery using our modified ALT design after total pharyngolaryngectomy between 2010 and 2017. Our modified ALT design converts this "classical" shape into a parallelogram so that the height of the modified design is always less than 8 cm, thus allowing for easy primary closure of the wound. The donor-site defects of all 10 patients were closed primarily. No donor-site complications and partial or total flap loss were observed. One patient experienced persistent wound infection with dehiscence, for which debridement was performed. The stricture and fistula rates were 10% (n = 1) and 20% (n = 2), respectively. The mean follow-up time is approximately 1 year. Minimizing donor-site morbidity is an important goal in reconstructive surgery. Our modified ALT flap design is simple, enabling easy primary closure of the donor-site defect, with improved results for the patient and operators. Furthermore, this design is also suitable for ALT flaps with widths larger than 8 cm.


Serum biomarkers as potential predictors of antitumor activity of cetuximab-containing therapy for locally advanced head and neck cancer.
We sought to identify biomarkers of antitumor activity in patients with locally advanced head and neck cancer treated with therapy containing cetuximab, an epidermal growth factor receptor (EGFR) inhibitor. Patients with stage III-IVB head and neck cancer received cisplatin, docetaxel, and cetuximab (TPE) followed by radiotherapy, cisplatin, and cetuximab (XPE) and maintenance cetuximab in a phase II clinical trial. Serum and tissue biomarkers were examined for treatment-related changes and for association with clinical outcomes. Concentrations of 31 cytokines, chemokines and growth factors were measured before and after 3 cycles (9 weeks) of induction TPE using multi-analyte immunobead-based profiling (Luminex Corp., Austin, TX), with selected analytes validated by a single analyte enzyme-linked immunosorbent assay. Tumor biomarkers included phosphorylated signal transducer and activator of transcription-3 (pSTAT3), EGFR and human papillomavirus (HPV). Thirty-one patients had baseline biomarkers and 25 had paired samples, pre- and post-TPE. Adjusting for false discovery, 14 analytes including MCP1c, IP-10, Leptin, interleukin (IL)-5, Eotaxin, IL-6, G-CSF, CXCL5 changed significantly post TPE induction. Serum vascular endothelial growth factor (VEGF) and IL-6 levels were associated with tumor response as assessed by positron emission tomography and progression-free survival, however, the association was not significant after adjustment for false discovery. Analytes were not associated with toxicities, smoking history, HPV status, EGFR amplification, or pSTAT3 tumor protein levels. Baseline serum biomarkers, in particular VEGF and IL-6, were identified as potentially useful prognostic markers of cetuximab-containing therapy. Validation is warranted in future studies specifically designed to detect biomarker associations.


Rabbit myometrial adrenergic sensitivity is increased by estrogen but is independent of changes in alpha adrenoceptor concentration.
The ability of estrogen to increase the alpha-1 adrenergic sensitivity of rabbit uterine smooth muscle was compared with its effects on the concentration of alpha adrenoceptor subtypes in myometrium. Compared to ovariectomized controls, estrogen treatment was found to increase the adrenergic contractile sensitivity of rabbit uterus determined in vitro. Estrogen treatment increased uterine alpha-2 adrenoceptor concentration nearly 5-fold. Mature rabbits (endogenous estrogen) had the same uterine sensitivity and alpha-2 adrenoceptor concentration as estrogen-treated rabbits. Alpha-1 receptor concentration was increased only in the estrogen-treated group, and was accompanied by increased maximal contractile response. Thus, the increase in adrenergic sensitivity after estrogen was correlated closely with an increased concentration of alpha-2 adrenoceptors. However, enhanced adrenergic sensitivity persisted after alpha-1 and alpha-2 receptor concentration returned to pre-estrogen levels in rabbits pretreated with estrogen before ovariectomy. Studies utilizing subtype-selective competitive antagonists verified that contractile response is mediated primarily by alpha-1 adrenoceptors, with no apparent influence of alpha-2 adrenoceptors. Finally, we found that adrenergic sensitivity is altered by temperature and divalent cation concentration, but these effects do not prevent the expression of the regulatory action of estradiol. We conclude that estrogen increases the alpha-1 adrenergic sensitivity of rabbit uterus without changes in alpha-1 receptors, and thus may act on postreceptor response events.(ABSTRACT TRUNCATED AT 250 WORDS)


Evidence for a synaptic plasma membrane associated adenylate kinase in the rat brain.
About 5% of the total adenylate kinase activity in the rat forebrain was found in a subcellular fraction enriched in synaptic plasma membrane (SPM). The enzyme remained membrane bound after washing by 1M potassium acetate. It was resistant to trypsin digestion under conditions which destroyed 90% of acetylcholinesterase activity. The SPM enzyme was solubilized by 0.25% Triton X-100 resulting in a 4-fold increase in activity. Similar effects were observed when SPM was treated with phospholipases, melittin and trifluoperazine. These results suggest the occurrence of an adenylate kinase closely associated with SPM the activity of which can only be fully expressed by disturbances to the hydrophobic lipid bilayer. The enzyme can be seen as strategically located to play a role in regenerating ATP required for the manifold activities of the synaptic membrane.


The immunohistochemical characterization of human fetal olfactory bulb and olfactory ensheathing cells in culture as a source for clinical CNS restoration.
Clinical studies have expanded the therapeutic olfactory ensheathing cells (OECs) transplantation to different human Central Nervous System (CNS) diseases. In fact, the OEC transplantation in clinic is a mixture of olfactory bulb cells; they even have not demonstrated that they have such a subpopulation yet. However, as a source of OECs transplantation, the development and identification of human fetal OECs are still need more understanding, because some surgery try to restoration CNS injury with a more purity of OEC cultures generated by a number of different procedures. In this article, twelve human fetal olfactory bulb (OB) samples were obtained from six fetuses in 20 weeks of gestation, it was studied by immunofluorescence on histological sections and cultured cells with multiple antibodies under confocal microscopy. The P75NTR positive OB-OECs (olfactory ensheathing cell from the olfactory bulb) were present in both outer olfactory nerve layers and glomerular layer. The percentage of OB cells in culture, about 22.31 was P75NTR positive, 45.77 was S100beta, and 31.92 was GFAP. P75NTR and GFAP were coexpressed with S100beta, respectively; however, P75NTR was not coexpressed with GFAP in human fetal OECs. It is suggested that the localization and development of human OECs in OB are different to those in rodent, and the P75NTR immunohistological staining is still necessary to identify and characterize human fetal OECs in culture before transplantation.


Effect of nano-curcumin on various diseases: A comprehensive review of clinical trials.
The antioxidant, anti-inflammatory, and antibacterial properties of curcumin have made it a valuable herbal product for improving various disorders, such as COVID-19, cancer, depression, anxiety, osteoarthritis, migraine, and diabetes. Recent research has demonstrated that encapsulating curcumin in nanoparticles might improve its therapeutic effects and bioavailability. To our knowledge, the efficacy of nano-curcumin on different aspects of health and disease has not been summarized in a study. Therefore, this review aimed to evaluate nano-curcumin's efficacy in various diseases based on the findings of clinical trials. In order to review publications focusing on nanocurcumin's impact on various diseases, four databases were searched, including PubMed, Scopus, Web of Science, and Google Scholar. This review highlights the potential benefits of nano-curcumin in improving a wide range of human diseases including COVID-19, neurological disorders, chronic disease, oral diseases, osteoarthritis, metabolic syndrome, and other diseases, especially as an adjunct to standard therapy and a healthy lifestyle.


Human mast cell tryptase: multiple cDNAs and genes reveal a multigene serine protease family.
Three different cDNAs and a gene encoding human skin mast cell tryptase have been cloned and sequenced in their entirety. The deduced amino acid sequences reveal a 30-amino acid prepropeptide followed by a 245-amino acid catalytic domain. The C-terminal undecapeptide of the human preprosequence is identical in dog tryptase and appears to be part of a prosequence unique among serine proteases. The differences among the three human tryptase catalytic domains include the loss of a consensus N-glycosylation site in one cDNA, which may explain some of the heterogeneity in size and susceptibility to deglycosylation seen in tryptase preparations. All three tryptase cDNAs are distinct from a recently reported cDNA obtained from a human lung mast cell library. A skin tryptase cDNA was used to isolate a human tryptase gene, the exons of which match one of the skin-derived cDNAs. The organization of the approximately 1.8-kilobase-pair tryptase gene is unique and is not closely related to that of any other mast cell or leukocyte serine protease. The 5' regulatory regions of the gene share features with those of other serine proteases, including mast cell chymase, but are unusual in being separated from the protein-coding sequence by an intron. High-stringency hybridization of a human genomic DNA blot with a fragment of the tryptase gene confirms the presence of multiple tryptase genes. These findings provide genetic evidence that human mast cell tryptases are the products of a multigene family.


Correlates of uptake of COVID-19 vaccines and motivation to vaccinate among Malawian adults.
COVID-19 vaccine coverage in most countries in Africa remains low. Determinants of uptake need to be better understood to improve vaccination campaigns. Few studies from Africa have identified correlates of COVID-19 vaccination in the general population. We surveyed adults at 32 healthcare facilities across Malawi, purposively sampled to ensure balanced representation of adults with and without HIV. The survey, informed by the World Health Organization's Behavioural and Social Drivers of Vaccination Framework, asked about people's thoughts and feelings about the vaccine, social processes, motivation to vaccinate, and access issues. We classified respondents' COVID-19 vaccination status and willingness to vaccinate, and used multivariable logistic regression to assess correlates of these. Among 837 surveyed individuals (median age was 39 years (IQR 30-49) and 56% were female), 33% were up-to-date on COVID-19 vaccination, 61% were unvaccinated, and 6% were overdue for a second dose. Those up-to-date were more likely to know someone who had died from COVID-19, feel the vaccine is important and safe, and perceive pro-vaccination social norms. Despite prevalent concerns about vaccine side effects, 54% of unvaccinated respondents were willing to vaccinate. Access issues were reported by 28% of unvaccinated but willing respondents. Up-to-date COVID-19 vaccination status was associated with positive attitudes about the vaccine and with perceiving pro-vaccination social norms. Over half of unvaccinated respondents were willing to get vaccinated. Disseminating vaccine safety messages from trusted sources and ensuring local vaccine availability may ultimately increase vaccine uptake.


Automatic detection of age-related macular degeneration pathologies in retinal fundus images.
Advanced techniques in image processing and analysis are being extensively studied to assist clinical diagnoses. Digital colour retinal fundus images are widely utilised to investigate various eye diseases. In this paper, we describe the detection of optic disc (OD), macula and age-related macular degeneration (ARMD) pathologies of the macular regions in colour fundus images. ARMD causes the loss of central vision in older adults. If the disease is detected early and treated promptly, much of the vision loss can be prevented. Eighty colour retinal fundus images were tested using our proposed algorithm. The Hough transform was employed for OD determination. A fundus coordinate system was established based on the macula location. An ARMD pathology detection methodology using a subtraction process after contrast-limited adaptive histogram equalisation operations was proposed. The accuracies of the automated segmentations of the OD, macula and ARMD pathologies obtained were 100%, 100% and 95.49%, respectively. These results show that our algorithm is a useful tool for detecting ARMD in retinal fundus images. The application of our method may reduce the time needed by ophthalmologists to diagnose ARMD pathology while providing dependable detection precision. Integration of our technique into traditional software could be used in clinical implementations as an aid in disease diagnosis and as a tool for quantitative evaluation of treatment effectiveness.


The periplasmic component of the DctPQM TRAP-transporter is part of the DctS/DctR sensory pathway in Rhodobacter sphaeroides.
Rhodobacter sphaeroides can use C4-dicarboxylic acids to grow heterotrophically or photoheterotropically, and it was previously demonstrated in Rhodobacter capsulatus that the DctPQM transporter system is essential to support growth using these organic acids under heterotrophic but not under photoheterotrophic conditions. In this work we show that in R. sphaeroides this transporter system is essential for photoheterotrophic and heterotrophic growth, when C4-dicarboxylic acids are used as a carbon source. We also found that over-expression of dctPQM is detrimental for photoheterotrophic growth in the presence of succinic acid in the culture medium. In agreement with this, we observed a reduction of the dctPQM promoter activity in cells growing under these conditions, indicating that the amount of DctPQM needs to be reduced under photoheterotrophic growth. It has been reported that the two-component system DctS and DctR activates the expression of dctPQM. Our results demonstrate that in the absence of DctR, dctPQM is still expressed albeit at a low level. In this work, we have found that the periplasmic component of the transporter system, DctP, has a role in both transport and in signalling the DctS/DctR two-component system.


Tissue inhibitor of metalloproteinase-4 deletion in mice impacts maternal cardiac function during pregnancy and postpartum.
Reversible physiological cardiac hypertrophy of the maternal heart occurs during pregnancy and involves extracellular matrix (ECM) remodeling. Previous mouse studies revealed that changes in ECM molecules accompany functional changes in the left ventricle (LV) during late pregnancy and postpartum. We evaluated the effect of global Timp4 deletion in female mice on LV functional parameters and ECM molecules during pregnancy and the postpartum period. Heart weights normalized to tibia lengths were increased in Timp4 knockout (Timp4 KO) virgin, pregnant, and postpartum day 2 mice compared with wild types. Serial echocardiography performed on pregnancy days 10, 12, and 18 and postpartum days (ppds) 2, 7, 14, 21, and 28 revealed that both wild-type and Timp4 KO mice increased end systolic and end diastolic volumes (ESV, EDV) by mid to late pregnancy compared with virgins, with EDV changes persisting through the postpartum period. When compared with wild types, Timp4 KO mice exhibited higher ejection fractions in virgins, at pregnancy days 10 and 18 and ppd2 and ppd14. High-molecular weight forms of COL1A1 and COL3A1 proteins in LV were greater in Timp4 KO virgins, and COL1A1 was higher in late pregnancy and on ppd2 compared with wild types. With exceptions, Timp4 KO mice during late pregnancy and the early postpartum period were able to maintain stroke volume similar to wild-type mice through increased ejection fraction. Although TIMP4 deletion in females exhibited altered ECM molecules, it did not adversely affect cardiac function during first pregnancies and lactation.NEW & NOTEWORTHY Pregnancy and lactation increase volume load on the heart. Defects in cardiac remodeling during pregnancy and postpartum can result in peripartum cardiomyopathy. TIMPs participate in cardiac remodeling. The present study reports the cardiac function in Timp4 knockout adult female mice during pregnancy and lactation. Timp4 knockout females at many time points have higher ejection fraction to maintain stroke volume. Global deletion of Timp4 was not detrimental to maternal heart function during first pregnancies and lactation.


Oxidant and antioxidant events during epidermal growth factor therapy to cutaneous wound healing in rats.
Cutaneous wound healing is a highly complex process, which includes inflammation, cell proliferation, matrix deposition and remodelling phases. Various growth factors, like epidermal growth factor (EGF), play an important role during wound healing. However, little is known about relationship between EGF and oxidant-antioxidant events in cutaneous wound healing models. Thus we planned to evaluate the connection between EGF therapy and oxidative stress in dermal tissue followed by wounding. Fifty-four adult male Wistar-albino rats were randomly divided into three groups: control, untreated and topical EGF administrated group. A linear full-thickness excision of 40 mm in length on both sides of spinal cord was made on the back of each rat and sutured under anaesthesia and sterile conditions. Excision was closed with 4/0 atraumatic silk suture. EGF solution was freshly prepared at 10 ng/ml dose in thilotears gel under aseptic conditions. Following the surgery, 1 ml of EGF solution was administered to wound strips one time in everyday. The animals were euthanised and wound tissues were collected on days 1, 5, 7 and 14. Thiobarbituric acid reactive substans (TBARS), glutathione (GSH), reactive nitrogen oxide species (NOx), ascorbic acid levels and superoxide dismutase activity were measured spectrophotometrically. TBARS levels decreased and NOx levels increased on day 5 after operation, and GSH levels were increased on day 14 in EGF administered group compared with untreated group. Our data showed that EGF may act like an antioxidant by scavenging toxic oxidation products in wound tissue. In addition, it may contribute healing of the wound tissue in earlier stages and suggest a potential effective role for antioxidant therapies, especially until day 5.


Timing effects of combined radioimmunotherapy and radiotherapy on a human solid tumor in nude mice.
Timing effects of radioimmunotherapy (RIT) combined with external-beam radiotherapy (RT) were assessed in human colon carcinoma xenografts. Initially, dose effects of fractionated RT and RIT were evaluated separately. Then, 30 Gy RT (10 fractions over 12 days) were combined with three weekly i.v. injections of 200 microCi of 131I-labeled anti-carcinoembryonic antigen monoclonal antibodies in four different treatment schedules. RIT was given either prior to, concurrently, immediately after, or 2 weeks after RT administration. The longest regrowth delay (RD) of 105 days was observed in mice treated by concurrent administration of RT and RIT, whereas the RDs of RT and RIT alone were 34 and 20 days, respectively. The three sequential combination treatments produced significantly shorter RDs ranging from 62 to 70 days. The tumor response represented by the minimal volume (MV) also showed that concurrent administration of RT and RIT gave the best result, with a mean MV of 4.5% as compared to MVs from 26 to 53% for the three sequential treatments. The results were confirmed in a second experiment, in which a RT of 40 Gy was combined with an identical RIT as above (three injections of 200 microCi of 131I-labeled monoclonal antibodies). At comparable toxicity levels, the maximum tolerated RT or RIT alone gave shorter RDs and less tumor shrinkage compared to simultaneous RT+ RIT. These results may be useful for designing clinical protocols of combined RIT and RT.


Some experience with in vivo staining of early laryngeal cancer in Jakarta, Indonesia.
Laryngeal cancer, clinically as well as pathologically, usually does not pose a difficult problem in diagnosis. The problem lies in the clinical diagnosis of early laryngeal cancer. We began to study and develop the in vivo staining technique for laryngeal lesions in our clinic, using toluidine blue, an acidophilic metachromatic dye. This preliminary study comprised eight cases of laryngeal lesions, five of which were carcinoma. Among these latter cases, besides carcinoma, we were able to detect dysplasia in two cases, carcinoma in situ in one case, and a false-positive area in one case. Noncarcinoma cases consisted of dysplasia, dysplasia in postradiation for carcinoma, and carcinoma in situ. In two cases of carcinoma, the tumor margin was accurately defined by positive staining area. This experience suggests that in vivo staining may be a useful method for early detection of laryngeal cancer used as an adjunct to microlaryngoscopy.


Effects of Pseudomonas fluorescens M3/6 bacterial protease on plasmin system and plasminogen activation.
Heat-stable proteases produced by the psychrotroph Pseudomonas fluorescens M3/6 have been shown to affect the plasmin system in milk, which in turn will affect the quality of processed milk. The M3/6 proteases cause dissociation of plasmin from casein in minimally processed milk. The objective of this work was to study the effect of M3/6 protease on the plasmin system, as well as its role in plasminogen activation, under commonly applied cheese-making conditions. Isolated M3/6 protease was added to raw milk, which then was pasteurized, and subjected to pH adjustments and CaCl2 addition. Casein and whey fractions were separated by chymosin treatment then analyzed for plasmin activity. Individual and interaction effects of M3/6 protease addition, pH treatment, and CaCl2 addition on plasmin activity were studied. Enzyme activity assays were carried out to study individually the effect of M3/6 protease on plasmin system components. Kinetic parameters were calculated to characterize the effect of M3/6 protease on plasminogen activation. Plasmin activity increased in the curd fractions of the protease-treated milk that was subjected to conditions most resembling cheese-making conditions, indicating that M3/6 protease triggered plasminogen activation rather than dissociation of plasmin from casein micelles. Results from the studies on plasminogen activation confirmed that the observed activation of plasminogen in protease-treated samples subjected to cheese making conditions was attributed to the stimulatory effect M3/6 protease had on plasminogen activators (PA). The M3/6 protease stimulated human and bovine PA by increasing their activity 4.5- and 2.5-fold, respectively. Similarly, the catalytic efficiencies of human urokinase-type PA and bovine PA were increased in the presence of M3/6 protease by 12- and 4-fold, respectively. Our research presented a basic step toward fully understanding the effect of bacterial proteases under different processing conditions, where the gathered information can aid in better control of processing conditions based on the desired outcome.


An efficient deep neural network to classify large 3D images with small objects.
3D imaging enables accurate diagnosis by providing spatial information about organ anatomy. However, using 3D images to train AI models is computationally challenging because they consist of 10x or 100x more pixels than their 2D counterparts. To be trained with high-resolution 3D images, convolutional neural networks resort to downsampling them or projecting them to 2D. We propose an effective alternative, a neural network that enables efficient classification of full-resolution 3D medical images. Compared to off-the-shelf convolutional neural networks, our network, 3D Globally-Aware Multiple Instance Classifier (3D-GMIC), uses 77.98%-90.05% less GPU memory and 91.23%-96.02% less computation. While it is trained only with image-level labels, without segmentation labels, it explains its predictions by providing pixel-level saliency maps. On a dataset collected at NYU Langone Health, including 85,526 patients with full-field 2D mammography (FFDM), synthetic 2D mammography, and 3D mammography, 3D-GMIC achieves an AUC of 0.831 (95% CI: 0.769-0.887) in classifying breasts with malignant findings using 3D mammography. This is comparable to the performance of GMIC on FFDM (0.816, 95% CI: 0.737-0.878) and synthetic 2D (0.826, 95% CI: 0.754-0.884), which demonstrates that 3D-GMIC successfully classified large 3D images despite focusing computation on a smaller percentage of its input compared to GMIC. Therefore, 3D-GMIC identifies and utilizes extremely small regions of interest from 3D images consisting of hundreds of millions of pixels, dramatically reducing associated computational challenges. 3D-GMIC generalizes well to BCS-DBT, an external dataset from Duke University Hospital, achieving an AUC of 0.848 (95% CI: 0.798-0.896).


[Ultra-weak luminescence of blood in cancer patients].
Ultra-weak luminescence of blood in 67 normal blood donors and 57 lung cancer patients was studied using the sensitive single photon counting system manufactured in China. The results showed that the blood emission intensity of lung cancer patients was higher than that of the normal blood donors with significant statistical difference (P less than 0.05). The characteristic peak of blue light ranging from 426.8 nm to 446.8 nm in lung cancer patients may imply that ultra-weak luminescence test be of value in the diagnosis of lung cancer.


Solvothermally Synthesized Hierarchical Aggregates of Anatase TiO2 Nanoribbons/Nanosheets and Their Photocatalytic-Photocurrent Activities.
Hierarchical aggregates of anatase TiO2 nanoribbons/nanosheets (TiO2-NR) and anatase TiO2 nanoparticles (TiO2-NP) were produced through a one-step solvothermal reaction using acetic acid or ethanol and titanium isopropoxide as solvothermal reaction systems. The crystalline structure, crystalline phase, and morphologies of synthesized materials were characterized using several techniques. According to our findings, both TiO2-NR and TiO2-NP were found to have polycrystalline structures, with pure anatase phases. TiO2-NR has a three-dimensional hierarchical structure made up of aggregates of TiO2 nanoribbons/nanosheets, while TiO2-NP has a nanoparticulate structure. The photocatalytic and photocurrent activities for TiO2-NR and TiO2-NP were investigated and compared with the widely used commercial TiO2 (P25), which consists of anatase/rutile TiO2 nanoparticles, as a reference material. Our findings showed that TiO2-NR has higher photocatalytic and photocurrent performance than TiO2-NP, which are both, in turn, higher than those of P25. Our developed solvothermal method was shown to produce a pure anatase TiO2 phase for both synthesized structures, without using any surfactants or any other assisted templates. This developed solvothermal approach, and its anatase TiO2 nanostructure output, has promising potential for a wide range of energy harvesting applications, such as water pollution treatment and solar cells.


Demonstration and solubilization of antigens expressed primarily on the surfaces of Candida albicans germ tubes.
Antisera against mycelial-phase, but not yeast-phase, Candida albicans absorbed with yeast-phase organisms preferentially stained germ tube segments of several strains of mycelial-phase C. albicans by the indirect fluorescent-antibody staining technique. Germ tube segment antigens were not found in significant amounts on blastospore segments or on yeast-phase organisms. Absorption of the mycelial-phase reference sera with yeast-phase C. stellatoidea, but not with C. tropicalis, C. guillermondii, or Saccharomyces cerevisiae, resulted in preferential germ tube segment staining of C. albicans. A dithiothreitol extract of mycelial-phase C. albicans organisms blocked staining of the germ tube segment, but a dithiothreitol extract of yeast-phase organisms did not. When dithiothreitol extracts from both phases were reacted against yeast-absorbed reference sera in tandem crossed and crossed line immunoelectrophoresis, a cross-reacting arc and several arcs unique to the mycelial-phase extract were noted. Immunofluorescent staining tests were performed, using appropriately absorbed sera from patients with candidiasis to stain a laboratory strain of C. albicans. Human tissue slices infected with C. albicans were used as targets for appropriately absorbed rabbit antisera. These human data indicated that antigens preferentially expressed on the germ tube in vitro were also expressed on filamentous structures of the fungus in infected human tissues. In vitro and in vivo, the invasive mycelial phase of C. albicans expresses certain antigens that are highly concentrated on the germ tube.


On the challenges of drawing conclusions from p-values just below 0.05.
In recent years, researchers have attempted to provide an indication of the prevalence of inflated Type 1 error rates by analyzing the distribution of p-values in the published literature. De Winter & Dodou (2015) analyzed the distribution (and its change over time) of a large number of p-values automatically extracted from abstracts in the scientific literature. They concluded there is a 'surge of p-values between 0.041-0.049 in recent decades' which 'suggests (but does not prove) questionable research practices have increased over the past 25 years.' I show the changes in the ratio of fractions of p-values between 0.041-0.049 over the years are better explained by assuming the average power has decreased over time. Furthermore, I propose that their observation that p-values just below 0.05 increase more strongly than p-values above 0.05 can be explained by an increase in publication bias (or the file drawer effect) over the years (cf. Fanelli, 2012; Pautasso, 2010, which has led to a relative decrease of 'marginally significant' p-values in abstracts in the literature (instead of an increase in p-values just below 0.05). I explain why researchers analyzing large numbers of p-values need to relate their assumptions to a model of p-value distributions that takes into account the average power of the performed studies, the ratio of true positives to false positives in the literature, the effects of publication bias, and the Type 1 error rate (and possible mechanisms through which it has inflated). Finally, I discuss why publication bias and underpowered studies might be a bigger problem for science than inflated Type 1 error rates, and explain the challenges when attempting to draw conclusions about inflated Type 1 error rates from a large heterogeneous set of p-values.


Building alliances from ambivalence: evaluation of abortion values clarification workshops with stakeholders in South Africa.
A retrospective evaluation of attitudinal, behavioural and knowledge change among diverse stakeholder groups was conducted in Limpopo Province of South Africa to assess the effectiveness of a series of values clarification (VC) interventions. Telephone and face-to-face interview (193) results revealed that over two-thirds (70.2%) reported behavioural changes and 93.2% reported increased compassion for women who seek and providers who render termination of pregnancy. Behaviours supportive of the law were more likely among those initially undecided about their opinion of termination of pregnancy (p < 0.05) than among those initially opposed or supportive to it. When combined with supportive follow-up, three-day VC workshops may be effective at increasing CTOPA knowledge, changing attitudes and spurring advocacy behaviour to support reproductive choice. Research studies with pre-post and case-control designs are needed to confirm these preliminary results.


Mental Health App Evaluation: Updating the American Psychiatric Association's Framework Through a Stakeholder-Engaged Workshop.
The app evaluation framework of the American Psychiatric Association (APA) has emerged as an adaptable tool for those seeking to navigate the ever-growing space of mental health apps. The authors describe a meeting convened in December 2019 to refine the APA framework. The expert panel comprised 16 individuals across health care fields, with representation from psychiatry, psychology, social work, nursing, clinical informatics, peer support specialists, and individuals with lived mental health experience. This meeting resulted in an update to the APA framework with the addition of clearer question descriptions and the release of an eight-question screener that may be useful in clinical settings.


Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s: the Framingham Heart Study.
Recent studies indicate that the prevalence of type 2 diabetes mellitus is increasing in the United States; less is known about trends in the incidence of type 2 diabetes mellitus. Participants free of diabetes mellitus (n=3104; mean age 47 years; 1587 women) from the Framingham Offspring Study who attended a routine examination in the 1970s, 1980s, or 1990s were followed up for the 8-year incidence of diabetes mellitus. Diabetes was defined as a fasting plasma glucose > or = 7.0 mmol/L or treatment with either insulin or a hypoglycemic agent. Pooled logistic regression was used to compare diabetes incidence across decades for participants between 40 and 55 years of age in each decade. The age-adjusted 8-year incidence rate of diabetes was 2.0%, 3.0%, and 3.7% among women and 2.7%, 3.6%, and 5.8% among men in the 1970s, 1980s, and 1990s, respectively. Compared with the 1970s, the age- and sex-adjusted odds ratio (OR) for diabetes was 1.40 (95% confidence interval [CI], 0.89 to 2.22) in the 1980s and 2.05 (95% CI, 1.33 to 3.14) in the 1990s (P for trend=0.0006). Among women, the OR was 1.50 (95% CI, 0.75 to 2.98) in the 1980s and 1.84 (95% CI, 0.95 to 3.55) in the 1990s (P for trend=0.07) compared with the 1970s, whereas among men, the OR was 1.33 (95% CI, 0.72 to 2.47) in the 1980s and 2.21 (95% CI, 1.25 to 3.90) in the 1990s (P for trend=0.003). Most of the increase in absolute incidence of diabetes occurred in individuals with body mass index > or = 30 kg/m2 (P for trend=0.03). In the present community-based sample of middle-aged adults, we observed a doubling in the incidence of type 2 diabetes over the last 30 years. Careful surveillance of changes in diabetes incidence may be necessary if current trends of excess adiposity continue.


Validation of a portable indirect calorimetry system for measurement of energy expenditure in sick preterm infants.
A portable indirect calorimeter adapted from adult use was validated for use in preterm infants. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were subsequently measured in 16 preterm infants breathing spontaneously in room air (canopy mode) and in nine preterm infants receiving intermittent positive pressure ventilation (ventilator mode). Validation of the system was performed using a gas injection technique with nitrogen to simulate VO2 and carbon dioxide for VCO2. Mean errors in validation of the canopy mode were 1.4% and 0.2% for VO2 and VCO2 with limits of agreement of 0.6 (+2SD) ml/min and -1.3 (-2SD) ml/min, and 0.9 (+2SD) ml/min and -2.3 (-2SD) ml/min respectively. In validation of the ventilator mode mean errors were -1.8% and -5.05% for VO2 and VCO2 with limits of agreement of 1.02 (+2SD) ml/min and -0.74 (-2SD) ml/min, and 0.93 (+2SD) ml/min and -1.45 (-2SD) ml/min respectively. Values of VO2 and VCO2 in 16 preterm infants in the canopy mode were 6.2 ml/kg/min (0.5 1SD) and 6.7 ml/kg/min (0.6 1SD) and in nine preterm infants in the ventilator mode 4.98 ml/kg/min (1.09 1SD) and 4.74 ml/min/kg (1.08 1SD) respectively. Mean energy expenditure was 45.5 kcal (191 kJ)kg/day for infants measured in the canopy mode and 35.5 kcal (149 kJ)/kg/day for ventilated infants. This metabolic system can be adapted for use in the newborn but accuracy is reduced when it is used in those weighing less than 1000 g.


Incidence of Metabolic Syndrome in Young Japanese Adults in a 6-Year Cohort Study: The Uguisudani Preventive Health Large-Scale Cohort Study (UPHLS).
To clarify the incidences of metabolic syndrome (MS) and risks in young Japanese adults by gender. A total of 58,901 adults who had undergone annual health check-ups in 2010 without a diagnosis of MS or missing data were divided into three age groups (20s through 40s) by gender. Participants were followed up for 6 years for new-onset MS according to Japanese criteria. The incidences of MS and risks were analyzed using the Cox proportional hazards model to adjust for confounding factors. The incidences of MS per 1,000 person-years were 2.2, 5.5, and 10.2 for women aged in their 20s, 30s, and 40s, respectively, and 26.3, 40.5, and 57.4 in the respective men groups. Compared with the group aged in their 40s, the hazard ratios of new MS were 0.19 (95% confidence interval [CI], 0.13-0.29) for women in their 20s and 0.50 (95% CI, 0.41-0.61) for women in their 30s, and 0.46 (95% CI, 0.42-0.50) and 0.70 (95% CI, 0.66-0.73) for men in their 20s and 30s, respectively, after adjustment for lifestyle factors. For women, MS was associated with smoking in their 20s and 30s, and eating speed in their 30s, and for men, was associated with physical activity, eating speed, alcohol intake in their 20s and 30s, and smoking in their 30s. Our findings suggest that the incidences of MS in the 20s and 30s are lower, but account for about 20-50% of women with MS and 50-70% of men with MS in their 40s. However, the data are not negligible and early lifestyle intervention for MS is necessary in young adults.


The circadian biology of the marbled crayfish.
The parthenogenetic marbled crayfish (Procambarus spec.) has recently been introduced as a new preparation for neuroethological studies. Since isogeneity apparently limits inter-individual variation, this otherwise typical decapod species may be especially valuable for circadian studies. Locomotor activity of isolated marbled crayfish and agonistic activity of small social groups maintain circadian rhythmicity in constant darkness. As potential signals of circadian time information, levels of 5HT, N-acetylserotonin and melatonin were determined in brains of marbled crayfish at different daytimes. However, location and structural organization of crustacean circadian pacemakers are still elusive. Immunocytochemical and backfill studies in the marbled crayfish revealed neural structures that may correspond to portions of circadian pacemaker systems in the insect optic lobe. Position and additional chemical contents in two pigment-dispersing hormone-expressing neuron groups resembled insect pigment-dispersing factor-expressing cells in the lamina and the accessory medulla, a neuropil discussed as center for integration of timing information. Here, we discuss new findings about the possible organization of the circadian system of the marbled crayfish in the light of current knowledge about circadian clocks in crustacea.


Effect of Finishing Time on Microleakage at the Composite-Repair Interface.
Repair is a conservative treatment of defective composite restoration. Sealing the repair interface is a critical factor to achieve successful repaired restorations. The aim of this study was to evaluatethe effect of three finishing times on the microleakage at the composite-repair interface. Eighty composite specimens (Z250) were made and aged for eight weeks in water. They were randomly divided into four groups. In the control group, repairing was done with no surface treatment and using bonding agent. In groups 2 to 4, the specimens were repaired following roughening, etching and use of Adper Single Bond, and finished immediately, after 20 minutes and after 24 hours, respectively. After thermocycling, the microleakage at the repair interface was assessed using dye-penetration technique. The results were analyzed using Kruskal-Wallis and Mann-Whitney tests (α=0.05). There was a significant difference among the four groups (P<0.001). The control group with the highest leakage showed a significant difference with the other groups (P<0.05). Immediate finishing showed a significantly higher leakage compared to 20-minute and 24-hour delayed finishing time (P<0.001). The two latter groups had no difference. Immediate finishing of the repaired restorations negatively affect the sealing at the repair interface, while 20-minute and 24-hour delayed finishing had no adverse effect on the interface sealing.


m-RESIST, a Mobile Therapeutic Intervention for Treatment-Resistant Schizophrenia: Feasibility, Acceptability, and Usability Study.
In the European Union, around 5 million people are affected by psychotic disorders, and approximately 30%-50% of people with schizophrenia have treatment-resistant schizophrenia (TRS). Mobile health (mHealth) interventions may be effective in preventing relapses, increasing treatment adherence, and managing some of the symptoms of schizophrenia. People with schizophrenia seem willing and able to use smartphones to monitor their symptoms and engage in therapeutic interventions. mHealth studies have been performed with other clinical populations but not in populations with TRS. The purpose of this study was to present the 3-month prospective results of the m-RESIST intervention. This study aims to assess the feasibility, acceptability, and usability of the m-RESIST intervention and the satisfaction among patients with TRS after using this intervention. A prospective multicenter feasibility study without a control group was undertaken with patients with TRS. This study was performed at 3 sites: Sant Pau Hospital (Barcelona, Spain), Semmelweis University (Budapest, Hungary), and Sheba Medical Center and Gertner Institute of Epidemiology and Health Policy Research (Ramat-Gan, Israel). The m-RESIST intervention consisted of a smartwatch, a mobile app, a web-based platform, and a tailored therapeutic program. The m-RESIST intervention was delivered to patients with TRS and assisted by mental health care providers (psychiatrists and psychologists). Feasibility, usability, acceptability, and user satisfaction were measured. This study was performed with 39 patients with TRS. The dropout rate was 18% (7/39), the main reasons being as follows: loss to follow-up, clinical worsening, physical discomfort of the smartwatch, and social stigma. Patients' acceptance of m-RESIST ranged from moderate to high. The m-RESIST intervention could provide better control of the illness and appropriate care, together with offering user-friendly and easy-to-use technology. In terms of user experience, patients indicated that m-RESIST enabled easier and quicker communication with clinicians and made them feel more protected and safer. Patients' satisfaction was generally good: 78% (25/32) considered the quality of service as good or excellent, 84% (27/32) reported that they would use it again, and 94% (30/32) reported that they were mostly satisfied. The m-RESIST project has provided the basis for a new modular program based on novel technology: the m-RESIST intervention. This program was well-accepted by patients in terms of acceptability, usability, and satisfaction. Our results offer an encouraging starting point regarding mHealth technologies for patients with TRS. ClinicalTrials.gov NCT03064776; https://clinicaltrials.gov/ct2/show/record/NCT03064776. RR2-10.1136/bmjopen-2017-021346.


The Impact of Adulticide on Culex Abundance and Infection Rate in North Shore of Cook County, Illinois.
Mosquito surveillance is critical to reduce the risk of West Nile virus (WNV) transmission to humans. In response to surveillance indicators such as elevated mosquito abundance or increased WNV levels, many mosquito control programs will perform truck-mounted ultra-low volume (ULV) adulticide application to reduce the number of mosquitoes and associated virus transmission. Despite the common use of truck-based ULV adulticiding as a public health measure to reduce WNV prevalence, limited evidence exists to support a role in reducing viral transmission to humans. We use a generalized additive and fused ridge regression model to quantify the location-specific impact of truck-mounted ULV adulticide spray efforts from 2010 to 2018 in the North Shore Mosquito Abatement District (NSMAD) in metropolitan Chicago, IL, on commonly assessed risk factors from NSMAD surveillance gravid traps: Culex abundance, infection rate, and vector index. Our model also takes into account environmental variables commonly associated with WNV, including temperature, precipitation, wind speed, location, and week of year. Since it is unlikely ULV adulticide spraying will have the same impact at each trap location, we use a spatially varying spray effect with a fused ridge penalty to determine how the effect varies by trap location. We found that ULV adulticide spraying has an immediate temporary reduction in abundance followed by an increase after 5 days. It is estimated that mosquito abundance increased more in sprayed areas than if left unsprayed in all but 3 trap locations. The impact on infection rate and vector index were inconclusive due to the large error associated with estimating trap-specific infection rates.


Executive function, but not memory, associates with incident coronary heart disease and stroke.
To evaluate the association of performance in cognitive domains executive function and memory with incident coronary heart disease and stroke in older participants without dementia. We included 3,926 participants (mean age 75 years, 44% male) at risk for cardiovascular diseases from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with Mini-Mental State Examination score ≥24 points. Scores on the Stroop Color-Word Test (selective attention) and the Letter Digit Substitution Test (processing speed) were converted to Z scores and averaged into a composite executive function score. Likewise, scores of the Picture Learning Test (immediate and delayed memory) were transformed into a composite memory score. Associations of executive function and memory were longitudinally assessed with risk of coronary heart disease and stroke using multivariable Cox regression models. During 3.2 years of follow-up, incidence rates of coronary heart disease and stroke were 30.5 and 12.4 per 1,000 person-years, respectively. In multivariable models, participants in the lowest third of executive function, as compared to participants in the highest third, had 1.85-fold (95% confidence interval [CI] 1.39-2.45) higher risk of coronary heart disease and 1.51-fold (95% CI 0.99-2.30) higher risk of stroke. Participants in the lowest third of memory had no increased risk of coronary heart disease (hazard ratio 0.99, 95% CI 0.74-1.32) or stroke (hazard ratio 0.87, 95% CI 0.57-1.32). Lower executive function, but not memory, is associated with higher risk of coronary heart disease and stroke. Lower executive function, as an independent risk indicator, might better reflect brain vascular pathologies.


Extracellular Matrix Influences Gene Expression and Differentiation of Mouse Trophoblast Stem Cells.
Trophoblast stem (TS) cells were first isolated from the mouse placenta; however, little is known about their maintenance and niche in vivo. TS cells, like other stem cells, have a unique microenvironment in which the extracellular matrix (ECM) is a component. Placental pathology is associated with ECM change. However, how these changes and the individual ECM components impact the maintenance or differentiation of TS cells has not been established. This study identified which ECM component(s) maintain the greatest expression of markers associated with undifferentiated mouse trophoblast stem (mTS) cells and which alter the profile of markers of differentiation based on mRNA analysis. mTS cells cultured on individual ECM components and subsequent quantitative polymerase chain reaction analysis revealed that laminin promoted the expression of markers associated with undifferentiated TS cells, fibronectin promoted gene expression associated with syncytiotrophoblast (SynT) layer II cells, and collagen IV promoted the expression of genes associated with differentiated trophoblast. To investigate whether pathological placental ECM influenced the expression of genes associated with different trophoblast subtypes, the mouse model of streptozotocin (STZ)-induced pancreatic β cell ablation and diabetes was used. Female mice administered STZ (blood glucose ≥300 mg/dL) or control (blood glucose ≤150 mg/dL) were mated. Placental pathology at embryonic day (E)14.5 was confirmed with reduced fetal blood space area, reduced expression of the pericyte marker αSMA, and decreased expression of ECM proteins. mTS cells cultured on ECM isolated from STZ placenta were associated with reduced expression of undifferentiated mTS markers and increased expression of genes associated with terminally differentiated trophoblast [Gcm-1 and SynA (SynT) and junctional zone Tpbpa and Prl2c2]. Altogether, these results support the value of using ECM isolated from the placenta as a tool for understanding trophoblast contribution to placental pathology.


New development of integrated CT simulation system for radiation therapy planning.
In order to put more accurate radiotherapy into practice, a radiotherapy planning system using CT, which is named CT simulation system, has been developed and introduced at Kobe University Hospital. The CT simulation system consists of a CT scanner, an image processing work-station, and a laser marking system. The target area of radiation is determined on each CT axial image or scout view in the work-station. Three-dimensional treatment planning is feasible on the basis of the two-dimensional tumor information in CT axial images. After setting treatment parameters, the contour of the radiation field on beam's eye view and the iso-center position are calculated by computer. This system makes it possible to choose an appropriate irradiation method and an optimal dose distribution. In the present study we examined the fundamental capability of this system. The laser marking system proved to have a very high degree of accuracy. The outcome of a phantom test raised the strong possibility that this system may be applied clinically. In addition to these basic findings, this paper describes preliminary clinical observations that support the good reproducibility of the radiation field projected with the CT simulator. In conclusion, this system is of high value for radiation therapy planning.


Oral health-related quality of life in patients with dental anxiety.
To investigate the frequency of impaired oral health-related quality of life (OHRQoL) in patients with dental anxiety. OHRQoL was measured with the German version of the 14-item Oral Health Impact Profile (OHIP) developed by Slade and Spencer (1994) in 173 adult patients with dental anxiety [Dental Anxiety Scale (DAS) score 15 or above and Dental Fear Survey (DFS) score 60 or above]. The OHIP summary scores were characterized with an empirical cumulative distribution function and compared with the level of impaired OHRQoL in the general population (n = 2026, age: 16-79 years). In addition, OHIP item prevalences (responses 'fairly often'/'very often') were compared between patients and population subjects. The correlation between DAS, DFS and OHIP scores was calculated using the Pearson correlation coefficient. A median value of 1 and a 90th percentile value of 13 were observed for general population subjects. In contrast, patients with phobic dental anxiety had a median OHIP-14 of 21 and the 90th percentile of 40. All problems mentioned in the OHIP-14 were more prevalent in patients than in population subjects. The most frequently occurring items in patients were 'self-conscious', 'life in general was less satisfying', and 'feeling tense' with prevalences of 50% or greater. In contrast, these items had prevalences of only 1-3% in the general population. A low to moderate relationship between OHRQoL and both dental anxiety measures (DAS and DFS) was observed (r = 0.25/0.26, P < 0.01). Patients with dental anxiety/fear suffer considerably from impaired OHRQoL and the degree of this impairment is related to the extent of dental anxiety/fear.


Human immunodeficiency virus reverse transcriptase. Functional mutants obtained by random mutagenesis coupled with genetic selection in Escherichia coli.
We describe catalytically active mutants of HIV RT (human immunodeficiency virus reverse transcriptase) generated by random sequence mutagenesis and selected in Escherichia coli for ability to complement the temperature-sensitive phenotype of a DNA polymerase I (Pol Its) mutant. We targeted amino acids Asp-67 through Arg-78 in HIV RT, which form part of the beta3-beta4 flexible loop and harbor many of the currently known mutations that confer resistance to nucleoside analogs. DNA sequencing of 109 selected mutants that complement the Pol Its phenotype revealed substitutions at all 12 residues targeted, indicating that none of the wild-type amino acids is essential. However, single mutations were not observed at Trp-71, Arg-72, and Arg-78, consistent with evolutionary conservation of these residues among viral RTs and lack of variation at these positions among isolates from patients. The mutations we recovered included most of those associated with drug resistance as well as previously unidentified mutations. Purification and assay of 14 mutant proteins revealed correlation between their DNA-dependent DNA polymerize activity in vitro and ability to complement the Pol Its phenotype. Activity of several mutants was resistant to 3'-azidothymidine triphosphate. We conclude that random sequence mutagenesis coupled with positive genetic selection in E. coli yields large numbers of functional HIV RT mutants. Among these are less active variants which are unlikely to be isolated from HIV-infected individuals and which will be informative of the roles of individual amino acids in the catalytic functions of the enzyme.


A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: genotype/phenotype correlations.
Achondrogenesis type 1B (ACG-1B), atelosteogenesis type 2 (AO-2), and diastrophic dysplasia (DTD) are recessively inherited chondrodysplasias of decreasing severity caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene on chromosome 5. In these conditions, sulfate transport across the cell membrane is impaired which results in insufficient sulfation of cartilage proteoglycans and thus in an abnormally low sulfate content of cartilage. The severity of the phenotype correlates well with the predicted effect of the underlying DTDST mutations: homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type 1B, while other structural or regulatory mutations usually result in one of the less severe phenotypes. The chondrodysplasias arising at the DTDST locus constitute a bone dysplasia family with recessive inheritance.


Near-total laryngectomy. Patient selection and technical considerations.
To investigate the speech and swallowing outcomes of patients undergoing near-total laryngectomy and to determine those perioperative factors that are associated with success. Retrospective analysis of a case series obtained from a hospital-based academic tertiary care center. Records of all patients who underwent near-total laryngectomy at this institution were reviewed. Wound healing problems, quality of speech, degree of aspiration, and need for shunt revision were recorded. Thirty-nine patients during a 10-year period underwent near-total laryngectomy. Good speech was obtained in 30 (76%). Severe aspiration was a complication in eight patients (21%), necessitating reversal of the shunt in four (10%). Certain technical aspects of this procedure that produce a "hooded" myomucosal shunt were crucial to proper shunt function. Severe aspiration and poor voice outcome were most likely in patients who experienced a postoperative pharyngocutaneous fistula. These fistulas tended to occur at the junction of the pharynx and the upper end of the myomucosal shunt. When this region broke down, the hooding of the shunt was disrupted and its function impaired. Careful patient selection is crucial to the creation of a functional myomucosal speaking shunt after near-total laryngectomy. In patients at high risk for developing a pharyngocutaneous fistula, where irreversible aspiration through the shunt is then likely, this operation should be avoided and a total laryngectomy with tracheoesophageal puncture considered instead.


Combined Anterior Transmaxillary (Caldwell-Luc) With an Endoscopic Endonasal Transpterygoid Approach for Resection of a Large Juvenile Nasopharyngeal Angiofibroma: 2-Dimensional Operative Video.
Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular benign tumor that originates in the sphenopalatine foramen and often spreads to adjacent compartments.1 Microsurgical resection with preoperative embolization remains the treatment of choice.2 We present a case of a large JNA involving multiple compartments. The patient is a 20-yr-old male who presented with long-term right nasal congestion. The MRI demonstrated a large enhancing mass that extended from the right nasal cavity and nasopharynx into the right pterygopalatine fossa (PPF), infratemporal fossa (ITF), and parapharyngeal space. Preoperative angiogram for embolization showed a highly vascular tumor with blood supply mainly from the internal maxillary artery and about 10% from a persistent mandibular branch of the internal carotid artery. Based on the UPMC JNA staging system, this tumor was a stage IV.2 A combined anterior transmaxillary (Caldwell-Luc) with an endoscopic endonasal transpterygoid approach was performed. The addition of the anterior transmaxillary approach increases the surgical freedom for traditional bipolar devices and improves the view and trajectory to more lateral structures like the PPF and ITF.3 Gross total resection was achieved without complications. The patient was discharged home with a partial V2 numbness (right superior gum) that improved with time. The endoscopic endonasal approach is a safe and effective technique even for large JNA. A multidisciplinary team consisting of an interventional radiologist, a skull base neurosurgeon, and an otorhinolaryngologist with expertise in endoscopic surgery may play a role for optimal surgical results. The patient consented for the procedure and for the video production.


Water recreation and illness severity.
The health endpoint of prior studies of water recreation has been the occurrence of gastrointestinal (GI) illness. This dichotomous measure fails to take into account the range of symptom severity among those with GI illness, and those who develop GI symptoms but who do not satisfy the definition of GI illness. Data from two US cohort studies were used to assess use of ordinal and semi-continuous measures of GI symptoms, such as duration of GI symptoms and responses to those symptoms such as medication use, interference with daily activities, and utilization of healthcare service. Zero-inflated negative binomial and logistic regression models were used to assess associations between severity and either the degree of water exposure or water quality. Among 37,404 water recreators without baseline GI symptoms, we observed individuals with relatively low severity satisfying the case definition of GI illness, while others with high severity not satisfying that definition. Severity metrics were associated with water exposure. The dichotomous GI illness outcome could be improved by considering symptom severity in future studies. Modeling ordinal and semi-continuous outcomes may improve our understanding of determinants of the burden of illness rather than simply the number of cases of illness attributable to environmental exposures.


Genetic analysis of cerebellar lipids in mice susceptible to audiogenic seizures.
The major neutral and acidic cerebellar lipids were studied in audiogenic seizure (AGS)-resistant C57BL/6 (B6) and AGS-susceptible DBA/2J (D2) mice. These cerebellar lipids were also studied in the D2.B6- Iasb congenic mice and in the B6D2F1 hybrids that are mostly AGS resistant. Except for the Iasb gene, which inhibits AGS susceptibility, the D2.B6- Iasb congenic mice are genetically similar to the D2 mice. Because subtle abnormalities in the chemical structure of membranes may underlie epilepsy, we wanted to determine if AGS susceptibility was associated with abnormalities in the distribution of cerebellar lipids. A new method for the analysis of total brain lipids was used in this study. Slight, but significant, differences were found between the B6 and D2 strains for the concentrations (microgram/100 mg wet weight) of sphingomyelin, phosphatidylcholine, and cerebrosides. However, these differences may not be associated with differences in AGS susceptibility since the concentrations of these lipids in the AGS-resistant D2.B6- Iasb and B6D2F1 mice were more similar to the D2 than the B6 concentrations. The expression of Iasb is not responsible for the lipid differences found between the B6 and D2 mice.


Couples' psychological adjustment to twin parenthood: mode of conception (spontaneous versus assisted reproduction) and gender differences.
To examine whether mode of conception and gender are associated with parents' psychological adjustment across the transition to twin parenthood. There is limited knowledge on the psychological adjustment of couples to twin parenthood during pregnancy and early postpartum, especially for fathers. The available research suggests that first-time mothers of twins conceived by assisted reproduction techniques (ART) may experience lower psychosocial well-being than mothers of spontaneously conceived (SC) twins. A total of 41 couples expecting twins, 25 of whom conceived spontaneously and 16 conceived by assisted reproduction techniques, completed measures of depressive and anxiety symptoms, marital relationship, attitudes to sex, and attitudes to pregnancy and the baby. ART parents showed a decline in marital relationship quality, no changes in attitudes to pregnancy and the baby and no changes in attitudes to sex over the postpartum. In contrast, SC parents did not change their perception of the marital relationship, reported more positive attitudes to pregnancy and the baby, and more positive attitudes to sex over the postpartum. Compared with the other groups (SC mothers and fathers, ART fathers), ART mothers exhibited a higher increase in depressive and anxiety symptoms from pregnancy to postpartum and only anxiety symptoms exhibited a decline trend over the postpartum. These findings suggest that ART parents may experience more psychological difficulties during the transition to twin parenthood than SC parents. ART mothers, in particular, appear to be more at risk of high levels of postpartum depressive symptoms.


The Pristionchus HOX gene Ppa-lin-39 inhibits programmed cell death to specify the vulva equivalence group and is not required during vulval induction.
In the two nematode species Caenorhabditis elegans and Pristionchus pacificus the vulva equivalence group in the central body region is specified by the Hox gene lin-39. C. elegans lin-39 mutants are vulvaless and the vulval precursor cells fuse with the surrounding hypodermis, whereas in P. pacificus lin-39 mutants the vulval precursor cells die by apoptosis. Mechanistically, LIN-39 might inhibit non-vulval fate (cell fusion in C. elegans, apoptosis in P. pacificus), promote vulval fate or do both. To study the mechanism of lin-39 function, we isolated P. pacificus cell death mutants and identified mutations in ced-3. Surprisingly, P. pacificus ced-3; lin-39 double mutants form a functional vulva in the absence of LIN-39 activity. Thus, in P. pacificus lin-39 specifies the vulva equivalence group by inhibiting programmed cell death. Furthermore, these data reveal an important difference in a later function of lin-39 between the two species. In C. elegans, LIN-39 specifies vulval cell fates in response to inductive RAS signaling, and in P. pacificus LIN-39 is not required for vulval induction. Thus, the comparative analysis indicates that lin-39 has distinct functions in both species although the gene is acting in a homologous developmental system.


Allometric scaling of the active hematopoietic stem cell pool across mammals.
Many biological processes are characterized by allometric relations of the type Y = Y(0)M(b) between an observable Y and body mass M, which pervade at multiple levels of organization. In what regards the hematopoietic stem cell pool, there is experimental evidence that the size of the hematopoietic stem cell pool is conserved in mammals. However, demands for blood cell formation vary across mammals and thus the size of the active stem cell compartment could vary across species. Here we investigate the allometric scaling of the hematopoietic system in a large group of mammalian species using reticulocyte counts as a marker of the active stem cell pool. Our model predicts that the total number of active stem cells, in an adult mammal, scales with body mass with the exponent 3/4. The scaling predicted here provides an intuitive justification of the Hayflick hypothesis and supports the current view of a small active stem cell pool supported by a large, quiescent reserve. The present scaling shows excellent agreement with the available (indirect) data for smaller mammals. The small size of the active stem cell pool enhances the role of stochastic effects in the overall dynamics of the hematopoietic system.


Inhibition of noradrenergic signalling in rodent orbitofrontal cortex impairs the updating of goal-directed actions.
In a constantly changing environment, organisms must track the current relationship between actions and their specific consequences and use this information to guide decision-making. Such goal-directed behaviour relies on circuits involving cortical and subcortical structures. Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents. The role of the latter in goal-directed behaviour has been debated, but recent data indicate that the ventral and lateral subregions of the OFC are needed to integrate changes in the relationships between actions and their outcomes. Neuromodulatory agents are also crucial components of prefrontal functions and behavioural flexibility might depend upon the noradrenergic modulation of the prefrontal cortex. Therefore, we assessed whether noradrenergic innervation of the OFC plays a role in updating action-outcome relationships in male rats. We used an identity-based reversal task and found that depletion or chemogenetic silencing of noradrenergic inputs within the OFC rendered rats unable to associate new outcomes with previously acquired actions. Silencing of noradrenergic inputs in the prelimbic cortex or depletion of dopaminergic inputs in the OFC did not reproduce this deficit. Together, our results suggest that noradrenergic projections to the OFC are required to update goal-directed actions.


Difference in Pain, Complication Rates, and Clinical Outcomes After Suprapatellar Versus Infrapatellar Nailing for Tibia Fractures? A Systematic Review of 1447 Patients.
To assess the effectiveness of suprapatellar (SP)-nailing versus infrapatellar (IP)-nailing of tibia fractures in anterior knee pain, complications (retropatellar chondropathy, infection, and malalignment) and physical functioning and quality of life. A clinical question-driven and thorough systematic review of current literature is provided. PubMed and Embase databases were searched for studies published between 2010 and 2020 relating to SP and IP-nailing of tibia fractures. The study is performed in concordance with PRISMA-guidelines. Studies eligible for inclusion were randomized controlled trials, prospective and retrospective observational studies reporting on outcomes of interest. Data extraction was performed independently by 2 assessors. Methodological quality and risk of bias was assessed according to the guidelines of the McMaster Critical Appraisal. Continuous variables are presented as means with SD and dichotomous variables as frequency and percentages. The weighted mean, standardized weighted mean differences, and 95% confidence interval were calculated. A pooled analysis could not be performed because of differences in outcome measures, time-points, and heterogeneity. Fourteen studies with 1447 patients were analyzed. The weighted incidence of anterior knee pain was 29% after SP-nailing and 39% after IP-nailing, without reported significance. There was a significant lower rate of malalignment after the SP-approach (4% vs. 26%) with small absolute differences in all planes. No substantial differences were observed in retropatellar chondropathy, infection, physical functioning, and quality of life. This systematic review does not reveal superiority of either technique in any of the respective outcomes of interest. Definitive choice should depend on the surgeon's experience and available resources. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Sleep stage classification based on respiratory signal.
One of the research tasks, which should be solved to develop a sleep monitor, is sleep stages classification. This paper presents an algorithm for wakefulness, rapid eye movement sleep (REM) and non-REM sleep detection based on a set of 33 features, extracted from respiratory inductive plethysmography signal, and bagging classifier. Furthermore, a few heuristics based on knowledge about normal sleep structure are suggested. We used the data from 29 subjects without sleep-related breathing disorders who underwent a PSG study at a sleep laboratory. Subjects were directed to the PSG study due to suspected sleep disorders. A leave-one-subject-out cross-validation procedure was used for testing the classification performance. The accuracy of 77.85 ± 6.63 and Cohen's kappa of 0.59 ± 0.11 were achieved for the classifier. Using heuristics we increased the accuracy to 80.38 ± 8.32 and the kappa to 0.65 ± 0.13. We conclude that heuristics may improve the automated sleep structure detection based on the analysis of indirect information such as respiration signal and are useful for the development of home sleep monitoring system.


Allele-Specific Quantitative PCR for Accurate, Rapid, and Cost-Effective Genotyping.
Customizable endonucleases such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) enable rapid generation of mutant strains at genomic loci of interest in animal models and cell lines. With the accelerated pace of generating mutant alleles, genotyping has become a rate-limiting step to understanding the effects of genetic perturbation. Unless mutated alleles result in distinct morphological phenotypes, mutant strains need to be genotyped using standard methods in molecular biology. Classic restriction fragment length polymorphism (RFLP) or sequencing is labor-intensive and expensive. Although simpler than RFLP, current versions of allele-specific PCR may still require post-polymerase chain reaction (PCR) handling such as sequencing, or they are more expensive if allele-specific fluorescent probes are used. Commercial genotyping solutions can take weeks from assay design to result, and are often more expensive than assembling reactions in-house. Key components of commercial assay systems are often proprietary, which limits further customization. Therefore, we developed a one-step open-source genotyping method based on quantitative PCR. The allele-specific qPCR (ASQ) does not require post-PCR processing and can genotype germline mutants through either threshold cycle (Ct) or end-point fluorescence reading. ASQ utilizes allele-specific primers, a locus-specific reverse primer, universal fluorescent probes and quenchers, and hot start DNA polymerase. Individual laboratories can further optimize this open-source system as we completely disclose the sequences, reagents, and thermal cycling protocol. We have tested the ASQ protocol to genotype alleles in five different genes. ASQ showed a 98-100% concordance in genotype scoring with RFLP or Sanger sequencing outcomes. ASQ is time-saving because a single qPCR without post-PCR handling suffices to score genotypes. ASQ is cost-effective because universal fluorescent probes negate the necessity of designing expensive probes for each locus.


Early farmers from across Europe directly descended from Neolithic Aegeans.
Farming and sedentism first appeared in southwestern Asia during the early Holocene and later spread to neighboring regions, including Europe, along multiple dispersal routes. Conspicuous uncertainties remain about the relative roles of migration, cultural diffusion, and admixture with local foragers in the early Neolithization of Europe. Here we present paleogenomic data for five Neolithic individuals from northern Greece and northwestern Turkey spanning the time and region of the earliest spread of farming into Europe. We use a novel approach to recalibrate raw reads and call genotypes from ancient DNA and observe striking genetic similarity both among Aegean early farmers and with those from across Europe. Our study demonstrates a direct genetic link between Mediterranean and Central European early farmers and those of Greece and Anatolia, extending the European Neolithic migratory chain all the way back to southwestern Asia.


Hyperthermia and thermal tolerance in normal and ataxia telangiectasia human cell strains.
Three normal human fibroblast strains, two human ataxia telangiectasia heterozygote cell strains, and two human ataxia telangiectasia homozygote cell strains were studied for their thermal responses between 41.0 and 46.0 degrees. The heat sensitivities of all cell strains were comparable, and all cell strains were relatively heat resistant compared to Chinese hamster cells. Both normal and ataxia telangiectasia human cells developed thermal tolerance during heating at temperatures less than or equal to 43 degrees and during incubation at 37 degrees after acute heating at 45.0 degrees. For survival measured down to the 5 to 10% level, heat survival curves for all seven human cell strains lacked shoulders, indicating the inability of such cells to accumulate sublethal heat damage. Analysis of the cell survival curve data by the method of Arrhenius showed that the thermal inactivation energies for human cells were 127 and 230 kcal/mol above and below the break at 43.5 degrees, respectively, and are about the same as for Chinese hamster cells and other animal cells, implying similar mechanisms of heat inactivation.


Epidemiology of subclinical ovine psoroptic otoacariasis in Great Britain.
Seven sheep flocks with subclinical psoroptic otoacariasis were investigated. Psoroptes species mites were isolated from 3.1 per cent of the 2676 sheep examined and the prevalence in the flocks ranged between 1.3 and 23.9 per cent, with the highest infestations in pedigree flocks. Unilateral or bilateral infestations were found in sheep of all ages. Adult and shearling rams, with prevalences of 21.5 and 14.2 per cent, respectively, were the most affected and two lambs, two and eight days old, were the youngest to be infested. There was no evidence of vertical transmission. The infestation affected several breeds of sheep. No other known hosts for Psoroptes species present on the premises were shown to be infested. Non-parasitic for-age mites were also isolated from the ear canals of the sheep and may have contributed to the clinical signs which, in adult sheep, ranged from aural haematomas/fibrosis (cauliflower ears), and violent head shaking and ear rubbing leading to excoriation and wounding of the ear and base of the ear. The signs in lambs included plaques of scab (often bloody) on the external ear cleft, excoriation of the base of the ear, ear scratching with the hind feet and inflammation of the external aspects of the horizontal canal. In all cases the internal pinnae were clear of typical psoroptic scabs. Psoroptes mites were isolated from 28.6 per cent of the damaged ears and from 7.8 per cent of the undamaged ears. There was no evidence of classical sheep scab in any of the flocks. Plunge dipping in diazinon, propetamphos or flumethrin, or the use of synthetic pyrethroid pour-on preparations and an oral drench of ivermectin had little effect because ear mite infestations were detected in the flocks after these treatments. An injection of ivermectin at 200 micrograms/kg bodyweight effectively eradicated the infestations when it was administered to these infested flocks.


[Functional characteristics of the electron transport chain in Candida mycoderma yeasts exposed to benzhydroxamic acid].
The effect of antimycin A and benzhydroxamic acid (BHA) on functioning of the electron transport system was studied with the resting cells of Candida mycoderma grown in a medium containing glucose and collected at the beginning of the deceleration phase. In the original ("control") cells, the processes of oxygen consumption were shown to be mediated mainly by the phosphorylating electron transport chain. When the cells were incubated withe glucose, the cyanide resistant electron transport chain (CRETC) started to operate in these processes. Antimycin A stimulated the operation of CRETC. BHA blocked CRETC and, at the same time, prevented the participation of pyridine nucleotides (PN) in the processes of oxygen utilization. Apparently, electron donors (or reduced equivalents) in the electron transport chain were flavin enzymes operating in the cytochrome b region of the chain instead of PN. Similar changes in the electron transport system (when PN were not involved in the processes of oxygen utilization) were observed if resting cells were incubated in the presence of ethanol.


UBL5/Hub1: An Atypical Ubiquitin-Like Protein with a Typical Role as a Stress-Responsive Regulator.
Members of the ubiquitin-like protein family are known for their ability to modify substrates by covalent conjugation. The highly conserved ubiquitin relative UBL5/Hub1, however, is atypical because it lacks a carboxy-terminal di-glycine motif required for conjugation, and the whole E1-E2-E3 enzyme cascade is likely absent. Though the conjugation-mediated role of UBL5/Hub1 is controversial, it undoubtedly functions by interacting non-covalently with its partners. Several interactors of UBL5/Hub1 identified to date have suggested broad stress-responsive functions of the protein, for example, stress-induced control of pre-mRNA splicing, Fanconi anemia pathway of DNA damage repair, and mitochondrial unfolded protein response. While having an atypical mode of function, UBL5/Hub1 is still a stress protein that regulates feedback to various stimuli in a similar manner to other ubiquitin-like proteins. In this review, I discuss recent progress in understanding the functions of UBL5/Hub1 and the fundamental questions which remain to be answered.


Drug-drug interaction analysis of pyronaridine/artesunate and ritonavir in healthy volunteers.
A multiple dose, parallel group study was conducted to assess for a drug-drug interaction between the pyronaridine/artesunate (PA) combination antimalarial and ritonavir. Thirty-four healthy adults were randomized (1:1) to receive PA for 3 days or PA with ritonavir (100 mg twice daily for 17 days, PA administered on Days 8-10). Pharmacokinetic parameters for pyronaridine, artesunate, and its active metabolite dihydroartemisinin (DHA) were obtained after the last PA dose and for ritonavir on Days 1 and 10. Ritonavir coadministration did not markedly change pyronaridine pharmacokinetics but resulted in a 27% increase in artesunate area under the curve (AUC) and a 38% decrease in DHA AUC. Ritonavir exposure was increased 3.2-fold in the presence of PA. The only relevant safety observations were increases in liver enzymes, only reaching a clinically significant grade in the PA + ritonavir arm. It was concluded that coadministered ritonavir and PA interact to alter exposure to artesunate, DHA, and ritonavir itself.


Prepro-thyrotropin-releasing hormone 178-199 increases sensitivity of AtT-20 cells to dexamethasone.
The prepro-thyrotropin-releasing hormone (ppTRH)-derived peptide, ppTRH178-199, has been proposed to inhibit ACTH release at the level of the pituitary and attenuate prolactin and behavioral responses to stress as well. The objective of this study was to elucidate a possible link between the effects of ppTRH178-199 and glucocorticoids on the inhibition of ACTH release in corticotrophs. Compared with mock-transfected cells, AtT-20 cells that were stably transfected with full-length ppTRH cDNA showed significantly increased sensitivity to dexamethasone, as measured by inhibition of ACTH release. In a group of control cells, expressing a mutated form of ppTRH cDNA lacking the ppTRH178-199 region, sensitivity to dexamethasone was not different from mock-transfected controls. Exogenous ppTRH178-199 also increased the inhibitory effect of dexamethasone in wild-type AtT-20 cells. The combined effect of dexamethasone and ppTRH cDNA in cells that express the latter was not due to increased endogenous secretion of ppTRH178-199 in response to dexamethasone, as dexamethasone was independently found to inhibit secretion of ppTRH178-199. Taken together, these data suggest that ppTRH178-199 can interact with the glucocorticoid negative feedback inhibition to regulate ACTH secretion.


Noradrenergic regulation of cholinergic differentiation.
When the sympathetic nerves that innervate rat sweat glands reach their targets, they are induced to switch from using norepinephrine as their neurotransmitter to acetylcholine. Catecholamines (such as norepinephrine) released by nerves growing to the sweat gland induce this phenotypic conversion by stimulating production of a cholinergic differentiation factor [sweat gland factor (SGF)] by gland cells. Here, culture of gland cells with sympathetic, but not sensory, neurons induced SGF production. Blockage of alpha 1- or beta-adrenergic receptors prevented acquisition of the cholinergic phenotype in sympathetic neurons co-cultured with sweat glands, and sweat glands from sympathectomized animals lacked SGF. Thus, reciprocal instructive interactions, mediated in part by small molecule neurotransmitters, direct the development of this synapse.


Pilot longitudinal mosquito surveillance study in the Danube Delta Biosphere Reserve and the first reports of Anopheles algeriensis Theobald, 1903 and Aedes hungaricus Mihályi, 1955 for Romania.
Mosquito-borne viruses (moboviruses) are of growing importance in many countries of Europe. In Romania and especially in the Danube Delta Biosphere Reserve (DDBR), mosquito and mobovirus surveillance are not performed on a regular basis. However, this type of study is crucially needed to evaluate the risk of pathogen transmission, to understand the ecology of emerging moboviruses, or to plan vector control programmes. We initiated a longitudinal mosquito surveillance study with carbon dioxide-baited Heavy Duty Encephalitis Vector Survey traps at four sampling sites to analyse the spatio-temporal pattern of the (i) mosquito species composition and diversity, (ii) functional groups of mosquitoes (oviposition sites, overwintering stage, and number of generations), and (iii) the occurrence of potential West Nile virus (WNV) vectors. During 2014, a total of 240,546 female mosquitoes were collected. All species were identified using morphological characteristics and further confirmed by mitochondrial cytochrome c oxidase subunit I (COI) gene analysis of selected specimens. The two most common taxa were Coquilettidia richiardii (40.9 %) and Anopheles hyrcanus (34.1 %), followed by Culex pipiens (sensu lato) (s.l.)/Cx. torrentium (7.7 %), Aedes caspius (5.7 %), Cx. modestus (4.0 %), An. maculipennis (s.l.) (3.9 %), and Ae. vexans (3.0 %). A further seven species were less common in the area studied, including two new records for Romania: An. algeriensis and Ae. hungaricus. Phylogenetic analysis of COI gene demonstrated the evolutionary relatedness of most species with specimens of the same species collected in other European regions, except Ae. detritus and An. algeriensis, which exhibited high genetic diversity. Due to the dominance of Cq. richiardii and An. hyrcanus (75 % of all collected specimens), the overall phenology and temporal pattern of functional groups basically followed the phenology of both species. A huge proportion of the mosquito population in the course of the entire sampling period can be classified as potential WNV vectors. With 40 % of all collected specimens, the most frequent species Cq. richiardii is probably the most important vector of WNV in the DDBR. This is the first DNA-barcoding supported analysis of the mosquito fauna in the DDBR. The detection of two new species highlights the lack of knowledge about the mosquito fauna in Romania and in the DDBR in particular. The results provide detailed insights into the spatial-temporal mosquito species composition, which might lead to a better understanding of mobovirus activity in Romania and thus, can be used for the development of vector control programs.