Sex differences in components of imagined perspective transformation.
Little research to date has examined whether sex differences in spatial ability extend to the mental self rotation involved in taking on a third party perspective. This question was addressed in the present study by assessing components of imagined perspective transformations in twenty men and twenty women. Participants made speeded left-right judgements about the hand in which an object was held by front- and back- facing schematic human figures in an "own body transformation task." Response times were longer when the figure did not share the same spatial orientation as the participant, and were substantially longer than those made for a control task requiring left-right judgements about the same stimuli from the participant's own point of view. A sex difference in imagined perspective transformation favouring males was found to be restricted to the speed of imagined self rotation, and was not observed for components indexing readiness to take a third party point of view, nor in left-right confusion. These findings indicate that the range of spatial abilities for which a sex difference has been established should be extended to include imagined perspective transformations. They also suggest that imagined perspective transformations may not draw upon those empathic social-emotional perspective taking processes for which females show an advantage.


Design of a 3D navigation template to guide the screw trajectory in spine: a step-by-step approach using Mimics and 3-Matic software.
Rapid development of 3D printing techniques has led to the design of navigation templates to assist with accurate insertion of pedicle screws in last decades. However, there are still without the precise step-by-step methods to design 3D navigation templates from computed tomography (CT) images. Our present article provides a detailed protocol to allow the readers or researchers to obtain the 3D navigation template easily, and assist with pedicle screw insertion in their future research and surgery. Using 3D navigation template-assisted pedicle screw fixation in spine surgery is low cost and can decrease the radiation exposure to both patients and surgeons.


Academy for Quality and Safety Improvement (AQSI) project to improve diagnosis and documentation of malnutrition in a community hospital.
Malnutrition is a significant public health problem that affects many patients in inpatient settings. Timely identification and addressing malnutrition in an inpatient setting presents an opportunity to improve patient care and reduce costs. There is a clear link between malnutrition, increased length of hospital stay, higher risk of readmissions and infections, skin breakdown, and higher hospital costs due to complications. We conducted a quality improvement project to increase the number of times patients were accurately diagnosed and successfully coded as malnourished. We used the Define, Measure, Analyse, Intervene, Control (DMAIC) process to complete this project. Data were collected for nearly a year using the Epic Report Tool developed explicitly for the project. Initial data showed that our hospital performed at 20% of patients diagnosed as malnourished, while the industry standard was 33%. A multidisciplinary team of physicians, nurses and dietitians identified critical areas of improvement, including incomplete nutritional assessments by nurses, delayed evaluations by dietitians and lack of documentation by physicians. We addressed these issues by partnering with nurse managers to provide education and individual accountability for missed screenings, expanding dietitian workflows to include an in-person assessment within 24 hours of consultation, and updating physician note templates to include smart phrases that automatically inserted nutritional evaluations from registered dietitians into notes. We also worked with hospital executives and administration to increase buy-in from participating care team members. Our interventions resulted in 100% of malnutrition screening tool being completed, 33% of patients being screened at risk of malnutrition, 98% of nutrition assessments being done within 24 hours of patient admission and 100% of providers documenting malnutrition findings. Our study found an immediate and significant increase in the number of times malnutrition was diagnosed and ultimately coded during billing with our interventions. This highlights the importance of timely identification and addressing malnutrition in an inpatient setting to improve patient care and reduce costs. The DMAIC process and multidisciplinary team approach proved to be effective in identifying and addressing the barriers to malnutrition diagnosis in our hospital setting.


Validation of colorectal cancer surgery data from administrative data sources.
Surgery is the primary treatment for colorectal cancer for both curative and palliative intent. Availability of high quality surgery data is essential for assessing many aspects of the quality of colorectal cancer care. The objective of this study was to determine the quality of different administrative data sources in identifying surgery for colorectal cancer with respect to completeness and accuracy. All residents in Alberta, Canada who were diagnosed with invasive colorectal cancer in years 2000-2005 were identified from the Alberta Cancer Registry and included in the study. Surgery data for these patients were obtained from the Cancer Registry (which collects the date of surgery for which the primary tumor was removed) and compared to surgery data obtained from two different administrative data sources: Physician Billing and Hospital Inpatient data. Sensitivity, specificity, positive predictive value, negative predictive value and observed agreement were calculated compared to the Cancer Registry data. The Physician Billing data alone or combined with Hospital Inpatient data demonstrated equally high sensitivity (97% for both) and observed agreement with the Cancer Registry data (93% for both) for identifying surgeries. The Hospital Inpatient data, however, had the highest specificity (80%). The positive predictive value varied by disease stage and across data sources for stage IV (99% for stages I-III and 83-89% for stage IV), the specificity is better for colon cancer surgeries (72-85%) than for rectal cancer surgeries (60-73%); validation measures did not vary over time. Physician Billing data identify the colorectal cancer surgery more completely than Hospital Inpatient data although both sources have a high level of completeness.


Fluoxetine and Fractures After Stroke: Exploratory Analyses From the FOCUS Trial.
Background and Purpose- The FOCUS trial (Fluoxetine or Control Under Supervision) showed that fluoxetine did not improve modified Rankin Scale scores (mRS) but increased the risk of fractures. We aimed to describe the fractures, their impact on mRS and factors associated with fracture risk. Methods- A United Kingdom, multicenter, parallel-group, randomized, placebo-controlled trial. Patients ≥18 years with a clinical stroke and persisting deficit assessed 2 to 15 days after onset were eligible. Consenting patients were allocated fluoxetine 20 mg or matching placebo for 6 months. The primary outcome was the mRS at 6 months and secondary outcomes included fractures. Results- Sixty-five of 3127 (2.1%) patients had 67 fractures within 6 months of randomization; 43 assigned fluoxetine and 22 placebo. Fifty-nine (90.8%) had fallen and 26 (40%) had fractured their neck of femur. The effect of fluoxetine on mRS (common odds ratio =0.951) was not significantly altered by excluding fracture patients (common odds ratio =0.961). Cox proportional hazards modeling showed that only age >70 year (hazard ratio =1.97; 95% CI, 1.13-3.45; P=0.017), female sex (hazard ratio =2.13; 95% CI, 1.29-3.51; P=0.003), and fluoxetine (hazard ratio =2.00; 95% CI, 1.20-3.34; P=0.008) were independently associated with fractures. Conclusions- Most fractures resulted from falls. Although many fractures were serious, and likely to impair patients' function, the increased fracture risk did not explain the lack of observed effect of fluoxetine on mRS. Only increasing age, female sex, and fluoxetine were independent predictors of fractures. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN83290762.


FLAG epitope positioned in an external loop preserves normal biophysical properties of CFTR.
We asked whether inclusion of the FLAG epitope in the fourth extracellular loop of the cystic fibrosis transmembrane conductance regulator (M2-901/CFTR), which permits detection of cell surface expression, affected CFTR's biophysical properties or channel regulation by kinases, phosphatases, and nucleotides. Channel activity of M2-901/CFTR was evaluated in numerous cell types and expression systems to characterize its gating and regulation. Our results show that M2-901/CFTR required adenosine 3',5'-cyclic monophosphate-dependent protein kinase phosphorylation to initiate channel activity. Subsequently, ATP alone was sufficient to support channel gating, and ADP inhibited channel opening. Current fluctuation analysis indicated that the nucleotide-dependent gating rates were indistinguishable from those of wild-type (wt) cystic fibrosis transmembrane conductance regulator (CFTR). Channel conductance in symmetric Cl- (11.2 pS), anion permeability ratio (1.66), and block by gluconate indicate that the anion conduction pathway is indistinguishable from wtCFTR. Sulfonylureas (glibenclamide and LY-295501) inhibited M2-901/ CFTR channel activity by an identical mechanism to that described for wtCFTR. Finally, CFTR-dependent insertion and retrieval of cell membrane was unaffected by the presence of the FLAG epitope. These results indicate that this structural alteration does not affect the control mechanisms for channel gating and suggest that the fourth extracellular loop of CFTR does not contribute to the ion pore. Detection of M2-901/CFTR by a commercially available monoclonal antibody (M2), together with presentation of normal functional properties, makes M2-901/CFTR a valuable tool to evaluate CFTR protein expression and cellular location.


The role of myokines in cancer: crosstalk between skeletal muscle and tumor.
Loss of skeletal muscle mass is a primary feature of sarcopenia and cancer cachexia. In cancer patients, tumor-derived inflammatory factors promote muscle atrophy via tumor-to-muscle effects, which is closely associated with poor prognosis. During the past decade, skeletal muscle has been considered to function as an autocrine, paracrine, and endocrine organ by releasing numerous myokines. The circulating myokines can modulate pathophysiology in the other organs, as well as in the tumor microenvironment, suggesting myokines function as muscleto-tumor signaling molecules. Here, we highlight the roles of myokines in tumorigenesis, particularly in terms of crosstalk between skeletal muscle and tumor. Better understanding of tumor-to-muscle and muscle-to-tumor effects will shed light on novel strategies for the diagnosis and treatment of cancer. [BMB Reports 2023; 56(7): 365-373].


A non-injected opioid analgesia protocol for acute pain crisis in adolescents and adults with sickle cell disease.
Initial management of the acute pain crisis (APC) of sickle cell disease (SCD) is often unsatisfactory, and might be improved by developing a standardised analgesia protocol. Here, we report the first stages in developing a standard oral protocol for adolescents and adults. Initially, we performed a dose finding study to determine the maximal tolerated dose of sublingual fentanyl (MTD SLF) given on arrival in the acute care facility, when combined with repeated doses of oral oxycodone. We used a dose escalation algorithm with two dosing ranges based on patient's weight (<50 kg or >50 kg). We also made a preliminary evaluation of the safety and efficacy of the protocol. The study took place in a large tertiary centre in London, UK. Ninety patients in the age range 14-60 years were pre-consented and 31 treatment episodes were evaluated. The first 21 episodes constituted the dose escalation study, establishing the MTD SLF at 600 mcg (>50 kg) or 400 mcg (<50 kg). Further evaluation of the protocol indicated no evidence of severe opioid toxicity, nor increased incidence of acute chest syndrome (ACS). Between 0 and 6 hours, the overall gradient of reduction of visual analogue pain score (visual analogue scale (VAS)) was 0.32 centimetres (cm) per hour (95% confidence interval (CI) = 0.20 to 0.44, p < 0.001). For episodes on MTD SLF, there was median (interquartile range (IQR)) reduction in VAS score of 2.8 cm (0-4.2) and 59% had at least a 2.6-cm reduction. These results are supportive of further evaluation of this protocol for acute analgesia of APC in a hospital setting and potentially for supervised home management.


Beware of thermal epiglottis! A case report describing 'teapot syndrome'.
The type of scalding injury known as 'teapot syndrome', where hot liquid is grabbed by the child with the aim of ingestion and falls over a child causing burns on the face, upper thorax and arms, is known to cause peri-oral and facial oedema. Thermal epiglottitis following scalds to face, neck and thorax is rare and can occur even in absence of ingestion of a damaging agent or intraoral burns, Awareness of the possibility of thermal epiglottitis, also in scald burns, is imperative to ensure prompt airway protection. We report the case of a child with thermal epiglottitis after a scalding burn from boiling milk resulting in mixed deep burns of the face, neck and chest, but no history of ingestion. Upon presentation there was a progressive stridor and signs of respiratory distress requiring intubation. Laryngoscopy revealed epiglottis oedema, confirming the diagnosis of thermal epiglottitis. Final extubation took place 5 days after initial burn. Thermal epiglottitis following scalds to face, neck and thorax is rare and can occur even in absence of ingestion and intra-oral damage. Burns to the peri-oral area should raise suspicion of additional damage to oral cavity and supraglottic structures, even in absence of intra-oral injury or initial respiratory distress. Awareness of the occurrence of thermal epiglottitis in absence of intra-oral injury is important to diagnose impending upper airway obstruction requiring intubation.


Glutamate slows axonal transport of neurofilaments in transfected neurons.
Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of neurofilaments are seen in several neurodegenerative diseases, and this suggests that neurofilament transport is defective. Excitotoxic mechanisms involving glutamate are believed to be part of the pathogenic process in some neurodegenerative diseases, but there is currently little evidence to link glutamate with neurofilament transport. We have used a novel technique involving transfection of the green fluorescent protein-tagged neurofilament middle chain to measure neurofilament transport in cultured neurons. Treatment of the cells with glutamate induces a slowing of neurofilament transport. Phosphorylation of the side-arm domains of neurofilaments has been associated with a slowing of neurofilament transport, and we show that glutamate causes increased phosphorylation of these domains in cell bodies. We also show that glutamate activates members of the mitogen-activated protein kinase family, and that these kinases will phosphorylate neurofilament side-arm domains. These results provide a molecular framework to link glutamate excitotoxicity with neurofilament accumulation seen in some neurodegenerative diseases.


Prevalence of risk factors for non-communicable disease in a rural area of Faridabad district of Haryana.
To estimate the prevalence and levels of common risk factors for noncommunicable disease in a rural population of Haryana. The study involved a survey of 1359 male and 1469 female respondents, aged 15-64 years. Multistage sampling was used for recruitment (PHCs/sub-centres/villages). All households in the selected villages were covered, with one male and one female interviewed in alternate household. WHO STEP-wise tool was used as the study instrument which included behavioural risk factor questionnaire and physical measurements of height, weight, waist circumference and blood pressure. The age adjusting was done using rural Faridabad data from Census 2001. The age adjusted prevalence of daily smoked tobacco was 41% for men and 13% for women. Daily smokeless tobacco use was 7.1% and 1.2% for men and women respectively. The prevalence of current alcohol consumption was 24.6% among men and none of the women reported consuming alcohol. The mean number of servings of fruits and vegetables per day was 3.7 for men and 2.7 for women. The percentage of people undertaking at least 150 minutes of physical activity in a week was 77.8% for men and 54.5% for women. Among men 9.0% had BMI > or = 25.0 compared to 15.2% among women. The prevalence of measured hypertension, i.e. > or = 140 SBP and/or > or = 90 DBP or on antihypertensive drugs was 10.7% among men and 7.9% among women. The study showed a high burden of tobacco use and alcohol use among men, inactivity and overweight among women and low fruit and vegetable consumption among both sexes in rural areas.


The depiction of brown adipose tissue is related to disease status in pediatric patients with lymphoma.
The objective of our study was to determine whether the depiction of brown adipose tissue (BAT) in PET/CT studies of pediatric patients with lymphoma is related to disease status. The PET/CT studies of 31 pediatric patients (17 boys and 14 girls) with Hodgkin or non-Hodgkin lymphoma were reviewed, and the prevalence of metabolically active BAT at diagnosis and the prevalence of BAT when there was no evidence of disease were compared. The percentage of PET/CT studies depicting BAT was greater when there was no evidence of disease than at diagnosis (10% vs 77%, respectively; p < 0.001). The McNemar test indicated a strong inverse correlation between the presence of disease and the presence of BAT (p < 0.001). This correlation was noted when all subjects were examined together and when subjects with Hodgkin lymphoma and those with non-Hodgkin lymphoma were analyzed separately (p < 0.001 and < 0.05, respectively). When baseline and follow-up PET/CT scans for all patients were analyzed for the presence of BAT using conditional logistic regression, both the season when the study was performed and disease status independently predicted BAT: The winter months positively predicted BAT and the presence of lymphoma was negatively correlated with the depiction of BAT on PET/CT. Age, sex, treatment, and weight did not provide additional information when added to the model. The knowledge that BAT is a predictor of disease status should contribute to the correct analysis of PET/CT studies in children with lymphoma.


Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice.
Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. Newly generated double-knockout ApoE(-/-):TLR9(-/-) mice and control ApoE(-/-) mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE(-/-):TLR9(-/-) mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4(+) T cells. Although ApoE(-/-):TLR9(-/-) mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE(-/-):TLR9(-/-) mice, CD4(+) T-cell accumulation was further investigated and depletion of these cells in ApoE(-/-):TLR9(-/-) mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE(-/-) mice resulted in a reduction of lesion severity. Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE(-/-) mice fed a high-fat diet. CD4(+) T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.


Antidiuretic hormone excretion at high altitude.
Urinary excretion of electrolytes, creatinine, urea, and antidiuretic hormone--measured as arginine vasopressin (AVP) by radioimmunoassay--was investigated in eight Himalayan mountaineers during ascent on foot from 1900- 5400 m. Specimens were collected from each individual whenever urine was voided, preserved with 1% boric acid, and subsequently pooled to give samples representative of 24-h collections. AVP was found to be reasonably stable under simulated conditions of storage. In all subjects, the observed AVP excretion rates were mostly in the lower region of the normal range and there was generally no correlation with altitude, urine osmolality, electrolyte excretion, or occurrence of AMS symptoms--even in a fatal case of cerebral oedema. It is concluded that AVP does not play a primary role in the changes in fluid balance which accompany either acclimatization to high altitude or the onset of AMS.


Single-cell force spectroscopy of fluid flow-tuned cell adhesion for dissecting hemodynamics in tumor metastasis.
Cell adhesion plays an important role in regulating the metastasis of cancer cells, and atomic force microscopy (AFM)-based single-cell force spectroscopy (SCFS) has become an important method to directly measure the adhesion forces of individual cells. Particularly, bodily fluid flow environments strongly affect the functions and behaviors of metastatic cells for successful dissemination. Nevertheless, the interactions between fluidic flow medium environment and cell adhesion remain poorly understood. In this work, AFM-based SCFS was exploited to examine the effects of fluidic flow environment on cellular adhesion. A fluidic cell culture medium device was used to simulate the fluidic flow environment experienced by cancer cells during metastasis, which was combined with AFM-based SCFS assay. A single living cancer cell was attached to the AFM tipless cantilever to prepare the single-cell probe for performing SCFS experiments on the mesothelial cells grown under the fluidic flow medium conditions, and the effects of experimental parameters (retraction speed, contact time, loading force) on the measured cellular adhesion forces were analyzed. Experimental results of SCFS assay show that cellular adhesion forces significantly decrease after growth in fluidic flow medium, whereas cellular adhesion forces increase after growth in static culture medium. Experiments performed with the use of spherical probes coated with cell adhesion-associated biomolecules also show the weakening of cell adhesion after growth in fluidic flow cell culture medium, which was subsequently confirmed by the confocal fluorescence microscopy experiments of cell adhesion molecules, vividly illustrating the remarkable effects of fluidic flow environment on cellular adhesion. The study provides a new approach to detect adhesion force dynamics involved in the interactions between cells and the fluidic flow environment at the single-cell level, which will facilitate dissecting the role of hemodynamics in tumor metastasis.


Inertial Measurement Unit-Derived Ergonomic Metrics for Assessing Arm Use in Manual Wheelchair Users With Spinal Cord Injury: A Preliminary Report.
Individuals with spinal cord injury (SCI) who use manual wheelchairs (MWCs) have a higher rate of rotator cuff pathology progression than able-bodied individuals. This study aimed to test the ability of risk and recovery metrics of arm use to differentiate between (1) MWC users with SCI and matched able-bodied participants (cross-sectional matched-sample study) and (2) MWC users with rotator cuff pathology progression over 1 year from those without pathology progression (longitudinal study). Thirty-four MWC users and 34 age- and sex-matched able-bodied individuals were recruited. Upper arm risk (humeral elevation >60°) and recovery (static ≥5 seconds and humeral elevation <40°) metrics were calculated from wireless inertial measurement units (IMUs) worn on the upper arms and torso in the free-living environment. Two separate magnetic resonance imaging studies were completed and assessed for a subset of 16 MWC users approximately 1 year apart. The frequency of risk events (p = .019), summated duration of recovery events (p = .025), and duration of each recovery event (p = .003) were higher for MWC users than able-bodied participants. The summated duration of risk events (p = .047), frequency of risk events (p = .027), and risk to recovery ratio (p = .02) were higher and the summated duration of recovery events (p = .036) and frequency of recovery events (p = .047) were lower for MWC users with rotator cuff pathology progression (n = 5) compared to those without progression (n = 11). IMU-derived metrics quantifying arm use at postures >60° and risk to recovery ratios may provide insights of potential risk factors for rotator cuff pathology progression.


Factors affecting the levels of protection transferred from mother to offspring following immune challenge.
The transfer of antibodies from mother to offspring is key to protecting young animals from disease and can have a major impact on responses to infection and offspring fitness. Such maternal effects also allow young that may be exposed to disease in early life to focus resources on growth and development at this critical period of development. Maternally transferred antibodies are therefore an important source of phenotypic variation in host phenotype as well as influencing host susceptibility and tolerance to infection across generations. It has previously been assumed the transfer of antibodies is passive and invariant and reflects the level of circulating antibody in the mother at the time of transfer. However, whether females may vary in the relative amount of protection transferred to offspring has seldom been explored. Here we show that females differ widely in the relative amount of specific blood antibodies they transfer to the embryonic environment (range 9.2%-38.4% of their own circulating levels) in Chinese painted quail (Coturnix chinensis). Relative transfer levels were unrelated to the size of a female's own immune response. Furthermore, individual females were consistent in their transfer level, both across different stages of their immune response and when challenged with different vaccine types. The amount of antibody transferred was related to female condition, but baseline antibody responses of mothers were not. However, we found no evidence for any trade-offs between the relative amount of antibody transferred with other measures of reproductive investment. These results suggest that the relative amount of antibodies transferred to offspring can vary significantly and consistently between females. Levels of transfer may therefore be a separate trait open to manipulation or selection with potential consequences for offspring health and fitness in both wild and domesticated populations.


Pollination ecology of Anthyllis vulneraria subsp. vulgaris (Fabaceae): nectar robbers as pollinators.
This paper examines the hypothesis that nectar robbing can affect plant reproductive success either positively or negatively. To this end, I investigated various aspects of the pollination ecology of a population of the herb Anthyllis vulneraria subsp. vulgaris in northwest Spain over 5 yr. By observing floral visitors, I found that the most important pollinator species was the long-tongued bee Anthophora acervorum, which accounted for ∼45% of recorded insect visits. However, just over 45% of visits were by the nectar-robbing bumble bees Bombus terrestris and B. jonellus. Although the incidence of robbing differed considerably over 5 yr of study, the frequency in every season was very high (66.4-76.5% of robbing) except for 1997 (0% robbing). Despite this high frequency of robbing, robbed flowers had a higher probability of setting fruit than nonrobbed flowers in all years of the study (mean: 82.0 vs. 51.0%; excluding 1997). This increased fruit set in robbed flowers is directly related to bumble bee behavior because the robbers' bodies came into contact with both the anthers and stigmas while robbing. Thus, the robbers effect pollination. These results suggest that the effect of nectar robbers on plant reproductive success is dependent both on the robbers' behavior and on flower/inflorescence structure. The importance of nectar-robbing bumble bees on the reproductive success of A. vulneraria and its yearly high frequency suggest that the relationship between robbers and this plant is part of a successful long-term mutualism.


Charisma in everyday life: Conceptualization and validation of the General Charisma Inventory.
Although both scholars and lay people are fascinated with charismatic individuals, relatively few theorists have attempted to define charisma. Much of the empirical research examining charisma has focused on leadership. Even within that literature, however, theorists have focused on charisma's outcomes, leaving unarticulated what charisma actually is. Here, we tested an operational conceptualization of charisma in the context of everyday life. Specifically, we proposed that charisma is composed of the interpersonally focused dimensions of influence (the ability to guide others) and affability (the ability to make other people feel comfortable and at ease). We validated this conceptualization in a series of studies. In Studies 1-3, we used exploratory and confirmatory factor analyses to construct a short 6-item measure of charisma, the General Charisma Inventory. Next, in Study 4, we used round-robin evaluations and informant reports to establish the interpersonal nature of charisma. Finally, we examined the incremental validity of the scale in the context of dyadic interactions and tested the impact of charisma on perceptions of persuasiveness from voices. We found that (a) lay people possess a consensual conception of charisma; (b) charisma consists of a composition of quantifiable dimensions; (c) charisma is distinct from other constructs of interest to psychologists and leadership theorists; (d) charisma is observable; and (e) assessments of charisma predict real world outcomes. Thus, the current work not only comprehensively conceptualizes and measures charisma as an empirical construct, but also demonstrates its potential importance for the routine interactions that people experience every day. (PsycINFO Database Record


Quality of patient-reported outcomes used for quality of life, physical function, and functional capacity in trials of childhood fractures.
This study evaluates the quality of patient-reported outcome measures (PROMs) reported in childhood fracture trials and recommends outcome measures to assess and report physical function, functional capacity, and quality of life using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) standards. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of OVID Medline, Embase, and Cochrane CENTRAL was performed to identify all PROMs reported in trials. A search of OVID Medline, Embase, and PsycINFO was performed to identify all PROMs with validation studies in childhood fractures. Development studies were identified through hand-searching. Data extraction was undertaken by two reviewers. Study quality and risk of bias was evaluated by COSMIN guidelines and recorded on standardized checklists. Searches yielded 13,672 studies, which were screened to identify 124 trials and two validation studies. Review of the 124 trials identified 16 reported PROMs, of which two had validation studies. The development papers were retrieved for all PROMs. The quality of the original development studies was adequate for Patient-Reported Outcomes Measurement Information System (PROMIS) Mobility and Upper Extremity and doubtful for the EuroQol Five Dimension Youth questionnaire (EQ-5D-Y). All other PROMs were found to have inadequate development studies. No content validity studies were identified. Reviewer-rated content validity was acceptable for six PROMs: Activity Scale for Kids (ASK), Childhood Health Assessment Questionnaire, PROMIS Upper Extremity, PROMIS Mobility, EQ-5D-Y, and Pediatric Quality of Life Inventory (PedsQL4.0). The Modified Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire was shown to have indeterminate reliability and convergence validity in one study and PROMIS Upper Extremity had insufficient convergence validity in one study. There is insufficient evidence to recommend strongly the use of any single PROM to assess and report physical function or quality of life following childhood fractures. There is a need to conduct validation studies for PROMs. In the absence of these studies, we cautiously recommend the use of the PROMIS or ASK-P for physical function and the PedsQL4.0 or EQ-5D-Y for quality of life. Cite this article: Bone Joint J 2020;102-B(12):1599-1607.


Accidentally on purpose: construction of a ferromagnetic, oxime-based [Mn(III)2] dimer.
The serendipitous self-assembly of the complex [Mn(III)(2)Zn(II)(2)(Ph-sao)(2)(Ph-saoH)(4)(hmp)(2)] (1),whose magnetic core consists solely of two symmetry equivalent Mn(iii) ions linked by two symmetry equivalent -N-O- moieties, provides a relatively simple model complex with which to study the magneto-structural relationship in oxime-bridged Mn(III) cluster compounds. Dc magnetic susceptibility measurements reveal ferromagnetic (J = +2.2 cm(-1)) exchange resulting in an S = 4 ground state. Magnetisation measurements performed at low temperatures and high fields reveal the presence of significant anisotropy, with ac measurements confirming slow relaxation of the magnetisation and Single-Molecule Magnetism behaviour. Simulations of high field, high frequency EPR data reveal a single ion anisotropy, D((Mn(III))) = -3.83 cm(-1). DFT studies on a simplified model complex of 1 reveal a pronounced dependence of the exchange coupling on the relative twisting of the oxime moiety with respect to the metal ion positions, as suggested previously in more complicated [Mn(III)(3)] and [Mn(III)(6)] clusters.


[Addison's disease: a clinico-epidemiologic study of 45 cases].
We present the clinical-epidemiological results obtained in a series of 45 patients diagnosed of Addison disease between 1967 and 1988. The incidence was 0.83 cases/100,000 inhabitants/year and the prevalence was 10 cases/100,000 inhabitants. The etiology was unknown in 44.4% of cases tuberculous in 24.4% and in 31.1% of cases the caused could not be established with the classical clinical and radiological criteria. Amongst the studied variables in each etiological group, we highlight the association with other autoimmune processes and the development of extraadrenal tuberculous infection after Addison disease diagnosis. We discuss the approach to etiological diagnosis and the convenience of tuberculostatic treatment in EAT cases.


Visualization of aneurysmal contours and perianeurysmal environment with conventional and transparent 3D MR cisternography.
We have developed conventional and transparent 3D MR cisternography to investigate the spatial relationship between the contours of aneurysmal complex and the perianeurysmal structures including the cranial nerves, dural fold, cranial base bone, and brain parenchyma. Volume data obtained by a T2-weighted 3D fast spin-echo sequence were reconstructed by using a perspective volume-rendering algorithm with a transluminal imaging technique. 3D MR cisternograms provide useful anatomic information in the therapeutic and follow-up management of unruptured cerebral aneurysms.


Photoactivation of endogenous latent transforming growth factor-β1 directs dental stem cell differentiation for regeneration.
Rapid advancements in the field of stem cell biology have led to many current efforts to exploit stem cells as therapeutic agents in regenerative medicine. However, current ex vivo cell manipulations common to most regenerative approaches create a variety of technical and regulatory hurdles to their clinical translation, and even simpler approaches that use exogenous factors to differentiate tissue-resident stem cells carry significant off-target side effects. We show that non-ionizing, low-power laser (LPL) treatment can instead be used as a minimally invasive tool to activate an endogenous latent growth factor complex, transforming growth factor-β1 (TGF-β1), that subsequently differentiates host stem cells to promote tissue regeneration. LPL treatment induced reactive oxygen species (ROS) in a dose-dependent manner, which, in turn, activated latent TGF-β1 (LTGF-β1) via a specific methionine residue (at position 253 on LAP). Laser-activated TGF-β1 was capable of differentiating human dental stem cells in vitro. Further, an in vivo pulp capping model in rat teeth demonstrated significant increase in dentin regeneration after LPL treatment. These in vivo effects were abrogated in TGF-β receptor II (TGF-βRII) conditional knockout (DSPP(Cre)TGF-βRII(fl/fl)) mice or when wild-type mice were given a TGF-βRI inhibitor. These findings indicate a pivotal role for TGF-β in mediating LPL-induced dental tissue regeneration. More broadly, this work outlines a mechanistic basis for harnessing resident stem cells with a light-activated endogenous cue for clinical regenerative applications.


Species and stage specificity of Leishmania donovani antigens.
Monoclonal antibodies D2 and D13 were produced in mice using Leishmania donovani promastigote membrane fractions. To study the species and stage specificity of the antigens recognized by these antibodies, we examined amastigotes prepared in vitro and cultured promastigotes by indirect immunofluorescence with monoclonal antibodies D2 and D13. Monoclonal antibody D2 showed weak reactivity for 9 of 9 strains of L. donovani complex promastigotes and 8 of 9 amastigotes. In contrast, only 2 of 22 strains from other complexes yielded equivocal reactions. Monoclonal antibody D13, however, had much broader reactivity. D13 reacted with all the promastigotes and amastigotes of L. donovani complex isolates as well as with 10 of 22 promastigotes and 8 of 13 amastigotes from other complexes. The high degree of species specificity seen with monoclonal antibody D2 provides a rationale for further study of this antibody and its purified antigen for parasite identification and serodiagnosis of visceral leishmaniasis. The strong fluorescent signal noted with D13 and the presence of the D13 epitope on all L. donovani complex parasites supports studies on its role as an antigen in immunoprophylaxis of visceral leishmaniasis.


The fitness of citrus tristeza virus defective RNAs is affected by the lengths of their 5'- and 3'-termini and by the coding capacity.
Populations of the Closterovirus Citrus tristeza virus (CTV) generally contain defective RNAs (dRNAs) that vary in size, abundance, and sequence. The variation in abundance of the different dRNAs in a population suggests selection for those of higher fitness. To examine factors affecting fitness of dRNAs, we investigated a series of in vitro constructed dRNAs for their ability to be amplified in protoplasts by an efficiently replicated CTV deletion mutant. The minimal sequences required for accumulation of the dRNAs were within the genomic 5' proximal approximately 1 kb and the 3' 270 nucleotides. However, other factors were involved, because a dRNA with only the minimal sequences failed to be replicated. Rescue of a nonviable dRNA by insertion of nonviral sequences between the termini suggested that "spacing" between terminal cis-acting signals influenced fitness. A continuous open reading frame (ORF) through most of the sequences derived from the 5' of the genome was a requirement for dRNA amplification. In general, insertions, deletions, or nucleotide substitutions were tolerated in the dRNAs as long as an ORF was retained, whereas dRNAs with mutations that prematurely terminated the ORF were not viable. To discriminate between a requirement for an essential protein and ribosomal travel, perhaps to present replication signals to the replicase complex, mutations were made to modify the potential protein but still maintain an ORF. Deletions, insertions of nonviral sequences, or switching of reading frames that altered the amino acid sequence of the protein, except the N-terminal 161 amino acids, did not destroy the fitness of the dRNAs. Yet termination of the ORF in the middle of nonviral sequences did destroy the ability of the dRNAs to be amplified. These results suggest that even though a continuous ORF was needed for fitness, its protein product did not affect the amplification of the dRNAs.


Mental Health, Quality of Life and Coping Strategies in Vulnerable Children During the COVID-19 Pandemic.
The coronavirus pandemic has led to a situation without precedent in modern history. The aim of this study is to analyse the consequences after one year of the pandemic on a group of children and adolescents assessed at the beginning of the pandemic in 2020 and to determine the most effective ways of psychologically coping with this pandemic. Two different, but equivalent, groups with a total of 604 (study I, 2020) and 743 (study II, 2021) children and adolescents in residential care, foster families, kinship families or family strengthening programs in Spain were evaluated using the SDQ (mental health measure), KIDSCREEN-10 index (quality of life measure) and Kidcope (coping behaviour measure). An independent sample t-test and a decision tree analysis were used. The mental health of children and adolescents decreased by 9.7%, and Self-Perceived quality of life did not change after one year of the COVID-19 pandemic. Nonactive coping strategies predicted worse mental health and worse quality of life. Problem solving served as a protective factor. One year after, the COVID-19 pandemic has an effect on the psychological wellbeing of children and adolescents, and the consequences can be reduced if proper coping strategies are used.


[The aspects of adenylate cyclase activity regulation in myocardium cell membranes during hypokinesia].
Nonstimulated and isoproterenol, GTF, GITF, NaF stimulated activities of the adenylate cyclase in sarcolemma in white rats' myocardium was studied after two weeks of hypokinesia. As was established, in restrained animals the sensitivity of adenylate cyclase to the specified agents was increased and transition to the bimodal GTF regulation took place. It is hypothesised that involvement of membrane-bound Gi-proteins in the adrenergic effects on cardiomyocytes is one of mechanisms of the cardiotropic effects of restraint and heart distresses.


A Multi-Compartment Hybrid Computational Model Predicts Key Roles for Dendritic Cells in Tuberculosis Infection.
Tuberculosis (TB) is a world-wide health problem with approximately 2 billion people infected with Mycobacterium tuberculosis (Mtb, the causative bacterium of TB). The pathologic hallmark of Mtb infection in humans and Non-Human Primates (NHPs) is the formation of spherical structures, primarily in lungs, called granulomas. Infection occurs after inhalation of bacteria into lungs, where resident antigen-presenting cells (APCs), take up bacteria and initiate the immune response to Mtb infection. APCs traffic from the site of infection (lung) to lung-draining lymph nodes (LNs) where they prime T cells to recognize Mtb. These T cells, circulating back through blood, migrate back to lungs to perform their immune effector functions. We have previously developed a hybrid agent-based model (ABM, labeled GranSim) describing in silico immune cell, bacterial (Mtb) and molecular behaviors during tuberculosis infection and recently linked that model to operate across three physiological compartments: lung (infection site where granulomas form), lung draining lymph node (LN, site of generation of adaptive immunity) and blood (a measurable compartment). Granuloma formation and function is captured by a spatio-temporal model (i.e., ABM), while LN and blood compartments represent temporal dynamics of the whole body in response to infection and are captured with ordinary differential equations (ODEs). In order to have a more mechanistic representation of APC trafficking from the lung to the lymph node, and to better capture antigen presentation in a draining LN, this current study incorporates the role of dendritic cells (DCs) in a computational fashion into GranSim. The model was calibrated using experimental data from the lungs and blood of NHPs. The addition of DCs allowed us to investigate in greater detail mechanisms of recruitment, trafficking and antigen presentation and their role in tuberculosis infection. The main conclusion of this study is that early events after Mtb infection are critical to establishing a timely and effective response. Manipulating CD8+ and CD4+ T cell proliferation rates, as well as DC migration early on during infection can determine the difference between bacterial clearance vs. uncontrolled bacterial growth and dissemination.


A cost-aggregating integer linear program for motif finding.
In the motif finding problem one seeks a set of mutually similar substrings within a collection of biological sequences. This is an important and widely-studied problem, as such shared motifs in DNA often correspond to regulatory elements. We study a combinatorial framework where the goal is to find substrings of a given length such that the sum of their pairwise distances is minimized. We describe a novel integer linear program for the problem, which uses the fact that distances between substrings come from a limited set of possibilities allowing for aggregate consideration of sequence position pairs with the same distances. We show how to tighten its linear programming relaxation by adding an exponential set of constraints and give an efficient separation algorithm that can find violated constraints, thereby showing that the tightened linear program can still be solved in polynomial time. We apply our approach to find optimal solutions for the motif finding problem and show that it is effective in practice in uncovering known transcription factor binding sites.


Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude.
Acute mountain sickness; prophylactic benefits of Free-radical-mediated damage to the blood-brain barrier may be implicated in the pathophysiology of acute mountain sickness (AMS). To indirectly examine this, we conducted a randomized double-blind placebo-controlled trial to assess the potentially prophylactic benefits of enteral antioxidant vitamin supplementation during ascent to high altitude. Eighteen subjects aged 35 +/- 10 years old were randomly assigned double-blind to either an antioxidant (n = 9) or placebo group (n = 9). The antioxidant group ingested 4 capsules/day(-1) (2 after breakfast/2 after evening meal) that each contained 250 mg of L-ascorbic acid, 100 IU of dl-a-tocopherol acetate and 150 mg of alpha-lipoic acid. The placebo group ingested 4 capsules of identical external appearance, taste, and smell. Supplementation was enforced for 3 weeks at sea level and during a 10-day ascent to Mt. Everest base camp (approximately 5,180 m). Antioxidant supplementation resulted in a comparatively lower Lake Louise AMS score at high altitude relative to the placebo group (2.8 +/- 0.8 points versus 4.0 +/- 0.4 points, P = 0.036), higher resting arterial oxygen saturation (89 +/- 5% versus 85 +/- 5%, P = 0.042), and total caloric intake (13.2 +/- 0.6 MJ/day(-1) versus 10.1 +/- 0.7 MJ/day(-1), P = 0.001); the latter is attributable to a lower satiety rating following a standardized meal. These findings indicate that the exogenous provision of water and lipid-soluble antioxidant vitamins at the prescribed doses is an apparently safe and potentially effective intervention that can attenuate AMS and improve the physiological profile of mountaineers at high altitude.


How Reactive are Druggable Cysteines in Protein Kinases?
Targeted covalent inhibitors (TCIs) have been successfully developed as high-affinity and selective inhibitors of enzymes of the protein kinase family. These drugs typically act by undergoing an electrophilic addition with an active-site cysteine residue, so design of a TCI begins with the identification of a "druggable" cysteine. These electrophilic additions generally require deprotonation of the thiol to form a reactive anionic thiolate, so the acidity of the residue is a critical factor. Few experimental measurements of the p Ka's of druggable cysteines have been reported, so computational prediction could prove to be very important in selecting reactive cysteine targets. Here we report the computed p Ka's of druggable cysteines in selected protein kinases that are of clinical relevance for targeted therapies. The p Ka's of the cysteines were calculated using advanced computational methods based on all-atom replica-exchange thermodynamic integration molecular dynamics simulations in explicit solvent. We found that the acidities of druggable cysteines within protein kinases are diverse and elevated, indicating enormous differences in their reactivity. Constant-pH molecular dynamics simulations were also performed on selected protein kinases, and the results confirmed this varied range in the acidities of druggable cysteines. Many of these active-site cysteines have low exposure to solvent molecules, elevating their p Ka values. Electrostatic interactions with nearby anionic residues also elevate the p Ka's of cysteine residues in the active site. The results suggest that some cysteine residues within kinase binding sites will be slow to react with a TCI because of their low acidity. Several oncogenic kinase mutations were also modeled and found to have p Ka's similar to that of the wild-type kinase.


An intervention resembling caloric restriction prolongs life span and retards aging in yeast.
The yeast Saccharomyces cerevisiae has a finite life span that is measured by the number of daughter cells an individual produces. The 20 genes known to determine yeast life span appear to function in more than one pathway, implicating a variety of physiological processes in yeast longevity. Less attention has been focused on environmental effects on yeast aging. We have examined the role that nutritional status plays in determining yeast life span. Reduction of the glucose concentration in the medium led to an increase in life span and to a delay in appearance of an aging phenotype. The increase in life span was the more extensive the lower the glucose levels. Life extension was also elicited by decreasing the amino acids content of the medium. This suggests that it is the decline in calories and not a particular nutrient that is responsible, in striking similarity to the effect on aging of caloric restriction in mammals. The caloric restriction effect did not require the induction of the retrograde response pathway, which signals the functional status of the mitochondrion and determines longevity. Furthermore, deletion of RTG3, a downstream mediator in this pathway, and caloric restriction had an additive effect, resulting in the largest increase (123%) in longevity described thus far in yeast. Thus, retrograde response and caloric restriction operate along distinct pathways in determining yeast longevity. These pathways may be exclusive, at least in part. This provides evidence for multiple mechanisms of metabolic control in yeast aging. Inasmuch as caloric restriction lowers blood glucose levels, this study raises the possibility that reduced glucose alters aging at the cellular level in mammals.


[Secondary gain and the need to be ill].
Freud introduced two concepts of illness gain-one was a more external conscious adaptive form of gain, called secondary gain, and the other was a more internal unconscious destructive form of gain, called the need to be ill. Both forms of illness gain are interdependent and secondary gain can generate a need to be ill. Empirical research was used to examine the question of how and why some disorders, such as post-traumatic stress disorder, repetitive strain injury, and whiplash injury, are liable to generate illness gain in affected individuals. This article describes how and why these disorders are becoming more common. It is important for the therapist to know the background of these disorders in order to be able to combat the associated secondary gain.


Synergistic Growth Inhibitory Effects of Eryngium kotschyi Extracts with Conventional Cytotoxic Agents: Cisplatin and Doxorubicin against Human Endometrium Cancer Cells.
Endometrial cancer is one of the most common types of cancer. For this reason, various studies have been carried out on its treatment and the effects of natural products on this disease. This study aimed to examine the growth inhibitory effects of Eryngium kotschyi Boiss. ethyl acetate [EKE] and butanol [EKB] obtained from the main methanol [EKM] extract from the aerial parts on human endometrium carcinoma [RL95-2] cells and their synergistic effect with cisplatin or doxorubicin. RL95-2 cells were treated with E. kotschyi extracts either alone or in combination with cisplatin or doxorubicin. The effects on cell growth were determined using the MTT assay and real-time cell analysis xCELLigence. The extracts demonstrated growth inhibitory activity, with a certain degree of selectivity against the RL95-2 cell line. Synergistic effects of EKE/cisplatin or doxorubicin at different concentration levels were demonstrated in RL95-2 cells. In some instances, the EKE/doxorubicin combinations resulted in antagonistic effects. The reduction level of cell viability was different and specific to each combination for the RL95-2 cell line. The growth inhibitory activity of cisplatin or doxorubicin, as a single agent, may be modified by combinations of the extracts and be synergistically enhanced in some cases. A significant synergistic effect of EKE on the RL95-2 cell line with cisplatin and doxorubicin was observed. This cytotoxic effect can be investigated in terms of molecular mechanisms. This study is the first of its kind in the literature. The mechanisms involved in this interaction between chemotherapeutic drugs and plant extracts remain unclear and should be further evaluated.


Prechtl's assessment of general movements: a diagnostic tool for the functional assessment of the young nervous system.
General movements (GMs) are part of the spontaneous movement repertoire and are present from early fetal life onwards until the end of the first half a year of life. GMs are complex, occur frequently, and last long enough to be observed properly. They involve the whole body in a variable sequence of arm, leg, neck, and trunk movements. They wax and wane in intensity, force and speed, and they have a gradual beginning and end. Rotations along the axis of the limbs and slight changes in the direction of movements make them fluent and elegant and create the impression of complexity and variability. If the nervous system is impaired, GMs loose their complex and variable character and become monotonous and poor. Two specific abnormal GM patterns reliably predict later cerebral palsy: 1) a persistent pattern of cramped-synchronized GMs. The movements appear rigid and lack the normal smooth and fluent character. Limb and trunk muscles contract and relax almost simultaneously. 2) The absence of GMs of fidgety character. So-called fidgety movements are small movements of moderate speed with variable acceleration of neck, trunk, and limbs in all directions. Normally, they are the predominant movement pattern in an awake infant at 3 to 5 months. Beside a sensitivity and specificity of 95% each, the assessment of GMs is quick, noninvasive, even nonintrusive, and cost-effective compared with other techniques, e.g., magnetic resonance imaging, brain ultrasound, and traditional neurological examination.


The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition.
In the absence of evidence of arteritis or Wegener's granulomatosis, the syndrome of lung hemorrhage and nephritis has been commonly associated with anti-glomerular basement membrane (GBM) antibodies. However, it has been increasingly recognized that many cases are associated with antineutrophil cytoplasmic antibodies (ANCAs). To review available clinical and pathologic findings to determine the diseases accounting for lung hemorrhage and nephritis. We studied the records of 750 patients from whom serum samples were sent to our laboratory for anti-GBM antibody assays between 1981 and 1993 and found 88 patients with evidence of lung hemorrhage and nephritis. Serum samples were retested, using current methods, for anti-GBM antibodies (against noncollagenous 1 domain of the alpha 3 chain of type IV collagen) and for antibodies to proteinase 3 and myeloperoxidase--the two types of ANCA of diagnostic value. Of 88 patients with evidence of lung hemorrhage and nephritis, 48 had ANCAs, six had anti-GBM antibodies, and seven had both. In 48 patients with ANCAs, the pathologic findings that accounted for the pulmonary renal syndrome were pauci-immune necrotizing and crescentic glomerulonephritis and pulmonary capillaritis. Only eight had convincing evidence (during life) of Wegener's granulomatosis and only one other had documented arteritis. In 27 patients without ANCAs or anti-GBM antibodies, a variety of unrelated renal and pulmonary diseases were found. The largest group of patients who present with the syndrome of lung hemorrhage and nephritis have ANCAs and not anti-GMB antibodies. Appropriate tests for antibodies to proteinase 3, antibodies to myeloperoxidase, and anti-GBM antibodies provide reliable guides for making a diagnosis in patients with this pulmonary renal syndrome.


Ligand Accessibility and Bioactivity of a Hormone-Dendrimer Conjugate Depend on pH and pH History.
Estrogen conjugates with a polyamidoamine (PAMAM) dendrimer have shown remarkably selective regulation of the nongenomic actions of estrogens in target cells. In response to pH changes, however, these estrogen-dendrimer conjugates (EDCs) display a major morphological transition that alters the accessibility of the estrogen ligands that compromises the bioactivity of the EDC. A sharp break in dynamic behavior near pH 7 occurs for three different ligands on the surface of a PAMAM-G6 dendrimer: a fluorophore (tetramethylrhodamine [TMR]) and two estrogens (17α-ethynylestradiol and diphenolic acid). Collisional quenching and time-resolved fluorescence anisotropy experiments with TMR-PAMAM revealed high ligand shielding above pH 7 and low shielding below pH 7. Furthermore, when the pH was cycled from 8.5 (conditions of ligand-PAMAM conjugation) to 4.5 (e.g., endosome/lysosome) and through 6.5 (e.g., hypoxic environment) back to pH 8.5, the 17α-ethynylestradiol- and diphenolic acid-PAMAM conjugates experienced a dramatic, irreversible loss in cell stimulatory activity; dynamic NMR studies indicated that the hormonal ligands had become occluded within the more hydrophobic core of the PAMAM dendrimer. Thus, the active state of these estrogen-dendrimer conjugates appears to be metastable. This pH-dependent irreversible masking of activity is of considerable relevance to the design of drug conjugates with amine-bearing PAMAM dendrimers.


Encephalitis associated with Borrelia burgdorferi infection in a horse.
Infection with Borrelia burgdorferi was associated with encephalitis in a horse. The horse lived in an area of Wisconsin endemic for B burgdorferi infection. Borrelia burgdorferi was isolated from the brain, but rabies virus was not detected in the brain. Serum obtained from the horse had a B burgdorferi antibody titer of 1:2,048, but was negative for antibodies to eastern and western encephalomyelitis.


Directing research funds to the right research projects: a review of criteria used by research organisations in Australia in prioritising health research projects for funding.
Healthcare budgets are limited, and therefore, research funds should be wisely allocated to ensure high-quality, useful and cost-effective research. We aimed to critically review the criteria considered by major Australian organisations in prioritising and selecting health research projects for funding. We reviewed all grant schemes listed on the Australian Competitive Grants Register that were health-related, active in 2017 and with publicly available selection criteria on the funders' websites. Data extracted included scheme name, funding organisation, selection criteria and the relative weight assigned to each criterion. Selection criteria were grouped into five representative domains: relevance, appropriateness, significance, feasibility (including team quality) and cost-effectiveness (ie, value for money). Thirty-six schemes were included from 158 identified. One-half of the schemes were under the National Health and Medical Research Council. The most commonly used criteria were research team quality and capability (94%), research plan clarity (94%), scientific quality (92%) and research impact (92%). Criteria considered less commonly were existing knowledge (22%), fostering collaboration (22%), research environment (19%), value for money (14%), disease burden (8%) and ethical/moral considerations (3%). In terms of representative domains, relevance was considered in 72% of the schemes, appropriateness in 92%, significance in 94%, feasibility in 100% and cost-effectiveness in 17%. The relative weights for the selection criteria varied across schemes with 5%-30% for relevance, 20%-60% for each appropriateness and significance, 20%-75% for feasibility and 15%-33% for cost-effectiveness. In selecting research projects for funding, Australian research organisations focus largely on research appropriateness, significance and feasibility; however, value for money is most often overlooked. Research funding decisions should include an assessment of value for money in order to maximise return on research investment.


Yap7 is a transcriptional repressor of nitric oxide oxidase in yeasts, which arose from neofunctionalization after whole genome duplication.
Flavohemoglobins are the main detoxifiers of nitric oxide (NO) in bacteria and fungi and are induced in response to nitrosative stress. In fungi, the flavohemoglobin encoding gene YHB1 is positively regulated by transcription factors which are activated upon NO exposure. In this study, we show that in the model yeast Saccharomyces cerevisiae and in the human pathogen Candida glabrata, the transcription factor Yap7 constitutively represses YHB1 by binding its promoter. Consequently, YAP7 deletion conferred high NO resistance to the cells. Co-immunoprecipitation experiments and mutant analyses indicated that Yap7 represses YHB1 by recruiting the transcriptional repressor Tup1. In S. cerevisiae, YHB1 repression also involves interaction of Yap7 with the Hap2/3/5 complex through a conserved Hap4-like-bZIP domain, but this interaction has been lost in C. glabrata. The evolutionary origin of this regulation was investigated by functional analyses of Yap7 and of its paralogue Yap5 in different yeast species. These analyses indicated that the negative regulation of YHB1 by Yap7 arose by neofunctionalization after the whole genome duplication which led to the C. glabrata and S. cerevisiae extant species. This work describes a new aspect of the regulation of fungal nitric oxidase and provides detailed insights into its functioning and evolution.


Unidirectional barbed suture for vesicourethral anastomosis during laparoscopic radical prostatectomy.
We investigated the impact of unidirectional barbed suture (UBS) for vesicourethral anastomosis (VUA) during laparoscopic radical prostatectomy. The polyglyconate UBS V-Loc 180 was used for VUA during laparoscopic radical prostatectomy in 30 consecutive patients who were diagnosed with organ-confined prostate cancer between January and October 2012. The operative and postoperative parameters were then compared with those of 30 consecutive patients who had previously undergone the same procedure but with the monofilament poliglecaprone suture Monocryl. All procedures were performed by the same experienced surgeon. VUA time was significantly shorter in the V-Loc group (13.2 ± 2.3 min) than in the Monocryl group (19.1 ± 3.3 min) (P < 0.001). The V-Loc group required significantly more stitches than the Monocryl group (11.4 ± 1.3 vs 10.6 ± 1.6 stitches; P = 0.031). The percentage of patients who required no more than one pad per day at 3 months postoperatively was significantly higher in the V-Loc group (63.3%) than in the Monocryl group (23.3%) (P = 0.020). No significant differences in other perioperative parameters were observed between the two groups. Using UBS prevents suture slippage and enables tieless anastomosis. VUA using a UBS may relieve surgeon stress because a rapid and secure anastomosis is achievable.


Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition.
The endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age-related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2-/- ) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2-/- mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy-induced bone loss due to a reduction in osteoclast number. The Cnr1/2-/- mice had reduced age-related bone loss when compared with wild-type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2-/- mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged-related bone loss was greater than in wild-type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age-related bone loss, whereas blockade of individual receptors may be detrimental.


Tobacco addiction: a biochemical model of nicotine dependence.
Nicotine is the main psychoactive substance present in tobacco, targeting in the CNS the nicotinic acetylcholine receptors (nAChR). The main effects of nicotine associated with smoking are nAChR upregulation, nAChR desensitization and modulation of the dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here analyze the available information under a model in which both receptor upregulation and receptor desensitization are responsible for establishing a mechanism of nicotine dependence, consequently having an important role in starting and maintaining tobacco addiction. We propose that negative feedbacks on dopamine release regulated by alpha4beta2 nAChRs are disrupted by nicotine. nAChR desensitization is the disrupting mechanism, while nAChR upregulation is the reinforcing process of nicotine dependence, which eventually initiates tobacco addiction. A conclusion of the model is that drugs used for smoking cessation should inhibit preferentially alpha4beta2 nAChRs and to have a low or null ability to upregulate nAChRs, as this characteristic allows the smoker to achieve downregulation without abstinence symptoms. A relationship between this hypothesis and smoking and schizophrenia is also discussed.


Src tyrosine kinases mediate activations of NF-kappaB and integrin signal during lipopolysaccharide-induced acute lung injury.
Src tyrosine kinases (TKs) are signaling proteins involved in cell signaling pathways toward cytoskeletal, membrane and nuclear targets. In the present study, using a selective Src TK inhibitor, PP1, we investigated the roles of Src TKs in the key pulmonary responses, NF-kappaB activation, and integrin signaling during acute lung injury in BALB/C mice intratracheally treated with LPS. LPS resulted in c-Src phosphorylation in lung tissue and the phospho-c-Src was predominantly localized in recruited neutrophils and alveolar macrophages. PP1 inhibited LPS-induced increases in total protein content in bronchoalveolar lavage fluid, neutrophil recruitment, and increases in the production or activity of TNF-alpha and matrix metalloproteinase-9. PP1 also blocked LPS-induced NF-kappaB activation, and phosphorylation and degradation of IkappaB-alpha. The inhibition of NF-kappaB activation by PP1 correlated with a depression of LPS-induced integrin signaling, which included increases in the phosphorylations of integrin beta(3), and of the focal adhesion kinase (FAK) family members, FAK and Pyk2, in lung tissue, and reductions in the fibrinogen-binding activity of alveolar macrophages. Moreover, treatment with anti-alpha(v), anti-beta(3), or Arg-Gly-Asp-Ser (RGDS), inhibited LPS-induced NF-kappaB activation. Taken together, our findings suggest that Src TKs play a critical role in LPS-induced activations of NF-kappaB and integrin (alpha(v)beta(3)) signaling during acute lung injury. Therefore, Src TK inhibition may provide a potential means of ameliorating inflammatory cascade-associated lung injury.


Diallyl disulfide down-regulates calreticulin and promotes C/EBPα expression in differentiation of human leukaemia cells.
Diallyl disulfide (DADS), the main active component of the cancer fighting allyl sulfides found in garlic, has shown potential as a therapeutic agent in various cancers. Previous studies showed DADS induction of HL-60 cell differentiation involves down-regulation of calreticulin (CRT). Here, we investigated the mechanism of DADS-induced differentiation of human leukaemia cells and the potential involvement of CRT and CCAAT enhancer binding protein-α (C/EBPα). We explored the expression of CRT and C/EBPα in clinical samples (20 healthy people and 19 acute myeloid leukaemia patients) and found that CRT and C/EBPα expressions were inversely correlated. DADS induction of differentiation of HL-60 cells resulted in down-regulated CRT expression and elevated C/EBPα expression. In severe combined immunodeficiency mice injected with HL-60 cells, DADS inhibited the growth of tumour tissue and decreased CRT levels and increased C/EBPα in vivo. We also found that DADS-mediated down-regulation of CRT and up-regulation of C/EBPα involved enhancement of reactive oxidative species. RNA immunoprecipitation revealed that CRT bound C/EBPα mRNA, indicating its regulation of C/EBPα mRNA degradation by binding the UG-rich element in the 3' untranslated region of C/EBPα. In conclusion, the present study demonstrates the C/EBPα expression was correlated with CRT expression in vitro and in vivo and the molecular mechanism of DADS-induced leukaemic cell differentiation.


Factors associated with intention to conceive and its communication to providers among HIV clients in Uganda.
Persons living with HIV/AIDS (PLHA) must discuss their fertility intentions with healthcare providers to receive the support needed to have children safely and limit transmission risks. However, few quantitative studies have examined correlates of fertility intentions, let alone the communication of such intentions with providers. We examined the prevalence and correlates of intentions to have children, and comfort discussing such plans with one's providers, in HIV clients at two HIV clinics in Uganda. Cross-sectional self-report data were collected from 233 patients who had primary partners. Bivariate correlates significant at the P < 0.10 level were included in logistic regression analysis. Of the 233 participants, 103 (44%) reported an intention to conceive a child in the near future. In multivariate analysis, younger age of both the patient and their partner, better physical health functioning and higher internalized HIV stigma were associated with having fertility intentions. One-third (35%) of those with fertility intentions expressed having difficulty discussing these intentions with their providers, which was associated with receiving care at the rural clinic and greater internalized HIV stigma. These findings highlight the need for reproductive health services that help clients accept themselves as PLHA and their fertility rights, thus promoting patient-doctor communication needed to promote safe child conception and delivery outcomes.


Responses of physicians to an objective safety and quality knowledge test: a cross-sectional study.
For physicians to practice safe high quality medicine they must have sufficient safety and quality knowledge. Although a great deal is known about the safety and quality perceptions, attitudes and beliefs of physicians, little is known about their safety and quality knowledge. This study tested the objective safety and quality knowledge of practicing US primary care physicians. Cross-sectional objective test of safety and quality knowledge. Primary care physicians practicing in the USA. Study consisted of 518 US practicing primary care physicians who answered an email invitation. Fifty-four percent were family medicine and 46% were internal medicine physicians.The response rate was 66%. The physicians took a 24-question multiple-choice test over the internet. The outcome was the percent correct. The average number of correct answers was 11.4 (SD, 2.69), 48% correct. Three common clinical vignettes questions were answered correctly by 45% of the physicians. Five common radiation exposures questions were answered correctly by 40% of the physicians. Seven common healthcare quality and safety questions were answered correctly by 43% of the physicians. Seven Donabedian's model of structure, process and outcome measure questions were answered correctly by 67% of the physicians. Two Institute of Medicine's definitions of quality and safety questions were answered correctly by 19.5% of the physicians. Forty-eight per cent of the physicians' answers to the objective safety and quality questions were correct. To our knowledge, this is the first assessment of the objective safety and quality knowledge of practicing US primary care physicians.


New opportunities for development of safe, effective live virus vaccines.
Effective vaccines are not available for most viral diseases. This situation may soon change when the full force of contemporary molecular biology is applied to immunoprophylaxis. In certain viral diseases, particularly those affecting the respiratory and gastrointestinal tracts, live attenuated vaccines are needed to confer effective protection. Until now the major obstacle to success has been genetic instability. It may be possible to construct stable, satisfactorily attenuated mutants by cloning viral DNA or RNA and then subjecting the cloned DNA to enzyme surgery to create viable deletion mutations. Modified cloned DNA derived from positive-strand viral RNA could then be transferred back into its virus by transfection of cells. Conversion of mutant cloned DNA into negative-strand RNA and transfer into its virus will require a more elaborate type of rescue.


Targeting Misconduct in Prison by Modifying Occupational Factors in Correctional Facilities.
Misconduct in prison is a phenomenon, which by its nature is hard to observe. Little is known about its origins and its modifiability. This study presents data on the level of misconduct in prison perceived by staff members and examines its impact on occupational factors. Data from officers, which also included i.e. team climate, job satisfaction, self-efficacy, and sick days, was collected at three different correctional units in Berlin, Germany (N = 60). The study reveals higher rates of perceived misconduct in prison on regular units as compared to treatment units within the observed facilities. In addition, regression analysis provides evidence for an association of rates of misconduct in prison, sick days, and low self-efficacy. Results are discussed in terms of providing a model that supports the idea of a network entailing occupational factors and misconduct in prison and which can be utilized to target misconduct in prison with suitable interventions.


Bilateral pallidotomy for acquired or heredodegenerative generalized dystonia in children.
Dystonias are relatively rare disorders characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Generalized dystonia is a therapeutic challenge because medications are unable to control dystonia adequately in most patients. These patients may be candidates for surgical therapy. The commonly used surgical procedures in these patients are pallidotomy and deep brain stimulation. Limited studies are available on the role of pallidotomy in children with acquired/heredodegenerative generalized dystonia. The objective of this study was to describe the authors' experience with bilateral pallidotomy in this group of patients. The authors retrospectively reviewed all pediatric patients (less than 18 years of age) with acquired/heredodegenerative generalized dystonia who underwent bilateral simultaneous pallidotomy at their center between January 2014 and January 2021. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores before and after surgery were recorded. Complications arising after the procedure were recorded as well. Ten patients (8 male and 2 female) with a mean (range) age of 11.1 (5-17) years were included in this study. The mean duration between disease onset and surgical intervention was 3.9 years. Two patients presented in status dystonicus. The mean ± SD (range) preoperative BFMDRS score of the patients without status dystonicus (n = 8) was 80 ± 18.9 (59.5-108). The mean ± SD BFMDRS score at the time of discharge from the hospital after surgery was 58.8 ± 37.9. Three patients had more than 20% change in BFMDRS score at the time of discharge from the hospital. The mean improvement was 25.5% at the end of 1 year. Of 5 surviving patients in the non-status dystonicus group, 3 patients had more than 40% change in BFMDRS score while the other 2 patients developed recurrence at the last follow-up (4.5 years). Status dystonicus abated after bilateral pallidotomy in both patients. Permanent bulbar complications were seen in 2 patients. Bilateral pallidotomy may result in clinically significant improvement in children with acquired/heredodegenerative generalized dystonia, although the benefits should be closely weighed against the risk of irreversible bulbar dysfunction. It is a viable option for children in resource-limited settings.


Artifact characterization and reduction in scanning X-ray Zernike phase contrast microscopy.
Zernike phase contrast microscopy is a well-established method for imaging specimens with low absorption contrast. It has been successfully implemented in full-field microscopy using visible light and X-rays. In microscopy Cowley's reciprocity principle connects scanning and full-field imaging. Even though the reciprocity in Zernike phase contrast has been discussed by several authors over the past thirty years, only recently it was experimentally verified using scanning X-ray microscopy. In this paper, we investigate the image and contrast formation in scanning Zernike phase contrast microscopy with a particular and detailed focus on the origin of imaging artifacts that are typically associated with Zernike phase contrast. We demonstrate experimentally with X-rays the effect of the phase mask design on the contrast and halo artifacts and present an optimized design of the phase mask with respect to photon efficiency and artifact reduction. Similarly, due to the principle of reciprocity the observations and conclusions of this work have direct applicability to Zernike phase contrast in full-field microscopy as well.


Nutrition and nutritional supplementation: Impact on skin health and beauty.
Skin acts as a natural barrier between internal and external environments thus plays an important role in vital biological functions such as protection against mechanical/chemical damages, micro-organisms, ultraviolet damage. Nutrition has a critical impact on strengthening skin's capabilities to fight against these multiple aggressions.Nutritional deficiencies are often associated with skin health disorders, while diets can either positively or negatively influence skin condition. More recently, the concept of nutritional supplementation has emerged as a new strategy in the daily practice of dermatology as well as a complementary approach to topical cosmetics in the field of beauty. Focusing on human clinical data, this paper proposes to illustrate the link between skin health and nutrition and to exemplify the beneficial actions of nutritional supplementation in skin health and beauty.


Acute myeloid leukemia associated with necrotizing temporal arteritis.
The clinical presentation of new onset headache, temporal artery tenderness, and elevated inflammatory markers is classical for giant cell arteritis (GCA). We describe a patient who presented with clinical features of GCA, but was found to have isolated necrotizing arteritis of the temporal artery in the setting of acute myeloid leukemia. This report emphasizes that if the temporal artery histology is not classical for GCA, or if the response to treatment is incomplete, further evaluation for systemic or paraneoplastic vasculitis should be considered.


Rescaling of perceived space transfers across virtual environments.
Research over the past 20 years has consistently shown that egocentric distance is underperceived in virtual environments (VEs) compared with real environments. In 2 experiments, judgments of object distance (Experiment 1) and object size (Experiment 2) improved after a brief period of walking through the VE with continuous visual feedback. Whereas improvement of blind-walking distance judgments could be attributable to recalibration of walking, improvement in perceived size is considered evidence for rescaling of perceived space, whereby perceived size and distance increased after walking interaction. Furthermore, improvements in judged distance and size transferred to a new VE. Distance judgments, but not size judgments, continued to improve after additional walking interaction in the new VE. These results have theoretical implications regarding the effects of walking interaction on perceived space, and practical implications regarding methods of improving perceived distance in VEs. (PsycINFO Database Record


Human immunodeficiency virus type 1 stimulates the expression and production of secretory leukocyte protease inhibitor (SLPI) in oral epithelial cells: a role for SLPI in innate mucosal immunity.
The innate immune response is a key barrier against pathogenic microorganisms such as human immunodeficiency virus type 1 (HIV-1). Because HIV-1 is rarely transmitted orally, we hypothesized that oral epithelial cells participate in the innate immune defense against this virus. We further hypothesized that secretory leukocyte protease inhibitor (SLPI), a 12-kDa mucosal antiviral protein, is a component of the host immune response to this virus. Here we demonstrated constitutive expression and production of SLPI in immortalized human oral keratinocytes. Brief exposure of cells to HIV-1 BaL and HXB2 significantly increased SLPI mRNA and protein production compared to that in mock-exposed cells (P < 0.01), as evaluated by real-time quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay. HIV-1-mediated stimulation of SLPI occurred at the transcriptional level, was dose and time dependent, was elicited by heat-inactivated and infectious viruses, and did not depend on cellular infection. Experiments with purified retroviral proteins showed that the stimulatory effect was induced specifically by external envelope glycoproteins from HIV-1 and simian immunodeficiency virus. SLPI responsiveness to HIV-1 was also observed in an unrelated oral epithelial cell line and in normal (nonimmortalized) human oral epithelial cells isolated from healthy uninfected gingival tissues. In this first report of SLPI regulation by HIV-1, we show that the expression and production of the antimicrobial and anti-inflammatory protein can be stimulated in oral epithelial cells by the virus through interactions with gp120 in the absence of direct infection. These findings indicate that SLPI is a component of the oral mucosal response to HIV-1.


Effect of resveratrol on intestinal tight junction proteins and the gut microbiome in high-fat diet-fed insulin resistant mice.
High-fat diet (HFD)-feeding induces changes in the microbiome and increases intestinal permeability by impairing tight junction (TJ) protein function, which may explain the insulin resistance (IR) and associated pathologies. We aimed to determine the effects of resveratrol (RES) on the gut microbiome and intestinal TJ proteins. Results showed that RES administration improved the lipid profile, and ameliorated the endotoxemia, inflammation, intestinal barrier defect and glucose intolerance in the HFD-fed mice. Furthermore, it modified the gut microbial composition, reducing the proportion of Firmicutes and the Firmicutes-to-Bacteroidetes ratio. Moreover, Verrucomicrobia and Akkermansia were much more abundant in the HFD + RES group. RES also significantly reduced the abundance of Bilophila and Ruminococcus. These findings suggest that RES may be useful for the treatment of IR and associated metabolic diseases.


A disaster medicine course for Canadian medical students: first implementation of a large-scale mass-casualty simulation.
Mass-casualty incidents have a significant global impact. Despite calls for improved disaster-preparedness training, most medical curriculums do not include formal disaster-medicine education. In 2021, the Medical Council of Canada introduced new disaster-medicine learning objectives. This article presents a mass-casualty-incident course for 3rd-year Canadian medical students. The course includes lectures, and a large-scale simulation of an explosion scene, field triage zone, and simulated emergency department (ED). The simulation incorporated "Dark-team-member" facilitators and 17 live actor and 8 mannequin patients with moulage. Pre-/post-event evaluation data was collected. One-hundred and twenty medical students participated in the course. Confidence in managing a real mass-casualty incident, on a scale from 1 to 10 (no-confidence to completely confident) significantly improved based on a Mann-Whitney U test, p < 0.05. Few formal medical student mass-casualty-incident courses exist. Combining "Dark-team-members" with live actors, imbedding clinician facilitators with medical students, and having a simulation with a continuous disaster scene to the ED are unique to this course. The methodology is presented for future replication.


Tumor-initiating activity of 4-fluoro-7,12-dimethylbenz[a]anthracene and 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene in female SENCAR mice.
We have determined the skin tumor-initiating activity in SENCAR mice of two A-ring derivatives of 7,12-dimethylbenz[a]anthracene (DMBA). 4-Fluoro-7,12-dimethylbenz[a]anthracene at a dose of 200 nmol per mouse exhibited weak activity, producing 0.6 papillopmas per mouse; doses of 10 and 20 nmol per mouse had no activity. A derivative of DMBA with the A-ring reduced, 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene (1,2,3,4,-H-DMBA), had substantial tumor-initiating activity when compared with the parent hydrocarbon. In one experiment, doses of 10 and 100 nmol per mouse gave rise to 1.6 and 9.5 papillomas per mouse, respectively; similar results were obtained in 3 additional experiments. Although the tumor-initiating activity of 1,2,3,4,-H4-DMBA was approximately one-tenth that of DMBA, this derivative was slightly (17%) more active than benzo[a]pyrene. 1,2,3,4-H4-DMBA was tested for the ability to induce mutations to 6-thioguanine-resistance in Chinese hamster V79 cells. In the absence of feeder cells capable of metabolizing polycyclic hydrocarbons, it was not mutagenic. However, in a cell-mediated mutation assay with secondary hamster embryo cells as activators, this derivative produced mutations in a dose-dependent manner and was approximately one-tenth as active as DMBA. These results indicate that metabolism of DMBA at positions 1-, 3-, 2- and 4- is important for biological activity and that for certain derivatives (i.e., 1,2,3,4-H4-DMBA), alternate pathways of metabolic activation may also be important.


Aberrant ERK 1/2 complex activation and localization in scrapie-infected GT1-1 cells.
Fatal neurodegenerative disorders such as Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases in humans, scrapie and bovine spongiform encephalopathy in animals, are characterized by the accumulation in the brain of a pathological form of the prion protein (PrP) denominated PrPSc. The latter derives from the host cellular form, PrPC, through a process whereby portions of its alpha-helical and coil structures are refolded into beta-sheet structures. In this work, the widely known in vitro model of prion replication, hypothalamic GT1-1 cell line, was used to investigate cellular and molecular responses to prion infection. The MAP kinase cascade was dissected to assess the phosphorylation levels of src, MEK 1/2 and ERK 1/2 signaling molecules, both before and after prion infection. Our findings suggest that prion replication leads to a hyper-activation of this pathway. Biochemical analysis was complemented with immunofluorescence studies to map the localization of the ERK complex within the different cellular compartments. We showed how the ERK complex relocates in the cytosol upon prion infection. We correlated these findings with an impairment of cell growth in prion-infected GT1-1 cells as probed by MTT assay. Furthermore, given the persistent urgency in finding compounds able to cure prion infected cells, we tested the effects on the ERK cascade of two molecules known to block prion replication in vitro, quinacrine and Fab D18. We were able to show that while these two compounds possess similar effects in curing prion infection, they affect the MAP kinase cascade differently. Taken together, our results help shed light on the molecular events involved in neurodegeneration and neuronal loss in prion infection and replication. In particular, the combination of chronic activation and aberrant localization of the ERK complex may lead to a lack of essential neuroprotective and survival factors. Interestingly, these data seem to define some common traits with other neurodegenerative disorders such as, for example, Alzheimer's disease.


Evaluation of 5-HTTLPR Gene Polymorphism and Resilience Components on the Development of Psychopathology in Adolescent Sexual Abuse Cases.
More than one-fourth adolescents are exposed to unexpected frightening experiences and traumas until adulthood. In this study, we aimed to determine the potential role of serotonin transporter (5-HTT) gene polymorphism regarding resilience factors in the symptom variability of individuals exposed to sexual abuse. Adolescents aged 11-17 years, who were admitted to the Marmara University Child Psychiatry Outpatient Clinic Forensic division with sexual abuse experience history, were informed about the research, and volunteers were included in the study. Turkish versions of "Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (K-SADS-PL)" was used to assess the psychopathology and functionality. The evaluation of participants also included self-reports based on "Eysenck Personality Inventory" and "Ways of Coping Inventory" for reflecting the resilience domain. The sample included 16 girls (88.9%) and 2 boys (11.1%), and the mean (±standard deviation) age was 14.58±1.97 years. Genotyping of the insertion/deletion polymorphism (5-HTTLPR) in the 5-HTT gene's transcriptional control zone was established, and 8 participants (44.4%) were determined to be of the LL genotype, while 7 (38.8%) were LS and 3 (16.6%) were SS carriers. Considering the relationship between coping styles regarding resilience and genetic variants, 87.5% of participants (n=7) exhibiting problem-focused coping style were determined found to carry the LL allele, while 90% (n=9) who exhibited emotion-focused coping styles were the SS-LS allele carriers (p=0.003). Our findings suggest that 5-HTTLPR gene polymorphism has a significant impact on the formation of coping styles. More studies are needed to determine other factors involved in the complex relationship between 5-HTTLPR gene polymorphism and development of psychopathology.


Sutureless vs sutured abdominal wall closure for gastroschisis: Operative characteristics and early outcomes from the Midwest Pediatric Surgery Consortium.
To report outcomes of sutured and sutureless closure for gastroschisis across a large multi-institutional cohort. A retrospective study of infants with uncomplicated gastroschisis at 11 children's from 2014 to 2016 was performed. Outcomes of sutured and sutureless abdominal wall closure were compared. Among 315 neonates with uncomplicated gastroschisis, sutured closure was performed in 248 (79%); 212 undergoing sutured closure after silo and 36 undergoing primary sutured closure. Sutureless closure was performed in 67 (21%); 37 primary sutureless closure, 30 sutureless closure after silo placement. There was no significant difference in gestational age, gender, birth weight, total days on TPN, and time from closure to initial oral intake or goal feeds. Sutureless closure patients had less general anesthetics, ventilator use/time, time from birth to final closure, antibiotic use after closure, and surgical site/deep space infections. Subgroup analysis demonstrated primary sutureless closure had less ventilator use and anesthetics than primary sutured closure. Sutureless closure after silo led to less ventilator use/time, anesthetics, and antibiotics compared to those with sutured closure after silo. Sutureless abdominal wall closure of neonates with gastroschisis was associated with less general anesthetics, antibiotic use, surgical site/deep space infections, and decreased ventilator time. These findings support further prospective study by our group. Level III.


Pancreatic ductal adenocarcinoma: Prognostic indicators of advanced disease.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with high metastatic risk. Prognosis remains poor even after resection. Previously our group identified biomarkers that improved diagnostic accuracy in PDAC beyond the established diagnostic tumour marker, CA19-9. Risk factors, symptoms and circulating biomarkers associated with a PDAC diagnosis may differ from those that alter disease progression and metastasis. This study aimed at assessing the risk factors, presenting symptoms and potential prognostic biomarkers in PDAC and determine their relationship with PDAC stage and/or metastatic status. Seventy-two PDAC patients with imaging available for TNM staging at presentation were enrolled following informed consent. Demographic and clinical data were captured. Blood was collected and 38 cytokines/angiogenic factors measured. Nonparametric association tests, univariate and multivariate logistic regression were performed using STATA version 14.2. A p-value≤0.05 was considered significant and odds ratios reported for effect size. Most risk factors and symptoms did not differ across the stages of cancer. Although male gender and smoking are risk factors for PDAC, the majority of study patients with metastatic PDAC were non-smoking females. In addition to CA19-9, the platelet count (p<0.01), IL-15 (p = 0.02) and GM-CSF (p<0.01) were significant, independent negative predictors of metastatic PDAC. Moreover, using specific cut-off values in a combined panel, the odds in a patient with all three biomarker levels below the cut-offs is 21 times more likely to have metastatic PDAC (p<0.0001). Platelet count, IL-15 and GM-CSF are potential prognostic indicators of metastatic disease in PDAC patients from our local South African population.