Fully Quantized Electron Transfer Observed in a Single Redox Molecule at a Metal Interface.
Long-range electron transfer is a ubiquitous process that plays an important role in electrochemistry, biochemistry, organic electronics, and single molecule electronics. Fundamentally, quantum mechanical processes, at their core, manifest through both electron tunneling and the associated transition between quantized nuclear vibronic states (intramolecular vibrational relaxation) mediated by electron-nuclear coupling. Here, we report on measurements of long-range electron transfer at the interface between a single ferrocene molecule and a gold substrate separated by a hexadecanethiol quantum tunneling barrier. These redox measurements exhibit quantized nuclear transitions mediated by electron-nuclear coupling at 4.7 K in vacuum. By detecting the electric force associated with redox events by atomic force microscopy (AFM), with increasing AFM oscillation amplitude, the intensity of the observed cantilever resonance frequency shift peak increases and then exhibits a series of discrete steps that are indicative of quantized nuclear transitions. The observed peak shapes agree well with a single-electron tunneling model with quantized nuclear state transitions associated with the conversion of the molecule between oxidized and reduced electronic states. This technique opens the door to simultaneously investigating quantized electron and nuclear dynamics in a diverse range of systems.


Sources of measurement error in an ECG examination: implications for performance-based assessments.
To assess the sources of measurement error in an electrocardiogram (ECG) interpretation examination given in a third-year internal medicine clerkship. Three successive generalizability studies were conducted. (1) Multiple faculty rated student responses to a previously administered exam. (2) The rating criteria were revised and study 1 was repeated. (3) The examination was converted into an extended matching format including multiple cases with the same underlying cardiac problem. The discrepancies among raters (main effects and interactions) were dwarfed by the error associated with case specificity. The largest source of the differences among raters was in rating student errors of commission rather than student errors of omission. Revisions in the rating criteria may have helped increase inter-rater reliability slightly however, due to case specificity, it had little impact on the overall reliability of the exam. The third study indicated the majority of the variability in student performance across cases was in performance across cases within the same type of cardiac problem rather than between different types of cardiac problems. Case specificity was the overwhelming source of measurement error. The variation among cases came mainly from discrepancies in performance between examples of the same cardiac problem rather than from differences in performance across different types of cardiac problems. This suggests it is necessary to include a large number of cases even if the goal is to assess performance on only a few types of cardiac problems.


The Impact of Posttraumatic Stress Disorder on the 6-Month Outcomes in Collaborative Care Management for Depression.
Posttraumatic stress disorder (PTSD) has symptoms that exist along a spectrum that includes depression and the 2 disorders may coexist. Collaborative care management (CCM) has been successfully used in outpatient mental health management (especially depression and anxiety) with favorable outcomes. Despite this, there exist limited data on clinical impact of a diagnosis of PTSD on depression outcomes in CCM. The present study used a retrospective cohort design to examine the association of PTSD with depression outcomes among 2121 adult patients involved in CCM in a primary care setting. Using standardized self-report measures, baseline depression scores and 6-month outcome scores were evaluated. Seventy-six patients had a diagnosis of PTSD documented in their electronic medical record. Patients with PTSD reported more severe depressive symptoms at baseline (Patient Health Questionnaire-9 score of 17.9 vs 15.4, P < .001) than those without PTSD. Controlling for sociodemographic and clinical characteristics, a clinical diagnosis of PTSD was associated with lower odds (AOR = 0.457, CI = 0.274-0.760, P = .003) of remission at 6 months and was also associated with higher odds (AOR = 3.112, CI = 1.921-5.041, P < .001) of persistent depressive symptoms at 6 months after CCM. When coexisting with depression, a diagnosis of PTSD was associated with worse depression outcomes, when managed with CCM in primary care. Opportunities still exist for more aggressive management of depression in these patients to help improve remission as well as reduce persistent depressive symptoms.


Distribution of CGRP and TRPV2 in Human Paranasal Sinuses.
Immunohistochemistry for protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP) and the transient receptor potential cation channel subfamily V member 2 (TRPV2) was performed on human paranasal sinuses. It was found that in the paranasal sinuses, mucous membranes contain PGP 9.5-immunoreactive (PGP 9.5-IR) nerve fibers. Such nerve fibers terminated around large blood vessels as fine varicosities. Isolated PGP 9.5-IR nerve fibers were scattered beneath the epithelium. Glandular tissues were also innervated by PGP 9.5-IR nerve fibers. These fibers were numerous in the maxillary and ethmoid sinuses, and relatively rare in the frontal and sphenoid sinuses. CGRP-IR nerve fibers were common in the maxillary sinus whereas TRPV2-IR nerve fibers were abundant in the ethmoid sinus. They were located around large blood vessels in the lamina propria. Many subepithelial nerve fibers contained TRPV2 immunoreactivity in the ethmoid sinus. CGRP- and TRPV2-IR nerve fibers were very infrequent in the frontal and sphenoid sinuses. In the human trigeminal ganglion (TG), sensory neurons contained CGRP or TRPV2 immunoreactivity. CGRP-IR TG neurons were more common than TRPV2-IR TG neurons. CGRP-IR TG neurons were of various cell body sizes, whereas TRPV2-IR TG neurons were mostly medium-to-large. In addition, human spinal and principal trigeminal sensory nuclei contained abundant CGRP- and TRPV2-IR varicosities. This study indicates that CGRP- and TRPV2-containing TG neurons probably innervate the paranasal sinus mucosae, and project into spinal and principal trigeminal sensory nuclei.


Bifunctional fluorescent probes for detection of amyloid aggregates and reactive oxygen species.
Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H2O2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H2O2. We characterized the optical properties of these probes using both bulk fluorescence measurements and single-aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of α-synuclein and pathophysiological H2O2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease.


Community-based participatory nursing research: a culturally focused case study.
This article provides highlights of a lecture, titled Community-based Participatory Research: A Culturally Focused Case Study, given at the Japan Academy of Nursing Science's 29th annual meeting in Chiba, Japan on 28 November 2009. Community-based participatory research (CBPR) is defined as research that includes both the researcher and the participant group in collaborative, egalitarian, and partnership processes to assess, define, problem-solve, evaluate, and disseminate an issue that is chosen by the stakeholders. A CBPR framework is highlighted and case-study examples from each stage are included. The barriers and facilitators for communities and researchers taking part in CBPR projects are described. Strategies to improve researcher competence in CBPR are listed. Community-based participatory research can be very fulfilling when incorporated into a faculty member's teaching, research, and service to the community.


Increase in perceived case suspiciousness due to local contrast optimisation in digital screening mammography.
To determine the influence of local contrast optimisation on diagnostic accuracy and perceived suspiciousness of digital screening mammograms. Data were collected from a screening region in the Netherlands and consisted of 263 digital screening cases (153 recalled,110 normal). Each case was available twice, once processed with a tissue equalisation (TE) algorithm and once with local contrast optimisation (PV). All cases had digitised previous mammograms. For both algorithms, the probability of malignancy of each finding was scored independently by six screening radiologists. Perceived case suspiciousness was defined as the highest probability of malignancy of all findings of a radiologist within a case. Differences in diagnostic accuracy of the processing algorithms were analysed by comparing the areas under the receiver operating characteristic curves (A(z)). Differences in perceived case suspiciousness were analysed using sign tests. There was no significant difference in A(z) (TE: 0.909, PV 0.917, P = 0.46). For all radiologists, perceived case suspiciousness using PV was higher than using TE more often than vice versa (ratio: 1.14-2.12). This was significant (P <0.0083) for four radiologists. Optimisation of local contrast by image processing may increase perceived case suspiciousness, while diagnostic accuracy may remain similar. Variations among different image processing algorithms for digital screening mammography are large. Current algorithms still aim for optimal local contrast with a low dynamic range. Although optimisation of contrast may increase sensitivity, diagnostic accuracy is probably unchanged. Increased local contrast may render both normal and abnormal structures more conspicuous.


Adsorption performance of Cd(II), Cr(III), Cu(II), Ni(II), Pb(II) and Zn(II) by aminated solution-blown polyacrylonitrile micro/nanofibers.
In this work, we prepared amidoxime-functionalized polyacrylonitrile (APAN) micro/nanofibers by modifying solution-blown PAN fibers with hydroxylamine hydrochloride, and investigated the adsorption performance of the APAN fibers for Cd(II), Cr(III), Cu(II), Ni(II), Pb(II) and Zn(II) from aqueous solutions. Batch experiments and quantitative analysis were conducted considering initial pH and contact time as controlling parameters. The equilibrium data were better explained by the Langmuir model with maximum adsorption capacities of 185, 204, 105, 104, 345 and 91 mg/g for Cd(II), Cr(III), Cu(II), Ni(II), Pb(II) and Zn(II), respectively. The adsorption kinetics were found to follow the pseudo-second-order kinetic model. The calculated thermodynamic parameters demonstrated that the adsorption of metal ions onto APAN fibers is feasible, spontaneous and endothermic. The five adsorption-desorption cycle experiments showed that APAN micro/nanofiber adsorbent exhibits good reusability, and has a potential application for the removal of heavy metals from wastewater.


Inhibiting the inhibition: a neuronal network for sound localization in reverberant environments.
The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects.


[Use of somatostatin analogue for intestinal and pancreatic fistulas].
The hormone somatostatin, a tetra-deca-peptide, was discovered in 1972. It inhibits the central nervous system and the endocrine and exocrine secretions of the gastrointestinal tract. The first clinical use of the hormone was to inhibit hormone-secreting tumors of the CNS. It has also been used to treat hormone-secreting tumors of the pancreas and GI tract. Treatment of small bowel and pancreatic fistulas has also been attempted. A new synthetic analogue of the hormone, SMS 210-995, (Sandostatin) has a long half-life and is highly effective after subcutaneous injection. It was used in the treatment of 3 patients with fistulas of the small bowel and pancreas. In all impressive reduction of fistula secretion was achieved within 24 hours. In 2 there was complete, spontaneous closure of the fistula: in 1 after 10 days and in the other after 15 days of treatment. In the 3rd, there was significant reduction of fistula output. There were no side-effects except for mild pain at the injection site in 1 patient. Previous reports and our own results indicate that this somatostatin analogue may be very useful in the nonsurgical treatment of GI tract fistulas.


Preoperative characteristics and compliance with follow-up after trabeculectomy surgery in rural southern China.
To evaluate preoperative characteristics and follow-up in rural China after trabeculectomy, the primary treatment for glaucoma there. Patients undergoing trabeculectomy at 14 rural hospitals in Guangdong and Guangxi Provinces and their doctors completed questionnaires concerning clinical and sociodemographic information, transportation, and knowledge and attitudes about glaucoma. Follow-up after surgery was assessed as cumulative score (1 week: 10 points, 2 weeks: 7 points, 1 month: 5 points). Among 212 eligible patients, mean preoperative presenting acuity in the operative eye was 6/120, with 61.3% (n=130) blind (≤6/60). Follow-up rates were 60.8% (129/212), 75.9% (161/212) and 26.9% (57/212) at 1 week, 2 weeks and 1 month, respectively. Patient predictors of poor follow-up included elementary education or less (OR=0.37, 95% CI 0.20 to 0.70, p=0.002), believing follow-up was not important (OR=0.62, 95% CI 0.41 to 0.94, p=0.02), lack of an accompanying person (OR=0.14, 95% CI 0.07 to 0.29, p<0.001), family annual income <US$800 (OR=0.28, 95% CI 0.11 to 0.72, p=0.008) and not requiring removal of scleral flap sutures postoperatively (OR=0.11, 95% CI 0.06 to 0.22, p<0.001). Age, sex, employment, travel distance/time/costs, patient preoperative clinical factors and physician factors were unassociated with follow-up. Follow-up after 2 weeks was inadequate to provide optimal clinical care, and surgery is being applied too late to avoid blindness in the majority of patients. Earlier surgery, support for return visits and better explanations of the importance of follow-up are needed. Directing all patients to return for possible scleral flap suture removal may be a valid strategy to improve follow-up.


Lead removal efficiency using biosorbents as alternative materials for permeable reactive barriers.
As alternative materials for heavy metal removal, this study investigated biosorbents to determine their suitability for permeable reactive barriers. The lead removal efficiencies of brown seaweed (Undaria pinnatifida) and reed (Phragmites australis) were determined under different conditions (batch and column system). The experimental results for these biomaterials fitted the Langmuir isotherm with high correlation values. It was verified that the influence of temperature on affinity was higher than that on adsorption capacity. While the lead removal efficiency of U. pinnatifida was higher than of P. australis in the batch experiments, lead removal efficiency decreased for both materials at approximately the same time in the column experiments. This indicates that the dominance of the chemical and physical adsorption mechanisms could result in differences in these systems.


Bandeau--the focal point of frontocranial remodeling.
Reconstructing the proper balance and harmony of the face begins with the manipulation and positioning of the bandeau. The bandeau or brow is the key architectural component of craniofacial reconstruction. Advancement of the supraorbital bar and forehead can result in functional improvements. This article details the historical development of the surgical procedures available for use in recontouring the forehead. Specific surgical procedures are described and evaluated including the method of removing an unsuitable, unusable bandeau, fashioning a new one from a strip of parietal cranial bone, and repositioning it. The advantages of the bilateral lamellar split bandeau are discussed.


Association of Ischemic Stroke Incidence, Severity, and Recurrence With Dementia in the Atherosclerosis Risk in Communities Cohort Study.
Ischemic stroke is associated with increased risk of dementia, but the association of stroke severity and recurrence with risk of impaired cognition is not well known. To examine the risk of dementia after incident ischemic stroke and assess how it differed by stroke severity and recurrence. The Atherosclerosis Risk in Communities (ARIC) study is an ongoing prospective cohort of 15 792 community-dwelling individuals from 4 US states (Mississippi, Maryland, Minnesota, and North Carolina). Among them, 15 379 participants free of stroke and dementia at baseline (1987 to 1989) were monitored through 2019. Data were analyzed from April to October 2021. Associations between dementia and time-varying ischemic stroke incidence, frequency, and severity were studied across an average of 4.4 visits over a median follow-up of 25.5 years with Cox proportional hazards models adjusted for sociodemographic characteristics, apolipoprotein E, and vascular risk factors. Incident and recurrent ischemic strokes were classified by expert review of hospital records, with severity defined by the National Institutes of Health Stroke Scale (NIHSS; minor, ≤5; mild, 6-10; moderate, 11-15; and severe, ≥16). Dementia cases adjudicated through expert review of in-person evaluations, informant interviews, telephone assessments, hospitalization codes, and death certificates. In participants with stroke, dementia events in the first year after stroke were not counted. At baseline, the mean (SD) age of participants was 54.1 (5.8) years, and 8485 of 15 379 participants (55.2%) were women. A total of 4110 participants (26.7%) were Black and 11 269 (73.3%) were White. A total of 1378 ischemic strokes (1155 incident) and 2860 dementia cases were diagnosed 1 year or more after incident stroke in participants with stroke, or at any point after baseline in participants without stroke, were identified through December 31, 2019. NIHSS scores were available for 1184 of 1378 ischemic strokes (85.9%). Risk of dementia increased with both the number and severity of strokes. Compared with no stroke, risk of dementia by adjusted hazard ratio was 1.76 (95% CI, 1.49-2.00) for 1 minor to mild stroke, 3.47 (95% CI, 2.23-5.40) for 1 moderate to severe stroke, 3.48 (95% CI, 2.54-4.76) for 2 or more minor to mild strokes, and 6.68 (95% CI, 3.77-11.83) for 2 or more moderate to severe strokes. In this study, risk of dementia significantly increased after ischemic stroke, independent of vascular risk factors. Results suggest a dose-response association of stroke severity and recurrence with risk of dementia.


Nitrogen utilization in pigs fed diets with soybean and rapeseed products leading to different ileal endogenous nitrogen losses.
Nitrogen (N) balance was determined in 36 pigs (BW 24 to 30 kg) fed diets inducing different ileal endogenous N losses (ENL). We tested the hypothesis that enhanced ENL may be indicative of a higher recycling of endogenous proteins that will induce a greater urinary N loss and a lower efficiency of the dietary N utilization for retention. The cornstarch-based diets contained either soy concentrate (SC), soybean meal (SBM), a mixture of toasted and untoasted soybean meal (mSBM), dehulled-toasted rapeseed cake (RC1), non-dehulled-toasted rapeseed cake (RC2), or dehulled-untoasted rapeseed cake (RC3). The diets were balanced for their content of apparent ileal digestible (ID) CP (108 g/kg feed) and apparent ID of Lys, Thr, Met+Cys, Trp, and Ile. Feeding level was 2.7 times ME for maintenance per kilogram BWx75 and restricted to 88% of the requirements for ID Lys as the first-limiting amino acid. During a 5-d period, urine and feces were collected daily in metabolism cages. Compared with the SC diet (low ENL), the diets with SBM (medium ENL) and mSBM (high ENL) resulted in a greater (P < .05) urinary N excretion. Nitrogen retention tended to be less (P = .08) in pigs fed diets that caused greater ENL. The utilization of ID N for retention in pigs fed the mSBM diet was lower (P < .05) than for those fed the SC diet. There were no differences in urinary N excretion, N retention, and the utilization of ID N for retention in pigs fed the rapeseed diets of different fiber contents (hulls as the NDF source). We concluded that, at similar intakes of the first-limiting ID amino acid, N retention in pigs fed soybeans tended to be reduced by greater ENL as induced by antinutritional factors (e.g., trypsin inhibitors). Rapeseed hulls, as the predominant fiber source, do not affect N retention and the utilization of ID N for retention.


Valine accumulation by alpha-aminobutyric acid-resistant mutants of Serratia marcescens.
alpha-Aminobutyric acid, norvaline, and norleucine, which are analogues of branched-chain amino acids, inhibited the growth of Serratia marcescens. The inhibitory effect of these three analogues was counteracted by branched-chain amino acids. A number of mutants resistant to these analogues were isolated. alpha-Aminobutyric acid-resistant (abu-r) mutants markedly accumulated l-valine in the culture medium, but the other analogue-resistant mutants did not. Acetohydroxy acid synthetase, which seems to be rate-limiting for the biosynthesis of l-valine, was derepressed in abu-r mutants. One of the abu-r mutants, no. 140, which accumulated over 8 mg of l-valine per ml, had about a 20-fold increase in the enzyme level. Most of the abu-r mutants had acetohydroxy acid synthetase activity which was sensitive to feedback inhibition by l-valine to the same extent as in the parent strain. However, the enzyme of two of abu-r mutants was less sensitive to l-valine, and one of the two was the best valine accumulator.


Cross-cultural validation and psychometric testing of the Norwegian version of TeamSTEPPS teamwork attitude questionnaire.
Healthcare professionals' attitudes play a significant role in influencing team behavior, and thereby affect the quality and safety of patient care. Culturally adapted and validated questionnaires may contribute valuable knowledge of professionals' attitudes toward teamwork. The aim of the study was to translate and cross-validate the TeamSTEPPS Teamwork Attitude Questionnaire (T-TAQ) into Norwegian, and to test the questionnaire for psychometric properties among Norwegian healthcare professionals. The T-TAQ, measuring five dimensions of attitude towards teamwork, was translated according to a model of back translation. Healthcare professionals (N = 247) from various hospital settings responded. A Pearson correlation coefficient, confirmatory factor analysis (CFA), test-retest reliability, Cronbach's alpha, and McDonald's omega were conducted. The inter-correlation test of the T-TAQ dimensions ranged from 0.16 to 0.54. The CFA showed a Root Mean Square Error of Approximation of (RMSEA) = 0.061. Test-retest showed Intraclass Correlation Coefficient scores from 0.73 to 0.86, with Cronbach's alpha and McDonald's omega demonstrating values from 0.53 to 0.76 (alpha) and 0.57 to 0.76 (omega) on the five dimensions. The Norwegian version of T-TAQ revealed potential concerning the psychometric property for measuring healthcare professionals' attitudes toward teamwork in hospital settings. Further testing with a sample that is more proportionally composed in terms of an interprofessional mix is therefore proposed.


Rabbit corneal endothelial cells modulated by polymorphonuclear leukocytes are fibroblasts. Comparison with keratocytes.
The authors previously reported that polymorphonuclear leukocytes modulate rabbit corneal endothelial cells into fibroblasts, which acquire the characteristics of fibroblasts. The progeny of the fibroblastic corneal endothelial cells (FCEC) were further studied to compare the characteristics of the fibroblast with those of keratocytes as a function of culture age. During 11 days in culture, FCEC showed 32 population doublings, whereas keratocytes underwent 10 population doublings. When collagen phenotypes of both cultures were analyzed as a function of culture age, labeled collagens in both cultures were fractionated into types I, III, and V. The proportion of each collagen was relatively unchanged in keratocytes regardless of culture age: type I accounted for 92-96%, type III for 2-6% and type V for 2-5%. In contrast, the profiles were significantly changed in FCEC: at day 2, type I accounted for 57%, type III for 37.5%, and type V 5.5%. Over the following 2 days, type I increased to approximately 75%, whereas type III collagen decreased to approximately 20%. As FCEC multilayered, type I collagen synthesis reached a stationary level of 80%, with 12% of type III. When the stoichiometry of type I collagen was compared, the alpha 1/alpha 2 ratio was 6.2 in FCEC and the ratio was 3.5 in keratocytes at day 2. The ratio reached a normal value at day 7 in FCEC and at day 3 in keratocytes. The synthesis of type I trimer and transient alteration of type I/III and the rapid growth rate at early stages of growth, indicate that FCEC behave like cells seen in wound healing or other rapidly growing tissues, in contrast to the stabilized keratocytes.


Role and regulation of p53 during an ultraviolet radiation-induced G1 cell cycle arrest.
p53 can play a key role in response to DNA damage by activating a G1 cell cycle arrest. However, the importance of p53 in the cell cycle response to UV radiation is unclear. In this study, we used normal and repair-deficient cells to examine the role and regulation of p53 in response to UV radiation. A dose-dependent G1 arrest was observed in normal and repair-deficient cells exposed to UV. Expression of HPV16-E6, or a dominant-negative p53 mutant that inactivates wildtype p53, caused cells to become resistant to this UV-induced G1 arrest. However, a G1 to S-phase delay was still observed after UV treatment of cells in which p53 was inactivated. These results indicate that UV can inhibit G1 to S-phase progression through p53-dependent and independent mechanisms. Cells deficient in the repair of UV-induced DNA damage were more susceptible to a G1 arrest after UV treatment than cells with normal repair capacity. Moreover, no G1 arrest was observed in cells that had completed DNA repair prior to monitoring their movement from G1 into S-phase. Finally, p53 was stabilized under conditions of a UV-induced G1 arrest and unstable when cells had completed DNA repair and progressed from G1 into S-phase. These results suggest that unrepaired DNA damage is the signal for the stabilization of p53, and a subsequent G1 phase cell cycle arrest in UV-irradiated cells.


Relationship of semen hyperviscosity with IL-6, TNF-α, IL-10 and ROS production in seminal plasma of infertile patients with prostatitis and prostato-vesiculitis.
Changes in levels of oxidative damage products in semen and their relationship to seminal fluid viscosity (SFV) have recently received increasing research interest. We analysed whether SFV was associated with ROS generation, levels of cytokines TNF-alpha (TNF-α), IL-6 and IL-10 and seminal leucocyte concentration, and whether ROS production was related to the extent of infections/inflammations at one (prostatitis) or two (prostato-vesiculitis) male accessory glands. We studied 169 infertile patients, with chronic bacterial prostatitis (PR, n = 74) and/or bilateral prostato-vesiculitis (PV, n = 95), as diagnosed by the ultrasound (US) criteria. Healthy fertile men (n = 42) served as controls. In the PV patient group, SFV, semen characteristics and ROS production had median values that were significantly higher than those found in PR patients and controls, although other sperm variables had values significantly lower than those found in PR patients or controls. In PV infertile patients, ROS generation and pro-inflammatory cytokines levels were higher than those found in PR infertile patients and controls, although seminal IL-10 levels in PV and PR patients were lower than those found in the controls. In PR patients, the levels of SFV were positively related to TNF-α (r = 0.67; P < 0.01), fMLP-stimulated ROS production in the 45% Percoll fraction (r = 0.687, P < 0.01) and the 90% Percoll fraction in basal condition (r = 0.695, P < 0.01), and after fMLP-stimulation (r = 0.688, P < 0.01). Thus, our data indicated that seminal hyperviscosity is associated with increased oxidative stress in infertile men and increased pro-inflammatory interleukins in patients with male accessory gland infection, more when the infection was extended to the seminal vesicles.


[Cutaneous reactions to gold salts].
Gold salts are used for rheumatoid arthritis, and also in resistant corticosteroid dermatoses such as pemphigus. Gold salts inhibit the expression of endothelial cell adhesion molecules, but activity varies from one molecule to another; thiomalate alone gives the same effect. Patients given gold salts have as high risk of cutaneous reactions, and a provisional diagnosis of "gold dermatisis" is insufficient. The mechanisms of cutaneous reactions are unknown and vary according to the molecules. Smokers, HLA Bw35 patients and perhaps atopic states are more prone to gold drug reaction. Inflammation at the site of injections is frequent but with no consequence. Accumulation (chrysiasis) may be observed with long-term treatment. The main problem is its diagnosis as it may mimic numerous dermatoses. Immunological adverse events are the most frequently encountered. Pruritus is frequently observed, more often with oral salts. Exanthemas are common and may disclose an associated visceral disease. Drug hypersensitivity is rare, but severe. All these types necessitate drug interruption although prescription has been continued after development of pityriasis rosea-like and eczematous eruptions in some series without worsening. Lichenoid eruptions require withdrawal, but the skin disease may continue. Oral presentation is frequent, either as a taste abnormality, or as stomatitis. Contact dermatitis may flare in patients sensitized to gold. Rare non-immunological skin diseases have been also observed. Careful dermatological assessment correlated with an imputability method and search of visceral side-effects could lead to a better choice for the patient. Skin tests are not reliable.


Strategic approach to concurrent aberrant left gastric vein and aberrant left hepatic artery in laparoscopic distal gastrectomy for early gastric cancer: A case report.
An aberrant left gastric vein (ALGV) directly entering the lateral segment of the liver is a rare variation in the portal vein system, whereas an aberrant left hepatic artery (ALHA) arising from the left gastric artery is observed relatively frequently. Here we report a case in which both ALGV and ALHA were encountered before laparoscopic distal gastrectomy with curative lymphadenectomy for gastric cancer. We accurately diagnosed these vessel anomalies preoperatively on abdominal contrast-enhanced CT. During surgery, we divided the ALGV at the point of entry to the liver and preserved the ALHA by dividing the branches toward the stomach, in consideration of curability and safety. The postoperative course was uneventful overall, although temporary mild liver dysfunction was observed. This case highlights the importance of preoperative evaluation and preparation in a rare case of concurrent ALGV and ALHA.


Selective inhibition of relaxation of guinea-pig trachea by charybdotoxin, a potent Ca(++)-activated K+ channel inhibitor.
Airway smooth muscle plasma membranes are rich in K+ channels of various types. Charybdotoxin (ChTX) is a potent blocker of the high-conductance Ca(++)-activated K+ channel in smooth muscle and produces a concentration-dependent contraction of guinea pig trachea. In the present study, pharmacologic experiments were performed on carbachol-contracted (0.34 microM) guinea-pig trachea contracted further with ChTX in order to determine if Ca(++)-activated K+ channels play a role in the responses to cAMP-dependent and cAMP-independent bronchodilators. Relaxation concentration response curves to the beta-agonists, isoproterenol and salbutamol; the phosphodiesterase inhibitor, aminophylline; the cAMP mimic, N6-2'-O-adenosine 3':5'-cyclic monophosphate the guanylate cyclase activator, sodium nitroprusside; and the K+ channel agonists, BRL-34915 and pinacidil, were obtained in the absence and presence of ChTX. The concentration response curves to isoproterenol and salbutamol were shifted to the right (approximately 27-fold and greater than 40-fold, respectively) by 180 nM ChTX, whereas concentration response curves to N6-2'-O-adenosine 3':5'-cyclic monophosphate and aminophylline were affected significantly less (shifted approximately 7.5-fold). Concentration response curves to the cGMP-dependent relaxant sodium nitroprusside were also altered by ChTX (17-fold rightward shift at 180 nM). In the presence of 60 nM ChTX, the concentration response curves to the above relaxants were shifted only 3- to 5-fold. In contrast, ChTX (60 and 180 nM) failed to produce a significant rightward shift in the concentration response curves to BRL-34915 or pinacidil. Relaxation to BRL-34915 was however, blocked by glybenclamide, suggesting differences in the mechanism of relaxation. Contraction of tissues with depolarizing concentrations of KCl (20-80 mM) inhibited responses to all bronchodilators. These results suggest that hyperpolarization of tracheal smooth muscle as a result of opening various types of K+ channels can lead to relaxation of carbachol-contracted tracheal smooth muscle.


Transfection of B7-1 cDNA empowers antigen presentation of blood malignant cells for activation of anti-tumor T cells.
To define roles of B7-1 co-stimulation factor expressed in human malignant cell lines in mediating anti-tumor T cell immune responses. Examining human leucocyte antigen (HLA) and B7 expressions on 8 human blood malignancies cell lines by flow cytometry. Transfecting B7-1 gene to B7-1 negative (B7(-)) Raji and B7(-) Jurkat cell lines by liposome, and comparing the potencies of blood malignant cell lines in the induction of T cell activation by examination of T cell cytokine mRNAs before and after transfection using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). High level of HLA I and II molecules were expressed in most human blood malignant cell lines examined, and the co-stimulatory factor B7-2 was also highly expressed. In contrast, another member of B7 family: B7-1 was either not expressed or very limitedly expressed in most of these hematopoietic malignant cell lines. Most importantly, transfection of B7-1 gene to B7(-). Raji and B7(-). Jurkat cell lines made these cell lines better antigen presenting cells for stimulation of anti-tumor T cell activation, which was demonstrated by up regulation of expression of T cell cytokines IL-2, IL-4 and INF-gamma mRNAs after incubation of these tumor cells with T cells for 24 h. B7 co-stimulation plays an important role in anti-tumor immunity. Transfection of B7-1 gene to the human hematopoietic malignant cell lines that are deficient in the B7-1 expression empowers their antigen presentation potency for activation of anti-tumor T cells. Our results suggested that repairing the deficiency of B7-1 co-stimulatory pathway in tumor cells might be a novel immunotherapeutic approach for human hematopoietic malignancies.


Additional Lymphaticovenular Anastomosis on the Posterior Side for Treatment of Primary Lower Extremity Lymphedema.
The efficacy of lymphaticovenular anastomosis (LVA) for the treatment of primary lymphedema has been reported. Previous research suggested the efficacy of LVA on the anterior side of the lower limb, but no research has yet underlined the effectiveness of LVA on the posterior side. In the present study, we aimed to investigate the efficacy of LVA on the posterior side of the lower leg for treatment of primary lymphedema, i.e., whether further improvement of primary lower extremity lymphedema could be expected by performing LVA on the posterior side of the lower limb in addition to the LVA on the anterior side, which is usually performed. Forty-five patients with primary lower extremity lymphedema who underwent LVA twice between March 2018 and September 2020 were retrospectively investigated. Patients were classified into two groups: those who underwent LVA on the posterior side in the second operation (PoLVA group) and those who underwent LVA on the medial and anterior sides again in the second operation (MeLVA group). All patients underwent LVA on the medial and anterior sides in the first operation, but no sufficient improvement was observed. The following factors in the second operation were compared between the two groups: skin incision length, the number of anastomoses, the diameters of the lymphatic vessels, the time required for the dissection of the lymphatic vessels and veins and the reduction in volume. LVA resulted in 227 anastomoses (106 anastomoses in the PoLVA group and 121 anastomoses in the MeLVA group) in 26 patients with primary lymphedema of the lower extremities in two surgeries. The reduction in lower extremity lymphedema index was significantly greater in the PoLVA group than that in the MeLVA group (10.5 ± 4.5 vs. 5.5 ± 3.6; p = 0.008), and the number of anastomoses in the PoLVA group was significantly lower than that in the MeLVA group (3.5 ± 0.6 vs. 4.6 ± 1.0; p = 0.038). LVA on the posterior side subsequent to LVA on the medial and anterior sides resulted in the further improvement of primary lower extremity lymphedema with fewer numbers of anastomoses.


Relationship between diet quality and carotid intima-media thickness in people with and without carotid atherosclerosis.
Dietary assessment and management appear to be essential to limit the impact of cardiovascular risk. This study aims to assess the association between diet quality as measured by Alternate Healthy Eating Index (AHEI) and coronary risk as determined by carotid artery intima-media thickness (CIMT) among Saudi adults. A case-control study was conducted in 210 participants who were matched for age and sex and recruited sequentially from King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Demographic and anthropometric variables were measured in all study participants. Dietary intake was measured by food frequency questionnaire. Obesity was highly prevalent among the study population. The mean AHEI score for the total sample was found to be 58.3 ± 1.67. There were no differences according to the presence and absence of atherosclerotic disease; 45% had a poor diet, and 39% had a diet that needs improvement. Participants with higher CIMT values tended to be of lower AHEI category. Negative correlations were observed between CIMT and AHEI scores and components after adjustment for age and energy intake. Adherence to a healthier diet, as reflected by a higher AHEI score, is associated with lower coronary risk, as estimated by CIMT value, independently from obesity and personal behavior factors.


Decay of information in short-term memory.
Self-paced recall in Broadbent's simultaneous listening task shows particular temporal patterns associated with report strategies. Accuracy is a decreasing function of the interval between presentation and report of an item, irrespective of report strategy. Results are related to an interaction between strategies of response selection and decay of information from memory.


Germline mosaicism of PHOX2B mutation accounts for familial recurrence of congenital central hypoventilation syndrome (CCHS).
Congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation, is caused by mutations in the PHOX2B gene. Most mutations occur de novo, but recent evidence suggests that up to 25% are inherited from asymptomatic parents with somatic mosaicism for these mutations. However, to date, germline mosaicism has not been reported. This report describes a family with recurrence of PHOX2B mutation-confirmed CCHS due to germline mosaicism. The first occurrence was a baby girl, noted on day 2 of life to have multiple episodes of apnea, bradycardia, and cyanosis while breathing room air. PHOX2B gene testing confirmed the diagnosis of CCHS with a heterozygous polyalanine repeat expansion mutation (PARM); genotype 20/27 (normal 20/20). Both parents tested negative for this mutation using fragment analysis (limit of detection<1%). Upon subsequent pregnancy [paternity confirmed using short tandem repeat (STR) analysis], amniocentesis testing identified the PHOX2B 20/27 genotype, confirmed with repeat testing. Elective abortion was performed at 21.5 weeks gestation. Testing of abortus tissue confirmed amniocentesis testing. The PHOX2B 20/27 expansion was not observed in a paternal sperm sample. This case represents the first reported family with recurrence of PHOX2B mutation-confirmed CCHS without detection of a parental carrier state or mosaicism, confirming the previously hypothesized possibility of germline mosaicism for PHOX2B mutations. This is an important finding for genetic counseling of CCHS families, suggesting that even if somatic mosaicism is not detected in parental samples, there is still reason for careful genetic counseling and consideration of prenatal testing during subsequent pregnancies.


Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant.
Epidermal growth factor receptor (EGFR) inhibitors interrupt EGFR-dependent cellular signaling pathways that lead to accelerated tumor growth and proliferation. Mutation of a threonine in the inhibitor binding pocket, known as the "gatekeeper", to methionine (T790M) confers acquired resistance to several EGFR-selective inhibitors. We studied interactions between EGFR inhibitors and the gatekeeper residues of the target protein. Thermodynamic integration (TI) with Amber14 indicates that the binding energies of gefitinib and AEE788 to the active state of the T790M mutant EGFR is 3 kcal/mol higher than to the wild type (WT), whereas ATP binding energy to the mutant is similar to the WT. Using metadynamics MD simulations with NAMD v2.9, the conformational equilibrium between the inactive resting state and the catalytically competent activate state was determined for the WT EGFR. When combined with the results obtained by Sutto and Gervasio, our simulations showed that the T790M point mutation lowers the free energy of the active state by 5 kcal/mol relative to the inactive state of the enzyme. Relative to the WT, the T790M mutant binds gefitinib more strongly. The T790M mutation is nevertheless resistant due to its increased binding of ATP. By contrast, the binding of AEE788 to the active state causes a conformational change in the αC-helix adjacent to the inhibitor binding pocket, that results in a 2 kcal/mol energy penalty. The energy penalty explains why the binding of AEE788 to the T790M mutant is unfavorable relative to binding to WT EGFR. These results establish the role of the gatekeeper mutation on inhibitor selectivity. Additional molecular dynamics (MD) simulations, TI, and metadynamics MD simulations reveal the origins of the changes in binding energy of WT and mutants.


Myocardial protective effect of lidocaine during experimental off-pump coronary artery bypass grafting.
Off-pump coronary artery bypass grafting (OPCABG) has recently gained popularity. During OPCABG, patients remain vulnerable to ischemic-reperfusion injury due to a temporary coronary occlusion without any active cardioprotection. Some strategies such as ischemic preconditioning (IP) and an intracoronary shunt have been applied with a view to minimizing the effects of ischemia, but the effects of these strategies remain controversial. This study was carried out to investigate the protective effect of lidocaine against myocardial ischemic-reperfusion injury. Twenty-one pigs were assigned to three groups, each consisting of seven pigs. In the control group, using a left internal thoracic artery (LITA) bypass circuit, the left anterior descending coronary artery (LAD) was occluded for 45 min followed by two hours of reperfusion. In the IP group, five min of occlusion followed by 15 min of reperfusion was performed. In the lidocaine group, 2 mg/kg of lidocaine was administered directly into the LAD just before the LAD occlusion. Infarct size expressed as a percentage of the area at risk was significantly smaller in the lidocaine group (2.7+/-4.2%) than in the control group (79.9+/-6.0%, p<0.001) or the IP group (57.0+/-25.9%, p<0.001). Lidocaine exhibited a potent myocardial protective effect in the present OPCABG model.


Racial and ethnic disparities in the diagnosis of breast cancer: changes in presenting stage in minority populations in Florida during 1981-2009.
We assessed whether presenting breast cancer stage has changed over time in Florida, and whether there is variation in this change with respect to race, ethnicity, and socioeconomic status (SES). Data were obtained from the Florida Cancer Data System. We included females with invasive breast cancer and complete information on race, ethnicity, and SES during 1981-2009 (n = 226,651). Associations between categorical variables were examined using Chi-square tests. Predictors of SEER stage at diagnosis (local, regional, and distant) were modeled with multinomial ordinal logistic regression models. There was a significant increase in local disease and a decrease in regional and distant disease at presentation (p < 0.0001) over the time period assessed. Compared to whites, black patients continue to have lower odds of local presentation (OR 0.73, 95% CI 0.63, 0.85), as do Hispanic patients (OR 0.80, 95% CI 0.76, 0.84) compared to non-Hispanics. The increase in local stage at diagnosis was greater for black than white patients, as was the decrease in regional and distant disease (p < 0.001). Hispanic women also had significant increase in localized disease and decrease in regional and distant disease (p < 0.001), but there was little difference in the change compared to non-Hispanic women. Localized breast cancer stage at diagnosis has become more common over time in all groups. Significant disparity persists, with black and Hispanic patients being less likely to present with localized disease than white patients overall. There was a greater change for black versus white patients, resulting in a narrowing in the racial gap in stage at diagnosis.


Lateral distribution of nonendometriotic benign ovarian cysts.
To investigate the left- and right-sided distribution of nonendometriotic benign ovarian cysts, data were collected on 406 women undergoing first-line surgery for tumours with various histotypes. Considering the unilateral cysts, the observed proportion of left lesions was 65/129 (50.4%) in the serous, 38/79 (48.1%) in the mucinous, 59/134 (44.0%) in the dermoid, 11/21 (52.4%) in the parovarian, and 3/7 (42.9%) in the miscellaneous cysts group, without significant differences from the expected 50%. This contrasts with the finding of a significantly more frequent development of endometriomas on the left ovary, and suggests that the pathogenesis of endometriotic and nonendometriotic cysts is different.


Knowledge about systemic fluoride supplements among pediatric dentistry faculty and practitioners.
As approximately 50 percent of the U.S. population does not have access to optimally fluoridated water, systemic fluoride supplements should be considered as an alternative. Faculty reported being very well informed about proper fluoride supplement protocol, whereas some practitioners were somewhat or well-informed.


2-thioriboflavin 5'-phosphate (2-thio-FMN) lactate oxidase.
The natural flavin of lactate oxidase, FMN, was removed and replaced by the synthetic flavin 2-thioriboflavin 5'-phosphate (2-thio FMN). Despite the difference in properties of the flavins, including an oxidation-reduction potential some 80 mV more positive than that of normal flavin the 2-thio-FMN enzyme behaves in practically all respects like the native enzyme. It catalyzes the oxidative decarboxylation of L-lactate with almost the same efficiency as the native enzyme and with similar kinetic constants for individual steps in the catalytic pathway. It forms covalent derivatives at the flavin N(5) and C(4a) positions in facile photochemical reactions analogous to those of the native enzyme. It also forms a flavin anion radical on photoreduction with 5-deazaflavin as catalyst and, as with the native enzyme, this radical is stabilized remarkably on formation of a complex with pyruvate. The spectral properties of the neutral flavin radical form of 2-thioflavin are also reported, as determined by photochemical reduction of 2-thio-FMN flavodoxin. Like native lactate oxidase, the 2-thio-FMN enzyme also forms a flavin N(5)-sulfite adduct in an equilibrium reaction with sulfite. These results demonstrate clearly with this enzyme that the native flavin may be removed and replaced by an artificial flavin, without altering the structural integrity of the protein.


Identification of aortic arch-specific quantitative trait loci for atherosclerosis by an intercross of DBA/2J and 129S6 apolipoprotein E-deficient mice.
The genetic background of apolipoprotein E (apoE) deficient mice influences atherosclerotic plaque development. We previously reported three quantitative trait loci (QTL), Aath1-Aath3, that affect aortic arch atherosclerosis independently of those in the aortic root in a cross between C57BL6 apoEKO mice (B6-apoE) and 129S6 apoEKO mice (129-apoE). To gain further insight into genetic factors that influence atherosclerosis at different vascular locations, we analyzed 335 F2 mice from an intercross between 129-apoE and apoEKO mice on a DBA/2J genetic background (DBA-apoE). The extent of atherosclerosis in the aortic arch was very similar in the two parental strains. Nevertheless, a genome-wide scan identified two significant QTL for plaque size in the aortic arch: Aath4 on Chromosome (Chr) 2 at 137 Mb and Aath5 on Chr 10 at 51 Mb. The DBA alleles of Aath4 and Aath5 respectively confer susceptibility and resistance to aortic arch atherosclerosis over 129 alleles. Both QTL are also independent of those affecting plaque size at the aortic root. Genome analysis suggests that athero-susceptibility of Aath4 in DBA may be contributed by multiple genes, including Mertk and Cd93, that play roles in phagocytosis of apoptotic cells and modulate inflammation. A candidate gene for Aath5 is Stab2, the DBA allele of which is associated with 10 times higher plasma hyaluronan than the 129 allele. Overall, our identification of two new QTL that affect atherosclerosis in an aortic arch-specific manner further supports the involvement of distinct pathological processes at different vascular locations.


Free Energy Perturbation Approach for Accurate Crystalline Aqueous Solubility Predictions.
Early assessment of crystalline thermodynamic solubility continues to be elusive for drug discovery and development despite its critical importance, especially for the ever-increasing fraction of poorly soluble drug candidates. Here we present a detailed evaluation of a physics-based free energy perturbation (FEP+) approach for computing the thermodynamic aqueous solubility. The predictive power of this approach is assessed across diverse chemical spaces, spanning pharmaceutically relevant literature compounds and more complex AbbVie compounds. Our approach achieves predictive (RMSE = 0.86) and differentiating power (R2 = 0.69) and therefore provides notably improved correlations to experimental solubility compared to state-of-the-art machine learning approaches that utilize quantum mechanics-based descriptors. The importance of explicit considerations of crystalline packing in predicting solubility by the FEP+ approach is also highlighted in this study. Finally, we show how computed energetics, including hydration and sublimation free energies, can provide further insights into molecule design to feed the medicinal chemistry DMTA cycle.


Lettuce be happy: A longitudinal UK study on the relationship between fruit and vegetable consumption and well-being.
While the role of diet in influencing physical health is now well-established, some recent research suggests that increased consumption of fruits and vegetables could play a role in enhancing mental well-being. A limitation with much of this existing research is its reliance on cross-sectional correlations, convenience samples, and/or lack of adequate controls. We aim to add to the emerging literature on the relationship between fruit and vegetable consumption and well-being by using longitudinal data from a study in the United Kingdom (UK). We employ panel data analytical techniques on three waves collected between 2010 and 2017 (i.e., following the same individuals over time) in the UK Household Longitudinal Survey. We also control for time-variant confounders such as diet, health, and lifestyle behaviours. Fixed effects regressions show that mental well-being (GHQ-12) responds in a dose-response fashion to increases in both the quantity and the frequency of fruit and vegetables consumed. This relationship is robust to the use of subjective well-being (life satisfaction) instead of mental well-being. We also document a hump-shaped relationship between fruit and vegetable consumption and age. Our findings provide further evidence that persuading people to consume more fruits and vegetables may not only benefit their physical health in the long-run, but also their mental well-being in the short-run.


Validation of an exposure system to particles for the diagnosis of occupational asthma.
We previously described a closed-circuit system for exposure to particles in humans. This system has three components: a particle generator, an exposure chamber connected to an orofacial mask, and monitors. We describe results of challenges in 56 subjects who underwent challenges with the apparatus using occupational sensitizers in particles. Fifty-six consecutive subjects referred for the investigation of occupational asthma to occupational sensitizers in particles were included. The agents were the following: flour and grains (n = 19), cedar (n = 10), psyllium (n = 9), guar gum (n = 9), drugs (n = 3), persulfate (n = 2), and miscellaneous (n = 4). The duration of exposure was progressive and varied from one breath to a maximum of 180 min depending on the reaction. When no significant fall in FEV1 occurred after exposure with the aerosolization device, the standard approach of tipping particles from one tray to another was used. Twenty-nine subjects (52 percent) had a significant (greater than or equal to 20 percent) fall in FEV1 after exposure. This includes 18 subjects with isolated immediate reactions, four with dual asthmatic reactions, and two with atypical reactions. In 20/24 instances (83 percent), the percentage of fall in FEV1 did not exceed 30 percent, thus showing that dose-response curves can generally be obtained in a safe way. In all instances except one (26/27 cases), subsequent exposures using the traditional method did not result in significant falls in FEV1. This new procedure results in safe tests in terms of the percentage of changes in FEV1 during the immediate reactions and very rare false-negative challenges.


[Continuous monitoring of oxygen saturation in the jugular vein bulb in severe head injuries. Management and case reviews].
Since october 1996, the Intensive Care Unit of the Hospital of Navarra has carried out continuous monitoring of oxygen saturation in the bulb of the internal jugular vein (SjO2). This technique, used in patients with severe cranioencephalic trauma (SCET), is designed to facilitate care an ensure the use of adequate therapeutic measures in such patients. The present study has two parts: In the first part, SjO2 monitoring is defined and catheter insertion techniques, technical problems, and nursing care are described. In the second part, a retrospective review is made of patients admitted to the unit from october 1996 to october 1997 who underwent SjO2 monitoring. A total of 11 cases are included, the common features of which were: SCET, intracranial pressure over 20 mmHg, Glasgow score of 8 or less, and abnormal CAT study. This study provides a basis for developing a nursing protocol because familiarity with the technique allows problems to be prevented and/or resolved.


Pd-catalyzed carbonylative α-arylation of aryl bromides: scope and mechanistic studies.
Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)2] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO-releasing compound, 9-methylfluorene-9-carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3-diketones. A mechanistic investigation of this transformation relying on 31P and 13C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)2] and DPPP was only reactive towards 4-bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative-addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3-diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd0 precursor, [Pd(η3-1-PhC3H4)(η5-C5H5)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)2], its oxidative addition with 4-bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α-arylation of 4-bromoanisole with either catalytic or stoichiometric [Pd(η3-1-PhC3H4)(η5-C5H5)] over a short reaction time, led to the 1,3-diketone product. Because none of the acylated enol was detected, this implied that a similar mechanistic pathway is operating as that observed for the same transformation with [Pd(dba)2] as the Pd source.


Acute coronary syndrome in the young: clinical characteristics, risk factors and prognosis.
To describe the characteristics of patients ≤40 years of age hospitalized for acute coronary syndrome, analyze the risk factors and identify the variables associated with prognosis. Case series of patients admitted between 2003 and 2012 inclusive in a tertiary hospital (123 consecutive cases admitted between 2003 and 2012), and case-control study (369 controls selected from the general population matched for sex and age with cases, at a ratio of 3:1). Mortality, likelihood of survival without readmission for heart-related problems, extent of coronary disease as determined by coronary angiography and cardiovascular risk factors. Mean age was 35.4±4.8 years and 83.7% of the participants were men. Myocardial infarction with abnormal Q wave (48%) and single-vessel involvement (44.7%) predominated. Intrahospital mortality was 1.6%. For the 108 patients eventually included in the follow-up, likelihood of readmission-free survival after 60 months was 69.3±4.8%. In the case group 36% of the patients admitted to using cocaine. Compared to controls, the prevalence in patients was higher for smoking (74.8 vs 33.1%, p<0001), diabetes (14.6% vs 5.1%, p=0.001), low HDL-cholesterol (82.9 vs 34.1%, p<0.001) and obesity (30.0 vs 20.3%, p=0.029). Decreased left ventricular ejection fraction (odds ratio=2.2, p=0.033) and smoking (odds ratio=7.8, p=0.045) were associated with readmission for coronary syndrome. Acute coronary syndrome in people younger than 40 years is associated with diabetes and unhealthy lifestyle: smoking, sedentary behavior (low HDL-cholesterol), cocaine use and obesity. The readmission rate is high, and readmission is associated with smoking and decreased ejection fraction.


Image-Guided Spine Interventions for Pain: Ongoing Controversies.
An expanding array of image-guided spine interventions have the potential to provide immediate and effective pain relief. Innovations in spine intervention have proceeded rapidly, with clinical adoption of new techniques at times occurring before the development of bodies of evidence to establish efficacy. Although new spine interventions have been evaluated by clinical trials, acceptance of results has been hindered by controversies regarding trial methodology. This article explores controversial aspects of four categories of image-guided interventions for painful conditions: spine interventions for postdural puncture headache resulting from prior lumbar procedures, epidural steroid injections for cervical and lumbar radiculopathy, interventions for facet and sacroiliac joint pain, and vertebral augmentations for compression fractures. For each intervention, we summarize the available literature, with an emphasis on persistent controversies, and discuss how current areas of disagreement and challenge may shape future research and innovation. Despite the ongoing areas of debate regarding various aspects of these procedures, effective treatments continue to emerge and show promise for aiding relief of a range of debilitating conditions.


Brain metastases in metastatic non-small cell lung cancer responding to single-agent gefitinib: a case report.
Brain metastases are a frequent finding in patients with non-small cell lung cancer (NSCLC). The present case reports the clinical course of a patient who was treated with gefitinib alone for progressive brain metastases after whole-brain irradiation treatment (WBRT). A 50-year-old women with primary stage IV NSCLC (bone metastases) developed brain metastases after 3 cycles of chemotherapy consisting of paclitaxel and carboplatin (CBDA). After completion of the WBRT, magnetic resonance imaging (MRI) indicated further progression. Two cycles of temozolomide and topotecan were applied; this was ineffective in preventing central nervous system progression. For symptomatic brain metastatic disease the patient received gefitinib as single-agent treatment. Within a few weeks of treatment there was an obvious clinical improvement. Follow-up of the brain 2 months after the start of treatment showed a decrease in both the size and number of brain metastases. Additional manifestations in the lungs and the skeletal system were re-assessed as stable disease during the treatment with gefitinib. Within 4 months of treatment there were no side-effects such as skin rash or any other systemic toxicity. Gefitinib may therefore have a role in the treatment of brain metastases from NSCLC.


Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept).
Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.


The 3' addition of CCA to mitochondrial tRNASer(AGY) is specifically impaired in patients with mutations in the tRNA nucleotidyl transferase TRNT1.
Addition of the trinucleotide cytosine/cytosine/adenine (CCA) to the 3' end of transfer RNAs (tRNAs) is essential for translation and is catalyzed by the enzyme TRNT1 (tRNA nucleotidyl transferase), which functions in both the cytoplasm and mitochondria. Exome sequencing revealed TRNT1 mutations in two unrelated subjects with different clinical features. The first presented with acute lactic acidosis at 3 weeks of age and developed severe developmental delay, hypotonia, microcephaly, seizures, progressive cortical atrophy, neurosensorial deafness, sideroblastic anemia and renal Fanconi syndrome, dying at 21 months. The second presented at 3.5 years with gait ataxia, dysarthria, gross motor regression, hypotonia, ptosis and ophthalmoplegia and had abnormal signals in brainstem and dentate nucleus. In subject 1, muscle biopsy showed combined oxidative phosphorylation (OXPHOS) defects, but there was no OXPHOS deficiency in fibroblasts from either subject, despite a 10-fold-reduction in TRNT1 protein levels in fibroblasts of the first subject. Furthermore, in normal controls, TRNT1 protein levels are 10-fold lower in muscle than in fibroblasts. High resolution northern blots of subject fibroblast RNA suggested incomplete CCA addition to the non-canonical mitochondrial tRNA(Ser(AGY)), but no obvious qualitative differences in other mitochondrial or cytoplasmic tRNAs. Complete knockdown of TRNT1 in patient fibroblasts rendered mitochondrial tRNA(Ser(AGY)) undetectable, and markedly reduced mitochondrial translation, except polypeptides lacking Ser(AGY) codons. These data suggest that the clinical phenotypes associated with TRNT1 mutations are largely due to impaired mitochondrial translation, resulting from defective CCA addition to mitochondrial tRNA(Ser(AGY)), and that the severity of this biochemical phenotype determines the severity and tissue distribution of clinical features.


Microglia-derived extracellular vesicles in homeostasis and demyelination/remyelination processes.
Microglia (MG) play a crucial role as the predominant myeloid cells in the central nervous system and are commonly activated in multiple sclerosis. They perform essential functions under normal conditions, such as actively surveying the surrounding parenchyma, facilitating synaptic remodeling, engulfing dead cells and debris, and protecting the brain against infectious pathogens and harmful self-proteins. Extracellular vesicles (EVs) are diverse structures enclosed by a lipid bilayer that originate from intracellular endocytic trafficking or the plasma membrane. They are released by cells into the extracellular space and can be found in various bodily fluids. EVs have recently emerged as a communication mechanism between cells, enabling the transfer of functional proteins, lipids, different RNA species, and even fragments of DNA from donor cells. MG act as both source and recipient of EVs. Consequently, MG-derived EVs are involved in regulating synapse development and maintaining homeostasis. These EVs also directly influence astrocytes, significantly increasing the release of inflammatory cytokines like IL-1β, IL-6, and TNF-α, resulting in a robust inflammatory response. Furthermore, EVs derived from inflammatory MG have been found to inhibit remyelination, whereas Evs produced by pro-regenerative MG effectively promote myelin repair. This review aims to provide an overview of the current understanding of MG-derived Evs, their impact on neighboring cells, and the cellular microenvironment in normal conditions and pathological states, specifically focusing on demyelination and remyelination processes.


Contextualization procedure and modeling of monocyte specific TLR signaling.
Innate immunity is the first line of defense against invasion of pathogens. Toll-like receptor (TLR) signaling is involved in a variety of human diseases extending far beyond immune system-related diseases, affecting a number of different tissues and cell-types. Computational models often do not account for cell-type specific differences in signaling networks. Investigation of these differences and its phenotypic implications could increase understanding of cell signaling and processes such as inflammation. The wealth of knowledge for TLR signaling has been recently summarized in a stoichiometric signaling network applicable for constraint-based modeling and analysis (COBRA). COBRA methods have been applied to investigate tissue-specific metabolism using omics data integration. Comparable approaches have not been conducted using signaling networks. In this study, we present ihsTLRv2, an updated TLR signaling network accounting for the association of 314 genes with 558 network reactions. We present a mapping procedure for transcriptomic data onto signaling networks and demonstrate the generation of a monocyte-specific TLR network. The generated monocyte network is characterized through expression of a specific set of isozymes rather than reduction of pathway contents. While further tailoring the network to a specific stimulation condition, we observed that the quantitative changes in gene expression due to LPS stimulation affected the tightly connected set of genes. Differential expression influenced about one third of the entire TLR signaling network, in particular, NF-κB activation. Thus, a cell-type and condition-specific signaling network can provide functional insight into signaling cascades. Furthermore, we demonstrate the energy dependence of TLR signaling pathways in monocytes.


Genome-wide analysis of SU(VAR)3-9 distribution in chromosomes of Drosophila melanogaster.
Histone modifications represent one of the key factors contributing to proper genome regulation. One of histone modifications involved in gene silencing is methylation of H3K9 residue. Present in the chromosomes across different eukaryotes, this epigenetic mark is controlled by SU(VAR)3-9 and its orthologs. Despite SU(VAR)3-9 was discovered over two decades ago, little is known about the details of its chromosomal distribution pattern. To fill in this gap, we used DamID-seq approach and obtained high-resolution genome-wide profiles for SU(VAR)3-9 in two somatic (salivary glands and brain ganglia) and two germline (ovarian nurse cells and testes) tissues of Drosophila melanogaster. Analysis of tissue and developmental expression of SU(VAR)3-9-bound genes indicates that in the somatic tissues tested, as well as in the ovarian nurse cells, SU(VAR)3-9 tends to associate with transcriptionally silent genes. In contrast, in the testes, SU(VAR)3-9 shows preferential association with testis-specific genes, and its binding appears dynamic during spermatogenesis. In somatic cells, the mere presence/absence of SU(VAR)3-9 binding correlates with lower/higher expression. No such correlation is found in the male germline. Interestingly, transcription units in piRNA clusters (particularly flanks thereof) are frequently targeted by SU(VAR)3-9, and Su(var)3-9 mutation affects the expression of select piRNA species. Our analyses suggest a context-dependent role of SU(VAR)3-9. In euchromatin, SU(VAR)3-9 may serve to fine-tune the expression of individual genes, whereas in heterochromatin, chromosome 4, and piRNA clusters, it may act more broadly over large chromatin domains.


Fast mapping of absorbing defects in optical materials by full-field photothermal reflectance microscopy.
We report a technique for rapidly mapping absorbing defects in optical materials, which act as laser-induced damage precursors, based on full-field photothermal reflectance microscopy. An intensity-modulated pump beam heats absorbing defects in the optical sample, creating localized, modulated refractive-index variations around the defects. A probe beam then illuminates the defect sites, and the measured amplitude of the reflectance variation is used to map the distribution of defects in the medium. Measurements show that this method offers a faster defect mapping speed of about 0.03 mm(2) per minute and a detectivity of a few tens of nanometers comparable to that of conventional scanning photothermal deflection microscopy.


Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca(2+) influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly.
In our previous studies, particular phenolic ingredients, such as 2-methoxy-4-methylphenol (2M4MP), of the antidiarrheic drug wood creosote significantly prevented cell death by both hydrogen peroxide and glutamate in cultured rat hippocampal neurons. In this study, we further evaluated the pharmacological properties of 2M4MP on Ca(2+) influx across native and acquired N-methyl-D-aspartate (NMDA) receptor (NMDAR) channels. The addition of 2M4MP significantly prevented the loss of cellular viability and the increase in intracellular free Ca(2+) levels as determined by Fluo-3 in cultured rat hippocampal neurons briefly exposed to NMDA. Brief exposure to NMDA also led to a marked increase in mitochondrial free Ca(2+) levels determined by Rhod-2, in addition to intracellular free Ca(2+) levels, in HEK293 cells expressing either NR1/NR2A or NR1/NR2B subunit channels. The further addition of the general NMDAR channel blocker dizocilpine similarly inhibited the increase of intracellular Ca(2+) levels by NMDA in both types of acquired NMDAR channels, whereas the NR2B subunit selective antagonist ifenprodil drastically inhibited the increase by NMDA in HEK293 cells expressing NR1/NR2B, but not NR1/NR2A, subunits. Similarly, 2M4MP significantly and selectively inhibited the NMDA-induced influx of Ca(2+) across acquired NR1/NR2B channels in a concentration-dependent manner. Moreover, prior daily oral administration of 2M4MP significantly reduced the infarct volume in the ipsilateral cerebral hemisphere in rats with middle cerebral artery occlusion 1 day after reperfusion. These results suggest that 2M4MP may protect neurons from excitotoxicity through preferential inhibition of Ca(2+) influx across NMDAR channels composed of NR1/NR2B subunits.


An Artificial Cadaveric Leg Blood Flow System for Endoscopic Vein Harvesting Simulation.
Despite being the most common training model for endoscopic vein harvesting, cadaveric legs are limited by their absence of blood flow, resulting in a faded vascular appearance. Because the saphenous vein and the surrounding tissue seem less distinguishable, dissection of the saphenous vein and bipolar coagulation of its branches becomes increasingly inefficient and difficult. An inexpensive artificial blood flow system was developed to overcome this limitation. A cadaveric leg was thawed to a soft and yielding degree, and the saphenous vein was dissected medial and proximal to the medial malleolus. An artificial blood solution was prepared by dissolving 4% protein powder, red dye, and a contrast agent-for x-ray visualization-in saline. The solution was perfused through the saphenous vein and artery. The open ends of the vessels were temporarily clamped after the perfusion had been completed. Blood flow within the vessels was confirmed via angiography and endoscopic visualization of the leg's vessels. A bleeding effect was observed when the saphenous vein was perforated or when a vascular branch was transected. Conversely, a tight seal indicated successful bipolar coagulation of a branch, providing an objective, quantifiable assessment parameter. The artificial blood flow system helps overcome the limitations of the cadaveric leg, creating a more realistic and inexpensive model for endoscopic vein harvesting simulation training.


Gender Differences in the Associations Between Informal Caregiving and Wellbeing in Low- and Middle-Income Countries.
Background: Health risks among informal caregivers have received inadequate attention in low and middle income countries. We examined cross-sectional data from 28611 adults 18 years and older in Ghana, India, Mexico, Russia and South Africa in the WHO Study on Global AGEing and Adult Health (SAGE) to examine gender differences in informal caregiving and wellbeing. Methods: Wellbeing was measured by self-rated health, difficulties with tasks, self-reported and diagnosed depression and anxiety. Informal caregiving was specific to adults and constructed as categorical variable with the respondent as: the main caregiver, non-caregiver but an adult in the household needs care, and no-one ill in the household; multinomial gender-stratified regression models assessed adjusted relative risk ratios (ARRRs). Results: Female caregivers were more likely to report moderate difficulties with life tasks [ARRR = 1.45 (95% CI: 1.01, 2.08)], feel mild-moderate anxiety [ARRR = 1.64 (95% CI: 1.22, 2.22)], and report feeling severely depressed [ARRR = 1.86 (95% CI: 1.28, 2.69)] compared to female non-caregivers. Even when women were not caregivers, having someone ill at home was associated with extreme difficulties with life tasks [ARRR = 2.32 (95% CI: 1.33, 4.04)]. Male caregivers, compared to no-one ill in the household, were more likely to report mild-moderate anxiety [ARRR = 1.8 (95% CI: 1.2, 3.7)] and severe-extreme anxiety [ARRR = 2.22 (95% CI: 1.07, 4.6)]. Conclusions: Caregiving for older adults results in greater health burdens, particularly mental health, for both women and men, though evidence shows that these burdens may be prominent and manifest in more diverse ways for women relative to men.


iPS cell-derived cardiogenicity is hindered by sustained integration of reprogramming transgenes.
Nuclear reprogramming inculcates pluripotent capacity by which de novo tissue differentiation is enabled. Yet, introduction of ectopic reprogramming factors may desynchronize natural developmental schedules. This study aims to evaluate the effect of imposed transgene load on the cardiogenic competency of induced pluripotent stem (iPS) cells. Targeted inclusion and exclusion of reprogramming transgenes (c-MYC, KLF4, OCT4, and SOX2) was achieved using a drug-inducible and removable cassette according to the piggyBac transposon/transposase system. Pulsed transgene overexpression, before iPS cell differentiation, hindered cardiogenic outcomes. Delayed in counterparts with maintained integrated transgenes, transgene removal enabled proficient differentiation of iPS cells into functional cardiac tissue. Transgene-free iPS cells generated reproducible beating activity with robust expression of cardiac α-actinin, connexin 43, myosin light chain 2a, α/β-myosin heavy chain, and troponin I. Although operational excitation-contraction coupling was demonstrable in the presence or absence of transgenes, factor-free derivatives exhibited an expedited maturing phenotype with canonical responsiveness to adrenergic stimulation. A disproportionate stemness load, caused by integrated transgenes, affects the cardiogenic competency of iPS cells. Offload of transgenes in engineered iPS cells ensures integrity of cardiac developmental programs, underscoring the value of nonintegrative nuclear reprogramming for derivation of competent cardiogenic regenerative biologics.


Drug Delivery for Ocular Allergy: Current Formulation Design Strategies and Future Perspectives.
The incidences of ocular allergy have been growing with the increase in pollution. Because of challenges in new drug development, there have been efforts to maximize the efficacy of existing drugs through drug delivery approaches. The effectiveness of drugs in ophthalmic conditions is primarily determined by permeability across the barrier, corneal retention, and sustained release. Thus, there have been widespread efforts to optimize these parameters to enhance efficacy through novel formulations. This review aims to analyze the approaches to drug delivery systems to encourage further research to optimize effectiveness. With this objective, research on drug delivery aspects of anti-allergy therapeutics was included and analyzed based on formulation/drug delivery technique, Food and Drug Administration approval limits, residence time, compatibility, pre-clinical efficacy, and potential for translational application. Conventional eye drops have concerns such as poor residence time and ocular bioavailability. The novel formulations have the potential to improve residence and bioavailability. However, the use of preservatives and the lack of regulatory approval for polymers limit the translational application. The review may assist readers in identifying novel drug delivery strategies and their limitations for the development of effective ophthalmic formulations for the treatment of ocular allergy.


Assessing Dietary Salt Intake and Pilot-Testing a Home-Based Intervention to Lower Salt Intake Among Filipino College Students.
To assess the knowledge, attitude, and behaviors related to dietary salt intake and develop a home-based intervention that helps lower salt intake among Filipino college students. Two-phase program development study utilizing descriptive and quasi-experimental design. Phase 1 determined the knowledge, attitude, and behaviors alongside the frequency of dietary salt intake of a consecutive sample (n = 118). Phase 2 involved the development and pilot-testing of a home-based intervention wherein a random sample (n = 35) selected from Phase 1 joined for pilot-testing. The study was conducted from October - November 2021 and utilized valid and reliable measures to test the knowledge, attitude, and behavior of the participants. Initial assessment showed knowledge regarding health risks of high salt intake and positive attitude toward health-promoting behaviors. Post-intervention showed improvement in attitude (p = 0.0004) and behavior (p = 0.001) related to dietary salt intake alongside health literacy (p = 0.036). There was no significant change in knowledge (p = 0.054). The home-based intervention involving the use of health education materials is successful in improving dietary salt intake patterns. Community health nurses may utilize home-based interventions to help develop health-promoting behaviors among young adults.


Prehospital hypoglycemia: the safety of not transporting treated patients.
Emergency medical services (EMS) personnel frequently encounter patients who refuse transport after being treated for a hypoglycemic episode. The outcomes of most of these patients are unknown. The purpose of this study was to determine the outcomes of patients treated and not transported for hypoglycemia and identify criteria that could be used to identify patients who did not require transport to hospital. This was a prospective, observational study involving all adult (>15 years) hypoglycemic patients (blood glucose less than 4 mmol/L by glucometer) attended to by the EMS system in the Halifax Metropolitan area in the province of Nova Scotia during a ten-month interval. There were 220 calls for adult patients with hypoglycemia. Of the 75 calls that resulted in transport, there were 17 further hypoglycemic episodes requiring a repeat call for an ambulance (22.7%) and three recurrences (4%). Of the 145 calls that did not result in transport, 40 further episodes of hypoglycemia (27.6%) and three recurrences (2%) were reported. These differences were not statistically significant (p=0.43 and 0.33, respectively). There was also no statistically significant difference in the intervals between hypoglycemic episodes for patients transported (51.1 days +/-65) compared with patients not transported for their previous hypogylcemic episode (40.7 days +/-53.5) (p=0.6). Of the 47 calls entered in the study, there were seven repeat calls for hypoglycemia (15%) and one recurrence (2.1%). The majority of patients did not follow up with their physician. Repeat episodes of hypoglycemia are common; however, recurrences within 48 hours are not. Admission to hospital is rarely required. There appears to be no difference in the incidence of recurrences and repeat episodes of hypoglycemia between transported and nontransported insulin-dependent patients, regardless of age. Given the high incidence of repeat episodes, paramedics and physicians need to emphasize the importance of follow-up.


Fucoidan Extracts Ameliorate Acute Colitis.
Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent a novel nutraceutical option for the management of IBD.


HAPNEST: efficient, large-scale generation and evaluation of synthetic datasets for genotypes and phenotypes.
Existing methods for simulating synthetic genotype and phenotype datasets have limited scalability, constraining their usability for large-scale analyses. Moreover, a systematic approach for evaluating synthetic data quality and a benchmark synthetic dataset for developing and evaluating methods for polygenic risk scores are lacking. We present HAPNEST, a novel approach for efficiently generating diverse individual-level genotypic and phenotypic data. In comparison to alternative methods, HAPNEST shows faster computational speed and a lower degree of relatedness with reference panels, while generating datasets that preserve key statistical properties of real data. These desirable synthetic data properties enabled us to generate 6.8 million common variants and nine phenotypes with varying degrees of heritability and polygenicity across 1 million individuals. We demonstrate how HAPNEST can facilitate biobank-scale analyses through the comparison of seven methods to generate polygenic risk scoring across multiple ancestry groups and different genetic architectures. A synthetic dataset of 1 008 000 individuals and nine traits for 6.8 million common variants is available at https://www.ebi.ac.uk/biostudies/studies/S-BSST936. The HAPNEST software for generating synthetic datasets is available as Docker/Singularity containers and open source Julia and C code at https://github.com/intervene-EU-H2020/synthetic_data.


Too little, too late, and in the wrong place: Alpha band activity does not reflect an active mechanism of selective attention.
Selective attention focuses visual processing on relevant stimuli in order to allow for adaptive behaviour despite an abundance of distracting information. It has been proposed that increases in alpha band (8-12 Hz) amplitude reflect an active mechanism for distractor suppression. If this were the case, increases in alpha band amplitude should be succeeded by a decrease in distractor processing. Surprisingly, this connection has not been tested directly; specifically, studies that have investigated changes in alpha band after attention-directing cues have not directly assessed the neuronal processing of distractors. We concurrently recorded alpha activity and steady-state visual evoked potentials (SSVEPs) to assess the processing of target and distractor stimuli. In two experiments, participants covertly shifted attention to one of two letter streams (left or right) to detect infrequent target letters 'X' while ignoring the other stream. In line with previous findings, alpha band amplitudes contralateral to the unattended location increased compared to a pre-cue baseline. However, there was no suppression of SSVEP amplitudes elicited by unattended stimuli, while there was a pronounced enhancement of SSVEPs elicited by attended stimuli. Furthermore, and crucially, changes in alpha band amplitude during attention shifts did not precede those in SSVEPs and hit rates in both experiments, indicating that changes in alpha band amplitudes are likely to be a consequence of attention shifts rather than the other way around. We conclude that these findings contradict the notion that alpha band activity reflects mechanisms that have a causal role in the allocation of selective attention.


Quantitative neuroanatomy of all Purkinje cells with light sheet microscopy and high-throughput image analysis.
Characterizing the cytoarchitecture of mammalian central nervous system on a brain-wide scale is becoming a compelling need in neuroscience. For example, realistic modeling of brain activity requires the definition of quantitative features of large neuronal populations in the whole brain. Quantitative anatomical maps will also be crucial to classify the cytoarchtitectonic abnormalities associated with neuronal pathologies in a high reproducible and reliable manner. In this paper, we apply recent advances in optical microscopy and image analysis to characterize the spatial distribution of Purkinje cells (PCs) across the whole cerebellum. Light sheet microscopy was used to image with micron-scale resolution a fixed and cleared cerebellum of an L7-GFP transgenic mouse, in which all PCs are fluorescently labeled. A fast and scalable algorithm for fully automated cell identification was applied on the image to extract the position of all the fluorescent PCs. This vectorized representation of the cell population allows a thorough characterization of the complex three-dimensional distribution of the neurons, highlighting the presence of gaps inside the lamellar organization of PCs, whose density is believed to play a significant role in autism spectrum disorders. Furthermore, clustering analysis of the localized somata permits dividing the whole cerebellum in groups of PCs with high spatial correlation, suggesting new possibilities of anatomical partition. The quantitative approach presented here can be extended to study the distribution of different types of cell in many brain regions and across the whole encephalon, providing a robust base for building realistic computational models of the brain, and for unbiased morphological tissue screening in presence of pathologies and/or drug treatments.


Bone mass measurement: how, where, when and why?
Low bone mass, by far the major causal factor in osteoporotic fractures, cannot be predicted from the clinical evaluation of risk factors for osteoporosis. Measurement of bone mass is commonly achieved by using dual-energy X-ray absorptiometry (DXA), which has replaced dual-photon absorptiometry (DPA); single-energy X-ray absorptiometry (SXA), which is likely to replace I-125 single-photon absorptiometry; and by using quantitative computed tomography (QCT). Measurement of ultrasound speed and attenuation across the calcaneum is another promising method still under investigation. Each method may have some advantage or disadvantage relating to practical aspects (cost, scanning time, availability) and technical aspects (radiation dose, accuracy, precision). Several clinical situations have been identified in which measurement of bone mass will be useful, including women after the menopause to select those who should receive bone-sparing agents, and patients with x-ray vertebral deformity to confirm the diagnosis of osteoporosis. DXA allows measurement of bone mass at different skeletal sites, including the lumbar spine (by anteroposterior and lateral view), the hip, the forearm, and the total skeleton. The choice of the site to be screened will often be dictated by clinical considerations such as age and associated osteoarthritis, but, in theory, should be oriented by the ability of bone mass measurement at each site to predict osteoporotic fractures. Several prospective studies have shown that a decrease of 1 standard deviation of bone mass is associated with a 1.5- to 3-fold increase of the relative risk of fracture. Measuring any site is probably equally predictive of the risk of all osteoporotic fractures, while measurement of the hip appears to be a better predictor of the risk of hip fracture.


Direct Electrical Probing of Periodic Modulation of Zinc-Dopant Distributions in Planar Gallium Arsenide Nanowires.
Selective lateral epitaxial (SLE) semiconductor nanowires (NWs), with their perfect in-plane epitaxial alignment, ability to form lateral complex p-n junctions in situ, and compatibility with planar processing, are a distinctive platform for next-generation device development. However, the incorporation and distribution of impurity dopants in these planar NWs via the vapor-liquid-solid growth mechanism remain relatively unexplored. Here, we present a detailed study of SLE planar GaAs NWs containing multiple alternating axial segments doped with Si and Zn impurities by metalorganic chemical vapor deposition. The dopant profile of the lateral multi-p-n junction GaAs NWs was imaged simultaneously with nanowire topography using scanning microwave impedance microscopy and correlated with infrared scattering-type near-field optical microscopy. Our results provide unambiguous evidence that Zn dopants in the periodically twinned and topologically corrugated p-type segments are preferentially segregated at twin plane boundaries, while Si impurity atoms are uniformly distributed within the n-type segments of the NWs. These results are further supported by microwave impedance modulation microscopy. The density functional theory based modeling shows that the presence of Zn dopant atoms reduces the formation energy of these twin planes, and the effect becomes significantly stronger with a slight increase of Zn concentration. This implies that the twin formation is expected to appear when a threshold planar concentration of Zn is achieved, making the onset and twin periodicity dependent on both Zn concentration and nanowire diameter, in perfect agreement with our experimental observations.


Apomorphine and levodopa infusion therapies for advanced Parkinson's disease.
Continuous infusion of levodopa or apomorphine provide constant dopaminergic stimulations are good alternatives to deep brain stimulation to control motor fluctuations in patients with advanced Parkinson's disease (PD). Apomorphine provides motor benefit similar to dopamine, but its long-term use is limited by compliance, mostly injection site skin reactions. Administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement of a satisfactory therapeutic response paralleled by a reduction in motor complication severity. However, this procedure is more invasive than apomorphine as it requires a percutaneous endoscopic gastrostomy Clinical experience with infusions shows that continuous dopaminergic stimulation of dopaminergic medications reduces dyskinesia and widens the therapeutic window in advanced PD.