Radiocarbon determination of fossil and contemporary carbon contribution to aerosol in the Pacific Islands.
Combustion emissions are of growing concern across all Pacific Island Countries, which account for >10,000 km2 of the earth's surface area; as for many other small island states globally. Apportioning emissions inputs for Suva, the largest Pacific Island city, will aid in development of emission reduction strategies. Total suspended particulate (TSP) and fine particulate (PM2.5) samples were collected for Suva City, a residential area (Kinoya, TSP) and a mainly ocean-influenced site (Suva Point, TSP) from 2014 to 2015. Percentages of contemporary and fossil carbon were determined by radiocarbon analysis (accelerator mass spectrometry); for non‑carbonate carbon (NCC), elemental carbon (EC) and organic carbon (OC). Source contributions to particulate matter were identified and the accuracy of previous emissions inventory and source apportionment studies was evaluated. Suva Point NCC concentrations (2.7 ± 0.4 μg/m3) were four times lower than for City (13 ± 2 μg/m3 in TSP) and Kinoya (13 ± 1 μg/m3 in TSP); demonstrating the contribution of land-based emissions activities in city and residential areas. In Suva City, total NCC in air was 81% (79%-83%) fossil carbon, from vehicles, shipping, power generation and industry; whilst in the residential area, 48% (46%-50%) of total NCC was contemporary carbon; reflecting the higher incidence of biomass and waste burning and of cooking activities. Secondary organic fossil carbon sources contributed >36% of NCC mass at the city and >29% at Kinoya; with biogenic carbon being Kinoya's most significant source (approx. 30% of NCC mass). These results support the previous source apportionment studies for the city area; yet show that, in line with emissions inventory studies, biomass combustion contributes more PM2.5 mass in residential areas. Hence air quality management strategies need to target open burning activities as well as fossil fuel combustion.


Phase IB study of 25-hydroxyvitamin D(3) treatment to diminish suppressor cells in head and neck cancer patients.
Patients with head and neck squamous cell carcinoma (HNSCC) have profound immune defects. These defects are associated with a poor prognosis and are mediated, in part, by an increased number of immune inhibitory CD34(+) progenitor cells in their peripheral blood and tumor. The CD34(+) cells suppress autologous T-cell functions. Our prior work had shown that the differentiation inducer 1alpha,25-dihydroxyvitamin D(3) could drive the differentiation of CD34(+) cells isolated from HNSCC patients into dendritic cells. A phase IB clinical trial was initiated with HNSCC patients to determine if 25-hydroxyvitamin D(3) treatment could diminish CD34(+) cell levels and improve immune function. Six patients per treatment group were orally administered 20 or 40 microg/day 25-hydroxyvitamin D(3) for six weeks. Peripheral blood was collected at 0, 1, 2, 4, 6, and 8 weeks, and assessed for markers of immune activity. Although no clinical responses were observed, results of these pilot studies showed that 25-hydroxyvitamin D(3) reduced the presence of immune suppressive CD34(+) cells and improved immune competence of HNSCC patients.


Exploring the trend of increased cervical intraepithelial neoplasia detection rates in the Netherlands.
Over the last decade, cervical intraepithelial neoplasia (CIN) detection has increased in the Netherlands. We investigated the underlying mechanism by quantifying the increase, and analyzing patterns of CIN and cervical cancer detection over time. We observed annual CIN and cervical cancer detection rates (DRs) per 10,000 primary smears within the Dutch screening programme for 2000-2011. Joinpoint analyses were performed to determine changes in time trends, logistic regression analyses to assess the relative risk of calendar time on histological outcomes, adjusted for demographic factors and type of primary cytology test used. Trends of increased detection occurred for all CIN grades (ie. DRs increased from 17.8 to 36.1, from 21.0 to 35.5, and from 43.4 to 64.6 for CIN I, II, and III from 2003 to 2009). After adjusting for demographic factors, DRs were still 2.11 (95% confidence interval (CI): 1.95, 2.29), 1.79 (95% CI: 1.66, 1.92) and 1.59 (95% CI: 1.50, 1.67) times larger in 2009. When also adjusting for the type of cytology test, DRs were 1.90 (95% CI: 1.62, 2.22), 1.48 (95% CI: 1.22, 1.79) and 1.55 (95% CI: 1.39, 1.73) times larger. No trends in cervical cancer DRs were found. The implementation of liquid-based cytology contributed to the CIN increase. If some of these extra detected CIN are regressive this leads to overdiagnosis. Other factors, such as an increased cervical cancer risk, and implementation of imaging-assisted reading, could also have contributed.


Quantitative Prediction of CYP3A4- and CYP3A5-Mediated Drug Interactions.
We verified a physiologically-based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5-mediated drug-drug interactions (DDIs). A midazolam (MDZ)-ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics-informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (FG ) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7-3.4 and 3.9-4.7-fold in intravenous administration and 11.4-13.4 and 17.0-19.7-fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A-mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers.


Is in-utero exposure to cannabis associated with the risk of attention deficit with or without hyperactivity disorder? A cohort study within the Quebec Pregnancy Cohort.
Prenatal cannabis effect on attention deficit with or without hyperactivity disorder (ADHD) remains to be determined. Our aim is to quantify the impact of in-utero exposure to cannabis on the risk of ADHD. Cohort study. Questionnaires were mailed to women sampled from the Quebec Pregnancy Cohort (QPC). Data from questionnaires were then linked with their QPC (built with administrative health databases, hospital patient charts and birth certificate databases). Respondents who gave birth to a singleton live born between January 1998 and December 2003 and were continuously enrolled in the Régie de l'assurance maladie du Québec (RAMQ) medication insurance plan for at least 12 months before the first day of gestation and during pregnancy. In-utero cannabis exposure was based on mothers' answers to the question on cannabis use during pregnancy (yes/no) and categorised as occasionally, regularly exposed and unexposed if they chose one of these categories. ADHD was defined by a diagnosis of ADHD through the RAMQ medical services or MedEcho databases or a prescription filled for ADHD medication through RAMQ pharmaceutical services between birth and the end of the follow-up period. Follow-up started at the birth and ended at the index date (first diagnosis or prescription filled for ADHD), child death (censoring), end of public coverage for medications (censoring) or the end of study period, which was December 2015 (censoring), whichever event came first. A total of 2408 children met the inclusion criteria. Of these children, 86 (3.6%) were exposed to cannabis in-utero and 241 (10.0%) had an ADHD diagnosis or medication filled. After adjustments for potential confounders, no significant association was found between in-utero cannabis exposure (occasional (1.22 (95% CI 0.63 to 2.19)) or regular (1.22 (95% CI 0.42 to 2.79))) and the risk of ADHD in children. In-utero exposure to cannabis seemed to not be associated with the risk ADHD in children.


Detection of Anaplastic Lymphoma Kinase-Rearranged Mesothelioma Cells in Ascites by Companion Diagnostics.
A case of peritoneal mesothelioma with an anaplastic lymphoma kinase (ALK) translocation was identified, and we conducted further studies to obtain diagnostic and therapeutic insights. We believe that this is the first report describing the cytology of this new tumor type. A teenage woman was referred for severe pleural effusion. Enhanced computed tomography indicated an abdominal mass with ascites. Laparoscopy revealed tumor dissemination from the pelvis to the upper abdomen. Because a high-grade serous carcinoma was suspected, ascitic cytology and biopsy were performed. Cytologically, the tumor displayed characteristics of both adenocarcinoma and reactive or neoplastic mesothelial cells. After extensive pathological evaluation, the tumor was diagnosed as malignant peritoneal mesothelioma. To verify the diagnosis and aid in developing a therapeutic strategy, several companion diagnostics were tried. Surprisingly, the tumor was ALK-positive, and ALK recombination was confirmed by an ALK break-apart test. Retrospectively, cells and tissue specimens were stained with ALK intercalated antibody-enhanced polymer. Tumor cells were clearly distinguished from the nonneoplastic background. Recombination in ALK was reconfirmed by the National Cancer Center Japan, and the patient was enrolled in a clinical trial for alectinib. Companion diagnostics-based cytology may provide a useful means of monitoring and evaluating a molecular-targeted therapy.


Sensor Effects in LCL-Type Grid-Connected Shunt Active Filters Control Using Higher-Order Sliding Mode Control Techniques.
The effects of measuring devices/sensors on improving the power quality (PQ) of electric networks are studied in this paper. In this context, improving the performance of an LCL-type grid connected to a three-phase three-wire shunt active filter (SAF) in the presence of voltage perturbations is studied. In order to ensure the high-quality performance of LCL-SAF in the presence of voltage perturbations, the robust continuous second-order sliding mode controller (2-SMC), including twisting and super-twisting controllers, and continuous higher-order sliding mode controller (C-HOSMC)-based approaches are employed. These controllers, whose outputs are processed by pulse-width modulation (PWM), allow minimization of the phase shift and prevent the generation of discontinuous chattering commands, which can severely damage the VSI components. Moreover, an integration of a generalized instantaneous power identification algorithm with an advanced phase locked loop (PLL) was proposed and experimentally tested to validate the effective performances of SAF under severe perturbations. Additionally, the studied approaches were tested via simulations taking into account a conventional nonlinear industrial load in a real textile factory environment, using measurements provided by power quality analyzers. Finally, the effects of the measuring devices, including the current and voltage sensors, on the accuracy and reliability of the SAF and, consequently, on the PQ of the electric power grid were studied via simulations and experimentally. The results of this study support the validity of the recently published patent.


Apelin Reduces Nitric Oxide-Induced Relaxation of Cerebral Arteries by Inhibiting Activation of Large-Conductance, Calcium-Activated K Channels.
Activation of the apelin/APJ receptor signaling system causes endothelium-dependent and nitric oxide (NO)-dependent relaxation in several peripheral arteries. The effects of apelin in cerebral arteries are unknown; however, apelin inhibits voltage-dependent increases in large-conductance, calcium-activated K channel (BKCa) currents in cerebral artery smooth muscle cells. Because NO-induced relaxation of cerebral arteries is mediated, in part, by activation of BKCa channels, the goals of this study were to determine the net effect of apelin in cerebral arteries, as well as test the hypothesis that the actions of apelin in cerebral arteries are secondary to stimulation of APJ receptors. Immunoblot and quantitative reverse transcription polymerase chain reaction analyses detected APJ receptors in cerebral arteries of male Sprague-Dawley rats, and immunofluorescence studies using confocal microscopy confirmed APJ receptor localization in smooth muscle cells. In myograph studies, apelin itself had no direct vasomotor effect but inhibited relaxations to the NO-donor, diethylamine NONOate, and to the endothelium-dependent vasodilator, bradykinin. These effects of apelin were mimicked by the selective BKCa-channel blocker, iberiotoxin, and suppressed by the APJ receptor antagonist, F13A. Apelin also inhibited relaxations evoked by the BKCa-channel openers, NS1619 and BMS 191011, but had no effect on relaxation to levcromakalim, a selective KATP-channel opener. Apelin had no effect on diethylamine NONOate-induced or bradykinin-induced increases in cyclic guanosine monophosphate levels. Patch clamp recordings demonstrated that apelin and iberiotoxin each suppressed the increase in BKCa currents induced by DEA and NS1619 in freshly isolated cerebral artery smooth muscle cells. The results demonstrate that apelin inhibits NO-induced relaxation of cerebral arteries through a mechanism involving activation of APJ receptors and inhibition of BKCa channels in cerebral arterial smooth muscle cells.


Scutellaria baicalensis Georgi regulates REV-ERBα/BMAL1 to protect against skin aging in mice.
Scutellaria baicalensis Georgi (SBG) is a traditional Chinese medicine widely used to treat disorders such as hypertension, dysentery and hemorrhaging. Here, we aimed to assess the pharmacological effects of SBG on skin aging and to investigate the underlying mechanisms. Mice with skin aging were established by treatment with D-galactose and ultraviolet-B. SBG (topical application) showed a protective effect on skin aging in mice, as evidenced by less formation of skin wrinkles, higher levels of SOD (superoxide dismutase) and HYP (hydroxyproline) as well as a lower level of MDA (malondialdehyde). In the meantime, skin MMP-1 and p53 expression were lower, epidermis was thinner and collagen amount was higher in SBG-treated mice. Anti-skin aging effects of SBG were also confirmed in NIH3T3 and HaCaT cells, as well as in mouse primary dermal fibroblasts and human primary epidermal keratinocytes. Furthermore, we found that loss of Rev-erbα (a known repressor of Bmal1) up-regulated skin BMAL1 (a clock component and a known anti-aging factor) and ameliorated skin aging in mice. Moreover, SBG dose-dependently increased the expression of BMAL1 in the skin of aged mice and in senescent NIT3H3 cells. In addition, based on a combination of Gal4 chimeric, luciferase reporter and expression assays, SBG was identified as an antagonist of REV-ERBα and thus an inducer of BMAL1 expression. In conclusion, SBG antagonizes REV-ERBα to up-regulate BMAL1 and to protect against skin aging in mice.


Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of the 5-HT3 receptor.
Homomeric complexes of 5-HT(3A) receptor subunits form a ligand-gated ion channel. This assembly does not fully reproduce the biophysical and pharmacological properties of native 5-HT(3) receptors which might contain the recently cloned 5-HT(3B) receptor subunit. In the present study, heteromeric assemblies containing human 5-HT(3A) and 5-HT(3B) subunits were expressed in HEK 293 cells to detail the functional diversity of 5-HT(3) receptors. We designed patch-clamp experiments with homomeric (5-HT(3A)) and heteromeric (5-HT(3AB)) receptors to emphasize the kinetics of channel activation and desensitization. Co-expression of the 5-HT(3B) receptor subunit reduced the sensitivity for 5-HT (5-HT(3A) receptor: EC(50) 3 micro M, Hill coefficient 1.8; 5-HT(3AB) receptor: EC(50) 25 micro M, Hill coefficient 0.9) and markedly altered receptor desensitization. Kinetic modeling suggested that homomeric receptors, but not heteromeric receptors, desensitize via an agonist-induced open-channel block. Furthermore, heteromeric 5-HT(3AB) receptor assemblies recovered much faster from desensitization than homomeric 5-HT(3A) receptor assemblies. Unexpectedly, the specific 5-HT(3) receptor agonist mCPBG induced an open-channel block at both homomeric and heteromeric receptors. Because receptor desensitization and resensitization massively affect amplitude, duration, and frequency of synaptic signaling, these findings are evidence in favor of a pivotal role of subunit composition of 5-HT(3) receptors in serotonergic transmission.


Housecalls in general practice.
Home visits by General Practitioners have declined in many countries. We performed a study of home visits in an inner city practice in Dublin. We noted that rates of housecalls have declined at our practice in recent years from an average of 45 per month in 2006 to an average of 35 per month in 2010. We found that 88 (88%) of the recent housecalls we undertook had a valid medical or social indication in the opinion of the visiting GP. 21 housecalls (21%) were done for solely social reasons. The vast majority of our recent housecalls i.e. 91 (91%) were to patients who are entitled to free medical care under the General Medical Services scheme and 75 (75%) were to patients who were over 65 years of age. 87 housecalls (87%) were to patients with multiple morbidities. With our ageing population it is likely that the housecall will not vanish from clinical practice.


Transmembrane mobility of phospholipids in sickle erythrocytes: effect of deoxygenation on diffusion and asymmetry.
We studied the effect of sickling on the transmembrane reorientation and distribution of phospholipids in the red blood cells of patients homozygous for sickle cell anemia (SS). To this purpose, we followed the redistribution kinetics of trace amounts of spin-labeled analogues of natural phospholipids first introduced in the membrane outer leaflet of normal or sickle erythrocytes exposed to air or nitrogen. Deoxygenation had no effect on the lipid redistribution kinetics in normal (AA) cell membranes. At atmospheric pO2, unfractionated SS cells were not different from normal cells. However, on deoxygenation inducing sickling, phosphatidylcholine passive diffusion was accelerated and the rate of the adenosine triphosphate-dependent transport of aminophospholipids was reduced, especially for phosphatidylserine. The stationary distribution of the aminophospholipids between the two leaflets was slightly less asymmetric, a phenomenon more pronounced with phosphatidylethanolamine. These changes were rapidly reversible on reoxygenation. When SS cells were separated by density, both dense and light cells exhibited the properties cited above. However, dense cells exposed to air possessed a lower aminophospholipid transport rate. These data favor the relationship between aminophospholipid translocase activity and phospholipid transmembrane asymmetry. Sickle cell disease is the first case of aminophospholipid translocase pathology.


Functional Status Change Among Children With Extracorporeal Membrane Oxygenation to Support Cardiopulmonary Resuscitation in a Pediatric Cardiac ICU: A Single Institution Report.
The purpose of this study is to describe the functional status of survivors from extracorporeal cardiopulmonary resuscitation instituted during in-hospital cardiac arrest using the Functional Status Scale. We aimed to determine risk factors leading to the development of new morbidity and unfavorable functional outcomes. This was a single-center retrospective chart review abstracting patient characteristics/demographic data, duration of cardiopulmonary resuscitation, duration of extracorporeal membrane oxygenation support, as well as maximum lactate levels within 2 hours before and after extracorporeal cardiopulmonary resuscitation. Cardiac arrest was defined as the administration of chest compressions for a nonperfusing cardiac rhythm. Extracorporeal cardiopulmonary resuscitation was defined by instituting extracorporeal membrane oxygenation during active chest compressions. Functional Status Scale scores were calculated at admission and on hospital discharge for patients who survived. Patients admitted in the pediatric cardiac ICU at C.S. Mott Children's Hospital from January 1, 2005, to December 31, 2015. Children less than 18 years who underwent extracorporeal cardiopulmonary resuscitation. Not applicable. Of 608 extracorporeal membrane oxygenation events during the study period, 80 were extracorporeal cardiopulmonary resuscitation (14%). There were 40 female patients (50%). Median age was 40 days (interquartile range, 9-342 d). Survival to hospital discharge was 48% (38/80). Median Functional Status Scale score at admission was 6 (interquartile range, 6-6) and at hospital discharge 9 (interquartile range, 8-11). Out of 38 survivors, 19 (50%) had a change of Functional Status Scale score greater than or equal to 3, that is consistent with new morbidity, and 26 (68%) had favorable functional outcomes with a change in Functional Status Scale score of less than 5. This is the first extracorporeal cardiopulmonary resuscitation report to examine changes in Functional Status Scale from admission (baseline) to discharge as a measure of overall functional outcome. Half of surviving patients (19/38) had new morbidity, while 68% (26/38) had favorable outcomes. Lactate levels, duration of cardiopulmonary resuscitation, and duration of extracorporeal membrane oxygenation were not found to be risk factors for the development of new morbidity and poor functional outcomes. Functional Status Scale may be used as a metric to monitor improvement of extracorporeal cardiopulmonary resuscitation outcomes and help guide research initiatives to decrease morbidity in this patient population.


Characteristics of adolescent depression.
Depression is a common psychiatric disorder that is acknowledged to be increasing in disease burden. The rates of adolescent depression is particularly concerning as they continue to increase. The seriousness and pervasive effects of depression on young people's lives supports the view that research that extends the knowledge in this area is vital. This is a descriptive study of the characteristics of depression in a sample of 121 adolescents attending an outpatient specialist adolescent mental health service in New Zealand. The adolescents were required to complete two self-report measures to assess presence of depressive symptoms, severity of depression, and particular characteristics of the depression. The findings revealed that irritability was the most common characteristic along with other interpersonal and thought processing symptoms. It is important that mental health nurses are able to identify the specific characteristics of adolescent depression that may differ from adult depression in order to manage this patient population effectively.


Life-threatening complication of recurrent laryngeal nerve monitoring with EMG reinforced silicone ETT.
We present 2 cases with complication of herniation of a specially designed endotracheal tube (ETT) cuff used for laryngeal nerve monitoring during thyroid surgery. Abrupt and total blockage of ventilation has occurred at 35th and 40th minutes of general anesthesia. In an animal trachea, we showed that overinflated cuff may herniate and block ETT tip easily. A 25-mm upward movement of the ETT is found as a contributing factor to cuff herniation.In patients intubated with electromyographic reinforced ETT, any event suggesting sudden ventilation blockage should be managed initially by prompt deflation of the cuff. The cuff should be inflated at the minimal necessary volume, and operating room staff should pay maximum attention to the stability of endotracheal and breathing tubes.


VA Study of Unstable Angina. 10-year results show duration of surgical advantage for patients with impaired ejection fraction.
In a randomized study of unstable angina, medically treated patients with impaired left ventricular (LV) ejection fractions (EF = 0.3 to 0.58) were at significantly higher risk of mortality than patients treated by coronary artery bypass graft surgery (CABG). Because the duration of this surgical advantage is unknown, 10-year cumulative mortality rates of patients with impaired LVEF were determined and compared with the previously observed rates at 2, 5, and 8 years. Of 468 patients with unstable angina, 237 were randomized to receive medical treatment alone and 231 patients to have CABG. Baseline characteristics, which were equally distributed between the two treatment groups, included age, LVEF, number of diseased coronary arteries, diabetes, clinical presentation (type I or type II), prior myocardial infarction, and smoking. Mortality was determined by life-table analysis and risk factors by logistic regression analysis. Patients were divided into terciles according to LVEF, and the mortality rates of medical and surgical patients in the lowest tercile were compared. The 10-year mortality rate for all medical patients was 38% and for all surgical patients, 39%. When LVEF was treated as a continuous variable, there was a significant relation between mortality and LVEF for medically treated patients but not for surgical patients. The cumulative mortality rate for the lowest-tercile (EF 0.3 to 0.58) medical patients was 49%; for the lowest-tercile surgical patients, 41% (P = .15). The surgical advantage for patients with impaired LVEF that was significant at 5 years (P = .03) and 8 years (P = .05) appears to have diminished at 10 years (P = .15).


Reconstruction With a 3D-Printed Megaprosthesis With Ankle Arthrodesis After Distal Tibial Tumor Resection.
Reconstruction after en bloc resection of the distal tibia has remained an unsettled issue despite many attempts with bone grafts or prostheses in the past. Failures of the previous methods have been attributed to inadequate mechanical strength, poor articular stability, failed osseointegration, and poor soft tissue coverage. To overcome these shortcomings, we designed and applied a 3D-printed megaprosthesis with ankle arthrodesis. A total of 13 patients underwent resection of a distal tibial tumor and reconstruction with a 3D-printed distal tibial megaprosthesis between January 2017 and November 2020. Mean age was 14.9±6.5 years. Diagnoses included 11 cases of osteosarcoma and 1 case each of low-grade phosphaturic mesenchymal tumor and rhabdomyosarcoma. Baseline characteristics, operative data, complication profiles, and oncologic, and functional outcomes were reviewed and analyzed. All 13 cases attained a wide or marginal resection. During a mean follow-up of 26.8±10.6 months, 1 patient experienced local recurrence and distant metastasis, whereas 3 other patients only developed distant metastasis. Periprosthetic infection subsequent to paronychia occurred in 1 patient 24 months after the operation. No other complications were observed. By the last follow-up, the mean MSTS-93 score was 28.0±1.5. In this relatively small cohort with short-term follow-up, reconstruction with the 3D-printed megaprosthesis with ankle arthrodesis was found to be a safe and efficacious method after resection of a distal tibial malignancy.


UBC-Nepal Expedition: Motor Unit Characteristics in Lowlanders Acclimatized to High Altitude and Sherpa.
With acclimatization to high altitude (HA), adaptations occur throughout the nervous system and at the level of the muscle, which may affect motor unit (MU) characteristics. However, despite the importance of MUs as the final common pathway for the control of voluntary movement, little is known about their adaptations with acclimatization. Ten lowlanders and Sherpa participated in this study 7 to 14 d after arrival at HA (5050 m), with seven lowlanders repeating the experiment at sea level (SL), 6 months after the expedition. The maximal compound muscle action potential (M max ) was recorded from relaxed biceps brachii. During isometric elbow flexions at 10% of maximal torque, a needle electrode recorded the MU discharge rate (MUDR) and MU potential (MUP) characteristics of single biceps brachii MUs. Compared with SL, acclimatized lowlanders had ~10% greater MUDR, ~11% longer MUP duration, as well as ~18% lower amplitude and ~6% greater duration of the first phase of the M max (all P < 0.05). No differences were noted between SL and HA for variables related to MUP shape (e.g., jitter, jiggle; P > 0.08). Apart from lower near-fiber MUP area for Sherpa than acclimatized lowlanders ( P < 0.05), no M max or MU data were different between groups ( P > 0.10). Like other components of the body, MUs in lowlanders adapt with acclimatization to HA. The absence of differences between acclimatized lowlanders and Sherpa suggests that evolutionary adaptations to HA are smaller for MUs than components of the cardiovascular or respiratory systems.


No-show patients in an ophthalmological out-patient department.
Information on no-show patients in an ophthalmological out-patient department was collected and analyzed during one month in 1992 and compared to one month in 1993, after the introduction of a new policy of allocating fines to those patients who did not show for their appointments. In October 1992, 118 patients (6.4% out of 1837 scheduled appointments) and in 1993, 94 patients (5.5% out of 1710 appointments) did not show for the appointment. The strabismus unit showed the highest percentage of no-show patients for both years (8.4% in 1992, 7.5% in 1993) and the low vision unit the lowest (4.6% in 1992, 4.1% in 1993). In 1992, Tuesday (8.9%), and in 1993 Monday (6.9%) were the weekdays with the highest percentages; the lowest was Wednesday (4.4% in 1992, 2.8% in 1993). By appointment type, consultations from other clinics had the highest percentage in both years (7.9% in 1992, 6.9% in 1993) while the lowest was visits to personnel other than a doctor (3.7% in both years). The age group 31-40 years had the most no-show patients in both years (10.9% in 1992, 10.2% in 1993). The lowest percentage was in the age group 61-80 years (2.6-4.9% in 1992, 3.0-2.7% in 1993). To minimize broken appointments, it is important to inform the patient well about his disease and the significance of the examinations and follow-up visits. As an economical result of the no-show patients, a calculated income equivalent to the salary of about 3 persons in the nursing staff was lost.


A parietal biomarker for ADHD liability: as predicted by the distributed effects perspective model of ADHD.
We previously hypothesized that poor task-directed sensory information processing should be indexed by increased weighting of right hemisphere (RH) biased attention and visuo-perceptual brain functions during task operations and have demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies. However, in our recent distributed effects model of ADHD, we surmised that this phenotype is not ADHD specific, but rather more broadly reflective of any circumstance that disrupts the induction and maintenance of an emergent task-directed neural architecture. Under this view, increased weighting of RH-biased attention and visuo-perceptual brain functions is expected to generally index neurocognitive sets that are not optimized for task-directed thought and action, and when durable expressed, liability for ADHD. The current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD was associated with common ADHD characteristics and comorbidities [i.e., ADHD risk factors (RFs)]. Barring one exception (non-right handedness), we found that it was. Rightward parietal asymmetry (RPA) was associated with carrying the DRD4-7R risk allele, being male, having mood disorder, and having anxiety disorder. However, differences in the specific expression of RPA were observed, which are discussed in relation to possible unique mechanisms underlying ADHD liability in different ADHD RFs. Rightward parietal asymmetry appears to be a durable feature of ADHD liability, as predicted by the Distributed Effects Perspective Model of ADHD. Moreover, variability in the expression of this phenotype may shed light on different sources of ADHD liability.


Pharmacological Histone Deacetylation Distinguishes Transcriptional Regulators.
Histone deacetylase (HDAC) enzymes control the acetylation status of transcription factors that regulate chromatin structure and gene function. The transcriptional regulatory factors that distinguish histone acetylation and deacetylation patterns by pharmacological HDAC inhibition (HDACi) have not yet been studied. We analysed sequencing datasets derived from human aortic endothelial cells (HAECs) stimulated with the HDAC inhibitors, Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). We integrated gene expression and histone acetylation profiles with the transcription factor binding site (TFBS) database derived from the Encyclopedia of DNA Elements (ENCODE) project. Overall, TFBS signatures observed in SAHA and TSA stimulated cells were analogous. Histone acetylation was observed at transcription factor binding sites of target genes associated with the silencing factors NRSF, EZH2 and SUZ12. Histone deacetylation was a prominent property of HDACi and correlated with changes in the expression of genes regulated by proteins in transcriptional control such as histone acetyltransferase P300 and lysine demethylase JARID1A, as well as the regulatory factors cMYC, YY1 and STAT family proteins. We identified several transcription factors and coregulators implicated in the regulation of histone modification at target genes mediated by pharmacological HDAC inhibition.


Fourier analysis and nonlinear optical systems.
The modulation transfer function is based on Fourier techniques which imply the validity of the principle of superposition. This is clearly violated in the nonlinear film development process. A pseudotransfer function is defined to represent an artificial linear filter which, if it replaced the actual optical and photographic process, would result in precisely the same image as would be produced by the real system. The significance of such a function in a statistical approach and the results of a typical calculation are presented for purpose of illustration.


Doping effects on proton incorporation and conduction in SrZrO3.
The doping effects on the proton incorporation and protonic conductivity of perovskite-type SrZrO3 were investigated using the density functional theory (DFT) with the generalized gradient approximation (GGA). The optimized geometries, formation energies of hydrogen defect and activation energies for hydrogen diffusion in SrZrO3 doped with Al, Sc, Ga, Y, Rh, In, and Yb were calculated. It was shown that the doping leads to large local distortions around hydrogen and dopant ion, affecting the protonic conduction in these oxides. The alignment of hydrogen levels varies with the dopant introduced into the SrZrO3. In In-, Y-, Sc-, Ga-, and Al-doped SrZrO3, the H+ is the lowest energy state in all the bandgap. But for Yb- and Rh-doped SrZrO3, the H+ is the lowest energy state only when the Fermi energy below 2.37 and 2.66 eV, respectively. The estimates of the activation energy show good agreement between the measured and calculated activation energies. Also, the hydrogen diffusion seems to become more difficult as the distance between hydrogen and dopant ion decreases.


Metal-cavity surface-emitting microlaser with hybrid metal-DBR reflectors.
We demonstrate a metal-cavity surface-emitting microlaser at room temperature using hybrid metal/distributed Bragg reflectors as well as substrate removal. Our devices operate under continuous-wave current injection at room temperature. The smallest laser is 1.0 μm in radius and ~4.0 μm in height with a circular beam shape and an output over 8 μW. The device lases at 995 nm wavelength with a threshold current of about 2.6 mA.


Unusual dimensionality effects and surface charge density in 2D Mg(OH)2.
We present two-dimensional Mg(OH)2 sheets and their vertical heterojunctions with CVD-MoS2 for the first time as flexible 2D insulators with anomalous lattice vibration and chemical and physical properties. New hydrothermal crystal growth technique enabled isolation of environmentally stable monolayer Mg(OH)2 sheets. Raman spectroscopy and vibrational calculations reveal that the lattice vibrations of Mg(OH)2 have fundamentally different signature peaks and dimensionality effects compared to other 2D material systems known to date. Sub-wavelength electron energy-loss spectroscopy measurements and theoretical calculations show that Mg(OH)2 is a 6 eV direct-gap insulator in 2D, and its optical band gap displays strong band renormalization effects from monolayer to bulk, marking the first experimental confirmation of confinement effects in 2D insulators. Interestingly, 2D-Mg(OH)2 sheets possess rather strong surface polarization (charge) effects which is in contrast to electrically neutral h-BN materials. Using 2D-Mg(OH)2 sheets together with CVD-MoS2 in the vertical stacking shows that a strong change transfer occurs from n-doped CVD-MoS2 sheets to Mg(OH)2, naturally depleting the semiconductor, pushing towards intrinsic doping limit and enhancing overall optical performance of 2D semiconductors. Results not only establish unusual confinement effects in 2D-Mg(OH)2, but also offer novel 2D-insulating material with unique physical, vibrational, and chemical properties for potential applications in flexible optoelectronics.


Addiction neuroscience goes nuclear: A role for the transcription factor RXRα.
Building on work defining the cocaine-modulated transcriptional landscape in mice, Godino and colleagues focus in this issue of Neuron1 on the role of a specific nuclear receptor, RXRα. Results demonstrate that modifying accumbens RXRα expression profoundly alters gene transcription, neuronal activity, and cocaine-induced behavioral responses.


[Relationship between genetic polymorphism of MCP-1 and acute pancreatitis in Han population of Suzhou in China].
To study the relationship between monocyte chemoattractant protein-1 gene (MCP-1) -2518A/G polymorphism and acute pancreatitis (AP) in the Han population of Suzhou, China. The polymorphisms were detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotypes and allele frequencies of MCP-1 -2518A/G were calculated and analyzed in 101 AP patients including 78 mild AP (MAP) patients and 23 severe AP (SAP) patients, and 120 healthy individuals as control group. The frequency of MCP-1 -2518 AA genotype in control group was significantly higher than that in SAP and MAP groups (P < 0.01). People with AG and GG genotypes had 5.896 times risk of developing MAP (P < 0.01, OR=5.896) compared with people with AA genotype. Subjects carrying G allele were at a 7-fold elevated risk for SAP (P < 0.05, OR=7.011) contrasted with subjects carrying AA genotype. However, no difference in AA genotypic distribution was noted between MAP and SAP groups (chi square=0.006, P=0.997). The frequency of G allele in healthy controls was obviously lower than that in MAP (P < 0.01, OR=0.318) and SAP groups (P < 0.01, OR=0.309). No difference of G allele frequency was found between SAP group and MAP group (P=0.623, OR=1.211). The MCP-1 -2518 AA genotype of the population in Suzhou may be a protective genotype of AP. People with higher frequency of G allele is more likely to suffer from AP. Nonetheless, the genotype of AA and the frequency of G allele couldn't predict the risk of SAP.


Using bioinformatics technology to mine the expression of serum exosomal miRNA in patients with traumatic brain injury.
Traumatic brain injury (TBI) is considered the most common traumatic neurological disease, is associated with high mortality and long-term complications, and is a global public health issue. However, there has been little progress in serum markers for TBI research. Therefore, there is an urgent need for biomarkers that can sufficiently function in TBI diagnosis and evaluation. Exosomal microRNA (ExomiR), a stable circulating marker in the serum, has aroused widespread interest among researchers. To explore the level of serum ExomiR after TBI, we quantified ExomiR expression levels in serum exosomes extracted from patients with TBI using next-generation sequencing (NGS) and explored potential biomarkers using bioinformatics screening. Compared with the control group, there were 245 ExomiR (136 up-regulated and 109 down-regulated) in the serum of the TBI group that changed significantly. We observed serum ExomiRs expression profiles associated with neurovascular remodeling, the integrity of the blood-brain barrier, neuroinflammation, and a cascade of secondary injury, including eight up-regulated ExomiRs (ExomiR-124-3p, ExomiR-137-3p, ExomiR-9-3p, ExomiR-133a-5p, ExomiR-204-3p, ExomiR-519a-5p, ExomiR-4732-5p, and ExomiR-206) and 2 down-regulated ExomiR (ExomiR-21-3p and ExomiR-199a-5). The results revealed that serum ExomiRs might become a new research direction and breakthrough for the diagnosis and pathophysiological treatment of patients with TBI.


A study of the fate of the buccal wall of extraction sockets of teeth with prominent roots.
The objective of this investigation was to determine the fate of thin buccal bone encasing the prominent roots of maxillary anterior teeth following extraction. Resorption of the buccal plate compromises the morphology of the localized edentulous ridge and makes it challenging to place an implant in the optimal position for prosthetic restoration. In addition, the use of Bio-Oss as a bone filler to maintain the form of the edentulous ridge was evaluated. Nine patients were selected for the extraction of 36 maxillary anterior teeth. Nineteen extraction sockets received Bio-Oss, and seventeen sockets received no osteogenic material. All sites were completely covered with soft tissue at the conclusion of surgery. Computerized tomographic scans were made immediately following extraction and then at 30 to 90 days after healing so as to assess the fate of the buccal plates and resultant form of the edentulous sites. The results were assessed by an independent radiologist, with a crest width of 6 mm regarded as sufficient to place an implant. Those sockets treated with Bio-Oss demonstrated a loss of less than 20% of the buccal plate in 15 of 19 test sites (79%). In contrast, 12 of 17 control sockets (71%) demonstrated a loss of more than 20% of the buccal plate. In conclusion, the Bio-Oss test sites outperformed the control sites by a significant margin. No investigator was able to predict which site would be successful without the grafting material even though all were experienced clinicians. This leads to the conclusion that a patient has a significant benefit from receiving grafting materials at the time of extraction.


Physical properties of RIr3 (R = Gd, Tb, Ho) compounds with coexisting polymorphic phases.
The binary compounds GdIr3, TbIr3 and HoIr3 are synthesized successfully and found to form with macroscopic co-existence of two polymorphic phases: AuBe5 (C15b) and AuCu3-type. The dc magnetization and heat capacity studies confirm that the C15b phase orders ferromagnetically, whereas the AuCu3 phase remains paramagnetic down to 2 K. The frequency dependent ac-susceptibility data, time dependent magnetic relaxation behavior and magnetic memory effect studies suggest that TbIr3 and HoIr3 are cannonical spin-glass systems, but no glassy feature could be found in GdIr3. The critical behavior of all three compounds has been investigated using the magnetization and heat capacity measurements around the transition temperature (TC). The critical exponents α, β, γ and δ have been estimated using different techniques such as the Arrott-Noakes plot, Kouvel-Fisher plot and critical isotherm as well as analysis of specific heat data and study of magnetocaloric effect. The critical analysis study identifies the type of universal magnetic class in which the three compounds belong.


Cysteine- and glycine-rich protein 3 regulates glucose homeostasis in skeletal muscle.
Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has diverse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.


Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.
T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.


Long Noncoding RNA Signatures Induced by Toll-Like Receptor 7 and Type I Interferon Signaling in Activated Human Plasmacytoid Dendritic Cells.
Long noncoding RNAs (lncRNAs) exhibit highly lineage-specific expression and act through diverse mechanisms to exert control over a wide range of cellular processes. lncRNAs can function as potent modulators of innate immune responses through control of transcriptional and posttranscriptional regulation of mRNA expression and processing. Recent studies have demonstrated that lncRNAs participate in the regulation of antiviral responses and autoimmune disease. Despite their emerging role as immune mediators, the mechanisms that govern lncRNA expression and function have only begun to be characterized. In this study, we explore the role of lncRNAs in human plasmacytoid dendritic cells (pDCs), which are critical sentinel sensors of viral infection and contribute to the development of autoimmune disease. Using genome-wide sequencing approaches, we dissect the contributions of Toll-like receptor 7 (TLR7) and type I interferon (IFN-I) in the regulation of coding and noncoding RNA expression in CAL-1 pDCs treated with R848 or IFNβ. Functional enrichment analysis reveals both the unique and synergistic roles of TLR7 and IFN-I signaling in the orchestration of pDC function. These observations were consistent with primary cell immune responses elicited by detection of viral infection. We identified and characterized the conditional TLR7- and IFN-I-dependent regulation of 588 lncRNAs. Dysregulation of these lncRNAs could significantly alter pDC maturation, IFN-I and inflammatory cytokine production, antigen presentation, costimulation or tolerance cues, turnover, or localization, all consequential events during viral infection or IFN-I-driven autoimmune diseases such as systemic lupus erythematosus. These findings demonstrate the differential responsiveness of lncRNAs to unique immune stimuli, uncover regulatory mechanisms of lncRNA expression, and reveal a novel and tractable platform for the study of lncRNA expression and function.


Digital health literacy and subjective wellbeing in the context of COVID-19: A cross-sectional study among university students in Ecuador.
The COVID-19 pandemic has generated an avalanche of information, which, if not properly addressed, generates uncertainty and limits healthy decision-making. On the other hand, the pandemic has exacerbated mental health problems among young people and adolescents, causing a worsening of their wellbeing. Previous studies have found that digital health literacy has a positive impact on people's attitudes toward the disease. This study aimed to analyze the association between digital health literacy on COVID-19 with subjective wellbeing in university students. A cross-sectional study was developed in 917 students from Ecuador. Subjective wellbeing was measured with the World Health Organization WellBeing Scale. Digital health literacy was assessed using the Spanish-translated version of the Digital Health Literacy Instrument adapted to the context of the COVID-19 pandemic. Bivariate and multivariate linear regressions were performed. Digital health literacy and subjective wellbeing proofed to be significantly higher among males and among students with higher social status. The association between digital health literacy and subjective wellbeing was significant; for each increase of one point in the digital health literacy scale, an average increase of 9.64 points could be observed on the subjective wellbeing scale (IC 95% 5.61 - 13.67, p-value <0.001). This correlation persisted after adjust by demographic and socioeconomic variables. Improving digital health literacy in health would improve the subjective wellbeing of university students. It is suggested strengthen the digital health literacy through public and university policies that promote access, search skills and discernment of digital information. Socioeconomic and gender inequalities related to digital health literacy need to be further investigated.


Ligand Decomposition during Nanoparticle Synthesis: Influence of Ligand Structure and Precursor Selection.
Aliphatic amine and carboxylic acid ligands are widely used as organic solvents during the bottom-up synthesis of inorganic nanoparticles (NPs). Although the ligands' ability to alter final NP properties has been widely studied, side reactivity of these ligands is emerging as an important mechanism to consider. In this work, we study the thermal decomposition of common ligands with varying functional groups (amines and carboxylic acids) and bond saturations (from saturated to polyunsaturated). Here, we investigate how these ligand properties influence decomposition in the absence and presence of precursors used in NP synthesis. We show that during the synthesis of inorganic chalcogenide NPs (Cu2ZnSnS4, Cu x S, and SnS x ) with metal acetylacetonate precursors and elemental sulfur, the ligand pyrolyzes, producing alkylated graphitic species. Additionally, there was less to no ligand decomposition observed during the sulfur-free synthesis of ZnO and CuO with metal acetylacetonate precursors. These results will help guide ligand selection for NP syntheses and improve reaction purity, an important factor in many applications.


Murine retroviral bone marrow transplantation models for the study of human myeloproliferative disorders.
Human myeloproliferative diseases are common hematologic disorders characterized by clonal overproduction of maturing myeloid or erythroid cells, often caused by expression of a mutant, dysregulated tyrosine kinase (TK). These diseases can be accurately modeled in laboratory mice by the retroviral transfer of a mutant TK gene into murine hematopoietic stem and progenitor cells, followed by transplantation of these cells into irradiated recipient mice. This yields a model system for analyzing the molecular pathophysiology of these conditions and provides a platform for testing therapies, particularly molecularly targeted new chemical entities (NCEs). The Basic Protocol in this unit describes the preparation of mouse bone marrow cells to express the relevant human oncogene before transplanting them into irradiated recipient mice. An alternate protocol describes a similar technique that allows specific induction of lymphoproliferative disease by some TKs. Support protocols for generating and titering retroviral stocks are also included.


Crystallization of the reovirus type 3 Dearing core. Crystal packing is determined by the lambda 2 protein.
Core particles of reovirus type 3 Dearing (T3D) crystallized in the face-centered cubic space group F432 with dimensions of 1270 A along each edge of the unit cell. Core particles of reovirus type 1 Lang (T1L) did not crystallize. Experiments with core particles derived from 27 different T1L x T3D reassortant viruses indicated that the L2 genome segment determined the capacity of cores to crystallize. This finding indicates important differences in the surface topography of the L2-translation product, the lambda 2 protein, of these two isolates, and suggests that important crystal contacts are mediated by this protein. These data are used to generate a model of the packing of reovirus core particles within the unit cell.


Triple chromosome pairing in an aneuploid bull spermatocyte.
A triple synaptonemal complex was observed between three midsized chromosomes in an aneuploid bull spermatocyte. Fifteen other spermatocytes examined from the same animal displayed normal chromosome complements and pairing. This is the second case reported of triple synapsis in a mammal and the first case in an apparently normal individual.


Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA).
We examined copy number changes in the genomes of B cells from 58 patients with chronic lymphocytic leukemia (CLL) by using representational oligonucleotide microarray analysis (ROMA), a form of comparative genomic hybridization (CGH), at a resolution exceeding previously published studies. We observed at least 1 genomic lesion in each CLL sample and considerable variation in the number of abnormalities from case to case. Virtually all abnormalities previously reported also were observed here, most of which were indeed highly recurrent. We observed the boundaries of known events with greater clarity and identified previously undescribed lesions, some of which were recurrent. We profiled the genomes of CLL cells separated by the surface marker CD38 and found evidence of distinct subclones of CLL within the same patient. We discuss the potential applications of high-resolution CGH analysis in a clinical setting.


Engineering root microbiomes for healthier crops and soils using beneficial, environmentally safe bacteria.
The Green Revolution developed new crop varieties, which greatly improved food security worldwide. However, the growth of these plants relied heavily on chemical fertilizers and pesticides, which have led to an overuse of synthetic fertilizers, insecticides, and herbicides with serious environmental consequences and negative effects on human health. Environmentally friendly plant-growth-promoting methods to replace our current reliance on synthetic chemicals and to develop more sustainable agricultural practices to offset the damage caused by many agrochemicals are proposed herein. The increased use of bioinoculants, which consist of microorganisms that establish synergies with target crops and influence production and yield by enhancing plant growth, controlling disease, and providing critical mineral nutrients, is a potential solution. The microorganisms found in bioinoculants are often bacteria or fungi that reside within either external or internal plant microbiomes. However, before they can be used routinely in agriculture, these microbes must be confirmed as nonpathogenic strains that promote plant growth and survival. In this article, besides describing approaches for discovering plant-growth-promoting bacteria in various environments, including phytomicrobiomes and soils, we also discuss methods to evaluate their safety for the environment and for human health.


Intravitreal tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, partially suppresses and regresses laser-induced choroidal neovascularization in a rat model.
The study investigated the effect of intravitreally administered tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, in a rat model of laser-induced choroidal neovascularization (CNV). CNV was induced by laser photocoagulation on day 0 in the eyes of Brown Norway rats. Intravitreal injection of tanibirumab or phosphate-buffered saline (PBS) was done on day 0 (prevention arm) or day 7 (treatment arm). Seven days after injection, the eyes were enucleated and retinal pigment epithelium-choroid-sclera flat mounts were prepared. Areas of CNV were determined in the flat mounts using tetramethylrhodamine isothiocyanate Bandeiraea simplicifolia (BS) isolectin labeling and intravenously administered fluorescein isothiocyanate-dextran and quantified using an image analysis program. In the prevention arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.2% and 53.9% in tanibirumab-treated eyes (20 and 60 μg, respectively) compared with PBS-treated control eyes on day 7 (P=0.038 and P<0.001, respectively). In the treatment arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.7% and 46.0% in tanibirumab-treated eyes (20 and 60 μg, respectively) compared with PBS-treated control eyes on day 14 (P=0.048 and P<0.001, respectively). Intravitreally administered tanibirumab partially suppressed the formation of new CNV and partially regressed preformed laser-induced CNV in the rat model. Tanibirumab may be a feasible treatment for CNV associated with age-related macular degeneration or other causes.


Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma.
Neoadjuvant immune-checkpoint inhibition is a promising emerging treatment approach for patients with surgically resectable macroscopic stage III melanoma. The neoadjuvant setting provides an ideal platform for personalized therapy owing to the very homogeneous nature of the patient population and the opportunity for pathological response assessments within several weeks of starting treatment, thereby facilitating the efficient identification of novel biomarkers. A pathological response to immune-checkpoint inhibitors has been shown to be a strong surrogate marker of both recurrence-free survival and overall survival, enabling timely analyses of the efficacy of novel therapies in patients with early stage disease. Patients with a major pathological response (defined as the presence of ≤10% viable tumour cells) have a very low risk of recurrence, which offers an opportunity to adjust the extent of surgery and any subsequent adjuvant therapy and follow-up monitoring. Conversely, patients who have only a partial pathological response or who do not respond to neoadjuvant therapy still might benefit from therapy escalation and/or class switch during adjuvant therapy. In this Review, we outline the concept of a fully personalized neoadjuvant treatment approach exemplified by the current developments in neoadjuvant therapy for patients with resectable melanoma, which could provide a template for the development of similar approaches for patients with other immune-responsive cancers in the near future.


Quality control in the microbiological serum folate assay.
Low values obtained in the microbiological assay of serum folate are often due to the presence of antibiotics in the test serum. The assay has been modified to permit consistent recognition of the presence and extent of such contamination. Other assay variables have been investigated and a quality control system devised which rapidly identifies the presence of inconsistencies in any one assay batch. The system further allows for the reporting of some clinically useful results from an imperfect assay batch thus reducing the necessity for reassay of some test sera.


[Lung ultrasonography in anesthesia and critical care medicine].
As ultrasound beam does not penetrate the air, it has long been thought that ultrasound imaging is not useful for evaluation of the pulmonary parenchyma. However, recent studies have shown that the artifact pattern generated by the lung can be used for the diagnosis of acute respiratory failure. Lung ultrasonography can provide us important informations inside the lung in a real-time fashion. Furthermore, general application of extended ultrasonography would be of greater benefit for perioperative diagnosis and intervention.


Evidence-based assessment of the efficacy of esomeprazole for the healing of erosive esophagitis.
Gastroesophageal reflux disease is generally a lifelong illness that affects many people. Erosive esophagitis can occur in up to 65% of patients with gastroesophageal reflux disease and more seriously, esophageal stricture, Barrett's esophagus and esophageal adenocarcinoma, can develop. The severity of symptoms is not a reliable indicator of the severity of erosive esophagitis and although endoscopy is the preferred method to diagnose and grade erosive esophagitis, its routine use is not practical. Therefore, early initiation of treatment with the most effective agent for treating this disease is a practical and logical strategy. Proton pump inhibitor therapy is preferred for the treatment of gastroesophageal reflux disease. This review provides a quantitative assessment of the efficacy of esomeprazole (Nexium, AstraZeneca), the most effective agent currently available.


Examining the Role of Aryldiazonium Salts in Surface Electroinitiated Polymerization.
Historically, the irreversible reduction of aryldiazonium salts has provided a reliable method to modify surfaces, demonstrating a catalogue of suitable diazonium salts for targeted applications. This work expands the knowledge of diazonium salt chemistry to participate in surface electroinitiated emulsion polymerization (SEEP). The influence of concentration, electronic effects, and steric hindrance/regiochemistry of the diazonium salt initiator on the production of polymeric films is examined. The objective of this work is to determine if a polymer film can be tailored, controlling the thickness, density, and surface homogeneity using specific diazonium chemistry. The data presented herein demonstrate a significant difference in polymer films that can be achieved when selecting a variety of diazonium salts and vinylic monomers. A clear trend aligns with the electron-rich diazonium salt substitution providing the thickest films (up to 70.9 ± 17.8 nm) with increasing diazonium concentration and electron-withdrawing substitution achieving optimal homogeneity for the surface of the film at a 5 mM diazonium concentration.


Stabilization and purification of ornithine transcarbamylase from Neisseria gonorrhoeae.
Ornithine transcarbamylase was stabilized in cell-free extracts by the presence of either carbamyl phosphate or glycerol. The enzyme was rapidly purified by a procedure consisting of ion-exchange chromatography and electrofocusing. The native molecular weight of the enzyme was determined by gel filtration to be 110,000. A subunit molecular weight of 36,000 was determined by polyacrylamide electrophoresis under dissociating conditions. These findings indicated a trimeric quaternary structure for the enzyme. The isoelectric point of the purified enzyme was 4.75, and no evidence of multiple forms of active enzyme was found in either crude or purified preparations. An inactive form of the enzyme appeared upon storage in the absence of stabilization buffer.


Copper(I) transfer into apo-stellacyanin using copper(I)-thiourea as a copper-thionein model.
The direct incorporation of Cu(I) from [Cu(I)(thiourea)3]Cl, a structural analogue of Cu-thionein, into apo-stellacyanin, was successful both aerobically and anaerobically. A characteristic c.d. band of Cu(I)-stellacyanin at 270 nm (0 = -12.5 X 10(3) degrees X cm2 X dmol-1) was seen. On oxidation with hexacyanoferrate(III) or by air, the correct Cu(II) binding into the active centre of this 'Type 1' Cu-protein was deduced from chiroptical measurements which were supported by e.p.r. data. Thus Cu-thiourea turned out to be an excellent Cu(I)-donor in aqueous systems for the complete reconstitution of mononuclear Blue copper proteins.


Preparing Nursing Students for Leadership Using a Disaster-Related Simulation.
Increasing numbers and severity of disasters across the globe require nurses to be prepared to provide leadership in disaster situations. To address this need, a combination of didactic and simulation exercises was used to provide a daylong experience emphasizing application of nursing leadership skills in disasters to senior baccalaureate students. Evaluation of learning outcomes demonstrated significant improvement in student self-efficacy related to leadership in disasters.


Endemicity of chytridiomycosis features pathogen overdispersion.
Pathogens can be critical drivers of the abundance and distribution of wild animal populations. The presence of an overdispersed pathogen load distribution between hosts (where few hosts harbour heavy parasite burdens and light infections are common) can have an important stabilizing effect on host-pathogen dynamics where infection intensity determines pathogenicity. This may potentially lead to endemicity of an introduced pathogen rather than extirpation of the host and/or pathogen. Overdispersed pathogen load distributions have rarely been considered in wild animal populations as an important component of the infection dynamics of microparasites such as bacteria, viruses, protozoa and fungi. Here we examined the abundance, distribution and transmission of the model fungal pathogen Batrachochytrium dendrobatidis (Bd, cause of amphibian chytridiomycosis) between wild-caught Litoria rheocola (common mist frogs) to investigate the effects of an overdispersed pathogen load distribution on the host population in the wild. We quantified host survival, infection incidence and recovery probabilities relative to infectious burden, and compared the results of models where pathogen overdispersion either was or was not considered an important feature of host-pathogen dynamics. We found the distribution of Bd load between hosts to be highly overdispersed. We found that host survival was related to infection burden and that accounting for pathogen overdispersion allowed us to better understand infection dynamics and their implications for disease control. In addition, we found that the pattern of host infections and recoveries varied markedly with season whereby (i) infections established more in winter, consistent with temperature-dependent effects on fungal growth, and (ii) recoveries (loss of infection) occurred frequently in the field throughout the year but were less likely in winter. Our results suggest that pathogen overdispersion is an important feature of endemic chytridiomycosis and that intensity of infection determines disease impact. These findings have important implications for our understanding of chytridiomycosis dynamics and the application of management strategies for disease mitigation. We recommend quantifying individual infectious burdens rather than infection state where possible in microparasitic diseases.


Non-cigarette combustible tobacco use and its associations with subsequent cessation of smoking among daily cigarette smokers: findings from the International Tobacco Control Four Country Smoking and Vaping Surveys (2016-20).
To examine whether polyuse of cigarettes and other smoked products (polysmoking) is predictive of quit attempts and quit success. A prospective multi-country cohort design. Australia, Canada, England and the United States. A total of 3983 adult daily cigarette smokers were surveyed in 2016 (wave 1 of data collection) and were re-contacted in 2018 (wave 2) (i.e. waves 1-2 cohort) in the International Tobacco Control Four Country Smoking and Vaping (ITC 4CV) surveys; and 3736 smokers were surveyed in 2018 and re-contacted in 2020 (wave 3) (i.e. waves 2-3 cohort). Participants were asked about their cigarette smoking and use of cigars, cigarillos, pipes and waterpipes. Outcomes were quit attempts between two survey waves and success, defined as having quit smoking all the combustible tobacco at the subsequent survey for 1 month or more. Levels of polysmoking were 12.7% in the waves 1-2 cohort and 10.5% for the waves 2-3 cohort. Compared with cigarette-only smokers, polysmokers were more likely to attempt to quit between waves 1 and 2 [54.9 versus 42.7%, adjusted odds ratio (aOR) = 1.37, 95% confidence interval (CI) = 1.08-1.74, P < 0.01], but not between waves 2 and 3 (43.8 versus 40.1%, aOR = 0.94, 95% CI = 0.72-1.22). Polysmoking predicted reduced likelihood of success in both cohorts among attempters and the overall samples. Between waves 2 and 3 there were significantly more transitions to non-daily smoking among the polysmokers (12.4 versus 5.3%, χ2 = 40.4, P < 0.001). There is a consistent association between polysmoking (use of cigarettes together with other smoked products) and reduced quit success for combustible tobacco, but it is probably due to increased likelihood of transitioning to non-daily use rather than complete cessation.


A mixture of pure cellulase, hemicellulase and pectinase improves broiler performance.
1. The effects of a mixture of pure enzymes (cellulase, hemicellulase and pectinase) and a commercial enzyme, Energex, were examined on performance and metabolisabilities in broiler chicks given a maize-soybean meal diet. Composition of the mixed enzyme was similar to Energex except that protease was not present. 2. Chicks were divided into three groups: control, mixed enzyme and Energex with 7 replicates per group. Male broiler chicks were raised at 25 degrees C in wire-floored cages for 12 d from 15 d of age. Feed and water were offered ad libitum. 3. The Energex group gained significantly more weight and the mixed enzyme group tended to gain more than the control. Feed intakes were similar and thus the feed conversion ratio of Energex was significantly improved while it tended to be improved by the mixed enzyme. 4. The mixed enzyme group showed significant improvement in carcase and muscle weight when compared with the control group. The mixed enzyme group also showed significant improvement in organic matter and crude protein metabolisabilities. In the groups given enzyme, abdominal fat weight tended to decrease. 5. It is concluded that a combination of cellulase, hemicellulase and pectinase is effective in improving organic matter and crude protein metabolisabilities and carcase yield of broilers on a maize-soybean meal diet.


Association between serum cystatin C and diabetic peripheral neuropathy: a cross-sectional study of a Chinese type 2 diabetic population.
Serum cystatin C (CysC) is a sensitive marker of kidney function and recent studies have shown that CysC plays a critical role in degenerative diseases in both the central and the peripheral nervous systems. The aim of this study was to explore the relationship between serum CysC and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes. In total, 937 type 2 diabetic patients were enrolled in this cross-sectional study. Serum CysC concentration was measured by immunoturbidimetry. DPN was evaluated by neurological symptoms, neurological signs, neurothesiometer, and electromyogram. Serum CysC levels were significantly higher in DPN patients (1.3 (1.1-1.5) mg/l) compared with patients with signs of DPN (1.1 (0.9-1.3) mg/l, P<0.001) and non-DPN patients (1.0 (0.9-1.3) mg/l, P<0.001). Multiple regression analysis revealed that DPN was associated with age, diabetes duration, HbA1c, and serum CysC. Spearman's correlation analysis showed that serum CysC was closely related with age, sex, diabetes duration, hypertension, glomerular infiltration rate, and serum creatinine (Cr) level. The patients were divided into quartiles according to the serum CysC levels. Compared with quartile 1 (referent), the risk of DPN was significantly higher in quartile 2 (odds ratio (OR), 1.753; 95% CI, 1.055-2.912; P<0.05), quartile 3 (OR, 2.463; 95% CI, 1.445-4.917; P<0.01), and quartile 4 (OR, 5.867; 95% CI, 2.075-16.589; P<0.01). Receiver-operating characteristic analysis revealed that the optimal cutoff point of serum CysC to indicate DPN was 1.25 mg/l in male patients and 1.05 mg/l in female patients. High serum CysC level indicated a onefold higher risk of DPN. High serum CysC level is closely associated with DPN and may be a potential biomarker for DPN in type 2 diabetic patients.


A highly efficient rice green tissue protoplast system for transient gene expression and studying light/chloroplast-related processes.
Plant protoplasts, a proven physiological and versatile cell system, are widely used in high-throughput analysis and functional characterization of genes. Green protoplasts have been successfully used in investigations of plant signal transduction pathways related to hormones, metabolites and environmental challenges. In rice, protoplasts are commonly prepared from suspension cultured cells or etiolated seedlings, but only a few studies have explored the use of protoplasts from rice green tissue. Here, we report a simplified method for isolating protoplasts from normally cultivated young rice green tissue without the need for unnecessary chemicals and a vacuum device. Transfections of the generated protoplasts with plasmids of a wide range of sizes (4.5-13 kb) and co-transfections with multiple plasmids achieved impressively high efficiencies and allowed evaluations by 1) protein immunoblotting analysis, 2) subcellular localization assays, and 3) protein-protein interaction analysis by bimolecular fluorescence complementation (BiFC) and firefly luciferase complementation (FLC). Importantly, the rice green tissue protoplasts were photosynthetically active and sensitive to the retrograde plastid signaling inducer norflurazon (NF). Transient expression of the GFP-tagged light-related transcription factor OsGLK1 markedly upregulated transcript levels of the endogeneous photosynthetic genes OsLhcb1, OsLhcp, GADPH and RbcS, which were reduced to some extent by NF treatment in the rice green tissue protoplasts. We show here a simplified and highly efficient transient gene expression system using photosynthetically active rice green tissue protoplasts and its broad applications in protein immunoblot, localization and protein-protein interaction assays. These rice green tissue protoplasts will be particularly useful in studies of light/chloroplast-related processes.


An Adaptive Injection Model for Pansharpening.
Pansharpening technology is used to acquire a multispectral image with high spatial resolution from a panchromatic (PAN) image and a multispectral (MS) image. The detail injection model is popular for its flexibility. However, the accuracy of the injection gain and the extracted details may greatly influence the quality of the pansharpened image. This paper proposes an adaptive injection model to solve these problems. For detail extraction, we present a Gaussian filter estimation algorithm by exploring the intrinsic character of the MS sensor and convolving the PAN image with the filter to adaptively optimize the details to be consistent with the character of the MS image. For the adaptive injection coefficient, we iteratively adjust the coefficient by balancing the spectral and spatial fidelity. By multiplying the optimized details and injection gain, the final HRMS is obtained with the injection model. The performance of the proposed model is analyzed and a large number of tests are carried out on various satellite datasets. Compared to some advanced pansharpening methods, the results prove that our method can achieve the best fusion quality both subjectively and objectively.


Feasibility of transcatheter aortic valve implantation in patients with coronary heights ≤7 mm: insights from the transcatheter aortic valve implantation Karlsruhe (TAVIK) registry.
Transcatheter aortic valve implantation (TAVI) in patients with low coronary heights is generally denied but is not impossible. Information about these high-risk procedures is sparse. Since May 2008, data of more than 3000 patients who had TAVI were prospectively collected in the institutional TAVI Karlsruhe registry. Characteristics, peri- and postoperative outcome of patients with low coronary heights of ≤7 mm were analysed according to the Valve Academic Research Consortium-2. Eighty-six patients with an average coronary height of 6.4 ± 1.1 mm (mean age 81.0 ± 5.3 years, logistic EuroSCORE I 19.6 ± 13.3%) were treated. TAVI was performed in 72 transfemoral (83.7%) and 14 transapical (16.3%) cases using 44 CoreValve/Evolut R (51.2%), 21 Sapien XT/S3 (24.4%), 14 ACURATE (16.3%), 5 Lotus (5.8%) and 2 Portico (2.3%) prostheses. Ten procedures were valve-in-valve (VinV) TAVI (VinV, 11.6%). The 72-h, 30-day, 1-year and follow-up (3.0 ± 1.6 years) mortality rates were 2.3%, 8.0%, 10.5% and 26.7%, respectively. Within 30 days, 4 cardiac deaths and 3 non-cardiac deaths occurred (4.7% and 3.5%). Three coronary obstructions (3.5%) occurred-2 during VinV TAVI. One patient was connected to extracorporeal circulation that could not be weaned later due to an unsuccessful percutaneous coronary intervention. Another patient, the only conversion (1.2%), required delayed surgical valve replacement. The third patient died of right heart failure after aortic dissection. The procedural success rate was 95.3%. VinV procedures were associated with increased follow-up deaths (P < 0.001; hazard ratio 7.96). Coronary-related complications in TAVI procedures in patients with coronary heights ≤7 mm occurred less frequently, but once they occurred, they were serious. These TAVI procedures are feasible, with a high procedural success rate, but meticulous preoperative planning should be mandatory. In VinV procedures, the follow-up mortality rate is increased; therefore, we do not recommend these procedures.


Probiotics and Amelioration of Rheumatoid Arthritis: Significant Roles of Lactobacillus casei and Lactobacillus acidophilus.
Rheumatoid arthritis is a chronic autoimmune disorder that can lead to disability conditions with swollen joints, pain, stiffness, cartilage degradation, and osteoporosis. Genetic, epigenetic, sex-specific factors, smoking, air pollution, food, oral hygiene, periodontitis, Prevotella, and imbalance in the gastrointestinal microbiota are possible sources of the initiation or progression of rheumatoid arthritis, although the detailed mechanisms still need to be elucidated. Probiotics containing Lactobacillus spp. are commonly used as alleviating agents or food supplements to manage diarrhea, dysentery, develop immunity, and maintain general health. The mechanism of action of Lactobacillus spp. against rheumatoid arthritis is still not clearly known to date. In this narrative review, we recapitulate the findings of recent studies to understand the overall pathogenesis of rheumatoid arthritis and the roles of probiotics, particularly L. casei or L. acidophilus, in the management of rheumatoid arthritis in clinical and preclinical studies.


Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure.
Impaired development and reduced lung capacity are risk factors of asthma and chronic obstructive pulmonary disease. Previously, our genomewide linkage analysis of C3H/HeJ (C3H) and JF1/Msf (JF1) mouse strains identified quantitative trait loci (QTLs) associated with the complex traits of dead space volume (Vd), total lung capacity (TLC), lung compliance (CL), and diffusing capacity for CO (D(CO)). We assessed positional candidate genes by comparing C3H with JF1 lung transcript levels by microarray and by comparing C3H, BALB/cByJ, C57BL/6J, A/J, PWD/PhJ, and JF1 strains, using exon sequencing to predict protein structure. Microarray identified >900 transcripts differing in C3H and JF1 lungs related to lung development, function, and remodeling. Of these, three genes localized to QTLs associated with differences in lung function. C3H and JF1 strains differed in transcript and protein levels of superoxide dismutase 3, extracellular [SOD3; mouse chromosome (mCh) 5: VD] and transcript of trefoil factor 2 (TFF2; mCh 17: TLC and D(CO)), and ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; mCh 15: TLC and CL). Nucleotide sequencing of Sod3, Tff2, and previously identified Relaxin 1 (Rln1; mCh 19: CL) uncovered polymorphisms that could lead to nonsynonymous amino acid changes and altered predicted protein structure. Gene-targeted Sod3(-/-) mice had increased conducting airway volume (Vd/TLC) compared with strain-matched control Sod3(+/+) mice, consistent with the QTL on mCh 5. Two novel genes (Tff2 and Enpp2) have been identified and two suspected genes (Sod3 and Rln1) have been supported as determinants of lung function in mice. Findings with gene-targeted mice suggest that SOD3 is a contributing factor defining the complex trait of conducting airway volume.


Advances in the Application of Nanomaterials to the Treatment of Melanoma.
Melanoma can be divided into cutaneous melanoma, uveal melanoma, mucosal melanoma, etc. It is a very aggressive tumor that is prone to metastasis. Patients with metastatic melanoma have a poor prognosis and shorter survival. Although current melanoma treatments have been dramatically improved, there are still many problems such as systemic toxicity and the off-target effects of drugs. The use of nanoparticles may overcome some inadequacies of current melanoma treatments. In this review, we summarize the limitations of current therapies for cutaneous melanoma, uveal melanoma, and mucosal melanoma, as well as the adjunct role of nanoparticles in different treatment modalities. We suggest that nanomaterials may have an effective intervention in melanoma treatment in the future.


Duodopa infusion treatment: a point of view from the gastroenterologist.
In patients with advanced Parkinson's disease, the continuous delivery to the small intestine via a jejunal tube of levodopa/carbidopa, formulated as a gel suspension (Duodopa) represents a new treatment method. The continuous release results in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral administration. The method which requires a very good collaboration between the neurologist and the gastroenterologist is used with increasing frequency in selected centres especially in severe patients. First, a classic PEG gastrostomy kit is placed under propofol sedation. This allows the passage of a pig tail catheter which is deployed in the jejunum and it is attached to a portable pump via a special tubing system. We present our experience of seven cases (5 males, mean age 60 years) with a follow up of one year. One patient died due to respiratory failure and aspiration pneumonia probably related to the endoscopic procedure. At one year, all patients agreed that the neurological benefit offsets the procedure related problems and the technical issues related to the enteral infusion system.


Conservative management of acute calculous cholecystitis complicated by pancreatitis in an elderly woman: A case report.
Acute calculous cholecystitis is a prevalent disease whose diagnosis and management still face significant debate. Although the overall incidence of gallstone disease is 18.8% in European women aged 30 to 69 years, there is little data and experience in managing acute calculous cholecystitis in populations over 80 years old. The incidence of acute cholecystitis among the elderly is probably increasing. For the reason, we here highlight the advantages and disadvantage of various treatment and management opens based on a 96-year-old patient. We present a rare case in which a 96-year-old woman suffered from abdominal pain, nausea, and lack of appetite for over a month. She was diagnosed with acute calculous cholecystitis and pancreatitis. She was successfully treated without surgery, regaining her physical health after 5 months. The question of how to manage acute calculous cholecystitis is extremely difficult in many aspects. The patient of very advanced age presented in this paper, not very well diagnosed and with a life-threating condition, survived because of careful treatment and reasonable decision-making. The take-away from this case is that, in a high-risk senile patient, strict conservative therapy of cholecystitis may be successful, as it can avoid the complications of surgery and leave the patient with a good quality of life.


Essential oils and Beauveria bassiana against Dermanyssus gallinae (Acari: Dermanyssidae): Towards new natural acaricides.
Essential oils (EOs) and entomopathogenic fungi such as Beauveria bassiana (Bb) strains have the potential to be used as alternative insecticides and acaricides for controlling ectoparasites as Dermanyssus gallinae. These compounds have some limitations in their use: the acaricidal effect of EOs is rapid, but short-lived, whilst that of Bb is delayed, but long-lived. To evaluate the effect of both compounds combined against D. gallinae, the non-toxic dose of Eucalyptus globulus, Eucalyptus citriodora, Thymus vulgaris and Eugenia caryophyllata essential oils were firstly calculated for "native" strains of Bb. Subsequently, the effects of the combination of selected EOs with Bb against nymph and adult poultry red mites (PRMs) was assessed. EO concentrations ranging from 0.0015 to 8% v/v (i.e., nine double dilutions) were used to evaluate their effect on germination, sporulation and vegetative growth rates of native strains of Bb. A total of 1440 mites (720 nymphs and 720 adults) were divided into three-treated group (TGs) and one control group (CG). In TGs, mites were exposed to Bb in combination with the selected EO (TG1), EO alone (TG2) or Bb (TG3) alone. In the CG, mites were exposed to 0.1% tween 80 plus EO solvent (CG). E. globulus and E. citriodora were toxic for Bb in concentrations higher than 0.2% and 0.003% respectively, whilst E. caryophyllata and T. vulgaris were toxic at all concentrations tested against Bb. Based on the results of the toxicity assays against Bb, E. globulus was chosen to be tested as acaricide resulting non-toxic for Bb at concentration lower than 0.4%. Increased mortality of D. gallinae adults was recorded in TG1 than those in other TGs from 4days post-infection (T+4DPI). A 100% mortality of D. gallinae was recorded in adults at T+9DPI and at T+10DPI in nymphs in TG1 and later than T+11DPI in the other TGs. Used in combination with E. globulus, Bb displayed an earlier acaricidal effect towards both haematophagous D. gallinae stages. The combination of B. bassiana and E. globulus at 0.2% might be used for controlling arthropods of medical and veterinary importance as D. gallinae.


The caenorhabditis elegans fate-determining gene mab-9 encodes a T-box protein required to pattern the posterior hindgut.
Caenorhabditis elegans mab-9 mutants are defective in hindgut and male tail development because of cell fate transformations in two posterior blast cells, B and F. We have cloned mab-9 and show that it encodes a member of the T-box family of transcriptional regulators. MAB-9 localizes to the nucleus of B and F and their descendents during development, suggesting that it acts cell autonomously in the posterior hindgut to direct cell fate. T-box genes related to brachyury have also been implicated in hindgut patterning, and our results support models for an evolutionarily ancient role for these genes in hindgut formation.


Change in self-efficacy, autonomous and controlled motivation predicting smoking.
Although motivational interviewing (MI) has been shown to be effective in changing health behaviors, its effects on smoking cessation have been mixed. The purpose of the present study is to assess factors of motivation and self-efficacy as they mediate the relationship between MI and smoking cessation. This is a secondary analysis of an MI based smoking cessation randomized trial. MI counseling was associated with change in smoking behaviors during a 12 months intervention but was not related to autonomous motivation, controlled motivation, or self-efficacy at baseline and 6 months, the hypothesized mediators. This study confirmed the pathway to quit smoking through increase in self-efficacy.


Palladium and platinum complexes of tellurium-containing imidodiphosphinate ligands: nucleophilic attack of Li[(P(i)Pr2)(TeP(i)Pr2)N] on coordinated 1,5-cyclooctadiene.
Homoleptic group 10 complexes of ditellurido PNP (PNP = imidodiphosphinate), heterodichalcogenido PNP and monotellurido PNP ligands, M[(TeP(i)Pr2)2N]2 (1: M = Pd; 2: M = Pt), M[(EP(i)Pr2)(TeP(i)Pr2)N]2 (3: M = Pd, E = Se; 4: M = Pt, E = Se; 5: M = Pd, E = S; 6: M = Pt, E = S) and M[(P(i)Pr2)(TeP(i)Pr2)N]2 (7: M = Pd; 8: M = Pt), respectively, were prepared by metathesis between alkali-metal derivatives of the appropriate ligand and MCl2(COD) in THF. Complexes 1-8 were characterised in solution by multinuclear (31P, 77Se, 125Te and 195Pt) NMR spectroscopy and, in the case of 1, 2, trans-7, cis-7 and trans-8, in the solid state by X-ray crystallography. The square-planar complexes 3-6 are formed as a mixture of cis- and trans-isomers on the basis of NMR data. The cis and trans isomers of 7 were separated by crystallisation from different solvents. In addition to trans-8, the reaction of Li[(P(i)Pr2)(TeP(i)Pr2)N] with MCl2(COD) produced the heteroleptic complex Pt[(P(i)Pr2)(TeP(i)Pr2)N][sigma:eta2-C8H12(P(i)Pr2NP(i)Pr2Te)] (9) resulting from nucleophilic attack on coordinated 1,5-cyclooctadiene. Complex 9 was identified by multinuclear (13C, 31P, 125Te and 195Pt) NMR spectroscopy, which revealed a mixture of geometric isomers, and by X-ray crystallography.


Two-Way CO2-Responsive Polymer Particles with Controllable Amphiphilic Properties.
Multiple stimuli-responsive amphiphilic block copolymers of poly(methacrylic acid) (PMAA) and poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) were used as emulsifiers to prepare two-way CO2 stimuli-responsive poly(methyl methacrylate) (PMMA) latex particles via aqueous emulsion polymerization. The polymerization at pH 2 and 50 °C produced mainly PDMAEMA-surfaced PMMA latex particles, whereas the polymerization at pH 12 and 50 °C produced mainly PMAA-surfaced particles. Both types of latex particles appeared to precipitate at higher pH values from the emulsifier of a longer PDMAEMA block length. The direction from precipitation to dispersion for PDMAEMA-surfaced particles or from dispersion to precipitation for PMAA-surfaced particles in response to CO2 bubbling of the pH 12 dispersion of particles depended on the PDMAEMA block length. Together, this study reveals that-by tuning the PDMAEMA block length in PMAA-b-PDMAEMA used as an emulsifier and polymerization at pH 2 or 12-PMMA latex particles can exhibit two-way CO2 responsiveness between dispersion and precipitation. Thus, due to their simple preparation and unique dual pH and CO2 responsiveness, these newly developed PMAA-b-PDMAEMA emulsifiers provide a highly efficient approach for the development of smart PMMA latex nanoparticles with desirable multifunctional properties.


Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor κB through the repression of IKKα/β phosphorylation.
Vitamin K is essential for blood coagulation and bone metabolism in mammals. This vitamin functions as a cofactor in the posttranslational synthesis of γ-carboxyglutamic acid (Gla) from glutamic acid residues. However, other functions of vitamin K have been reported recently. We previously found that vitamin K suppresses the inflammatory reaction induced by lipopolysaccharide (LPS) in rats and human macrophage-like THP-1 cells. In this study, we further investigated the mechanism underlying the anti-inflammatory effect of vitamin K by using cultures of LPS-treated human- and mouse-derived cells. All the vitamin K analogues analyzed in our study exhibited varied levels of anti-inflammatory activity. The isoprenyl side chain structures, except geranylgeraniol, of these analogues did not show such activity; warfarin did not interfere with this activity. The results of our study suggest that the 2-methyl-1,4-naphtoquinone ring structure contributes to express the anti-inflammatory activity, which is independent of the Gla formation activity of vitamin K. Furthermore, menaquinone-4, a form of vitamin K₂, reduced the activation of nuclear factor κB (NFκB) and inhibited the phosphorylation of IKKα/β after treatment of cells with LPS. These results clearly show that the anti-inflammatory activity of vitamin K is mediated via the inactivation of the NFκB signaling pathway.


Insulin resistance after renal transplantation: impact of immunosuppressive and antihypertensive therapy.
The purpose of the present study was to validate various surrogate estimates of insulin sensitivity (IS) in a renal transplant population and to assess the influence of immunosuppressive and antihypertensive therapy on insulin resistance (IR) after renal transplantation. A total of 167 consecutive renal transplant recipients without previously known diabetes underwent a 75-g oral glucose tolerance test (OGTT) 3 months after renal transplantation. A total of 43 patients also underwent a euglycemic-hyperinsulinemic glucose clamp study. Six OGTT-derived IS indexes were validated against the euglycemic-hyperinsulinemic glucose clamp-derived IS index (ISI(CLAMP)). The OGTT-derived ISI(TX) correlated closely with the ISI(CLAMP) (r = 0.58, P < 0.001). The other surrogate estimates of IS were also significantly but less well correlated with the ISI(CLAMP) (Spearman's correlation; r = -0.45 to 0.41, P = 0.003-0.050). In the univariate model, BMI, daily prednisolone dose, creatinine clearance, hypertension, number of antihypertensive agents, and use of diuretics or beta-blockers were negatively associated with ISI(TX) (P < 0.05). After multiple regression analysis, BMI (P < 0.001), daily prednisolone dose (P < 0.001), cytomegalovirus infection (P = 0.030), and triglycerides (P = 0.034) were shown to be independent predictors of posttransplant IR. The OGTT-derived ISI(TX) may be a useful estimate of IS in Caucasian renal transplant recipients. Increasing daily prednisolone dose is an independent predictor of IR after renal transplantation. Hypertension and the use of beta-blockers and diuretics may also deteriorate IR in this group of patients.


Nutrient-enhanced diet reduces noise-induced damage to the inner ear and hearing loss.
Oxidative stress has been implicated broadly as a cause of cell death and neural degeneration in multiple disease conditions; however, the evidence for successful intervention with dietary antioxidant manipulations has been mixed. In this study, we investigated the potential for protection of cells in the inner ear using a dietary supplement with multiple antioxidant components, which were selected for their potential interactive effectiveness. Protection against permanent threshold shift (PTS) was observed in CBA/J mice maintained on a diet supplemented with a combination of β-carotene, vitamins C and E, and magnesium when compared with PTS in control mice maintained on a nutritionally complete control diet. Although hair cell survival was not enhanced, noise-induced loss of type II fibrocytes in the lateral wall was significantly reduced (P < 0.05), and there was a trend toward less noise-induced loss in strial cell density in animals maintained on the supplemented diet. Taken together, our data suggest that prenoise oral treatment with the high-nutrient diet can protect cells in the inner ear and reduce PTS in mice. The demonstration of functional and morphologic preservation of cells in the inner ear with oral administration of this antioxidant supplemented diet supports the possibility of translation to human patients and suggests an opportunity to evaluate antioxidant protection in mouse models of oxidative stress-related disease and pathology.