Implementation of a self-monitoring application to improve on-task behavior: A high school pilot study.
Technological innovations offer promise for improving intervention implementation in secondary, inclusive classrooms. A withdrawal design was employed with two high school students in order to assess the effectiveness of a technologically-delivered, self-monitoring intervention in improving on-task behavior in a science classroom. Two students ages 14 and 15 with diagnoses of specific learning disability (student 1) and attention deficit hyperactivity disorder (ADHD: student 2) were selected by case manager referral due to difficulties with on-task behavior despite long-term administration of psychostimulant medication. After baseline data were collected, both students were trained in the use of a self-monitoring application (I-Connect) delivered via a handheld tablet. On-task prompts were delivered at five min intervals in an ABAB withdrawal design. The intervention resulted in positive, stable improvements in the primary dependent variable of on-task behavior for both students and less clear improvement in the generalization variable of disruptive behavior.


Tuning Nitrate Electroreduction Activity via an Equilibrium Adsorption Strategy: A Computational Study.
Converting nitrates into industrial-value chemicals is of great significance for environmental sustainability. Herein, the electrochemical nitrate reduction reaction (NO3RR) performances of transition metal (TM) anchored g-C3N4 (TM/g-C3N4) were systematically evaluated using density functional theory and ab initio molecular dynamics. A novel equilibrium adsorption model was constructed to screen the excellent catalysts, accelerating high-throughput calculations. As found, Hf/g-C3N4 exhibits remarkable activity with a limiting potential of 0.11 V. Besides, the superior electrode selectivity overwhelmingly depresses the formation of byproducts and greatly speeds up the NO3RR. The electronic structure analysis discloses the origin of the electrocatalytic activity for TM/g-C3N4 and indicates why the IVB group elements have an outstanding role. Finally, the formation energy of the clusters and ab initio molecular dynamics simulations prove their structure has fine stability. This work not only offers high-performance electrode candidates for the NO3RR but also opens up a precedent of electrocatalysis in the field of wastewater treatment of explosives.


Systemic Mycoplasma synoviae infection in broiler chickens.
Systemic Mycoplasma synoviae infection in 47-day-old broiler chickens with septicaemic lesions and increased carcass condemnation rate is reported. The clinical history included respiratory signs and an enlarged keel bursa. Condemnations at the processing plant were due to airsacculitis and keel bursitis. Involvement of several organs, including the keel bursa, liver, spleen, brain, choroid of the eye, nerves and skeletal muscle associated with vasculitis, and the isolation of M. synoviae from the liver and keel bursa are only occasionally seen in field cases. Random amplified polymorphic DNA analysis of the M. synoviae isolated from the broiler chickens in this study had a different pattern when compared with the reference M. synoviae strains, WVU-1853, MS-H and F10-2AS, and another M. synoviae isolated from broiler breeders from the same company, but had a similar DNA pattern to an M. synoviae isolated from broiler chickens and turkeys owned by the same company. This finding suggests a horizontally acquired infection rather than vertical transmission.


Severe hypoglycemia in diabetic patients: frequency, causes, prevention.
Over a 12-mo period, the frequency of severe hypoglycemic episodes was measured in a population of approximately 400 (50% type I) diabetic patients treated with insulin. There were 32 severe insulin reactions in 26 patients, a patient-yr incidence of 8%. The major precipitating causes were patients' errors (nine), and too much insulin or a wrong combination (six). In seven cases no cause could be found. For the group as a whole there was clear evidence of overtreatment as measured by insulin doses (0.89 +/- 0.43 U/kg/day versus 0.65 +/- 0.34 U/kg/day in a convenience group of 100 patients from the same diabetic population [P less than 0.05] ). Furthermore, 6-12 mo after the event the mean insulin dose had decreased from 0.82 +/- 0.25 to 0.69 +/- 0.27 U/kg/day in the subgroup of 20 hypoglycemic patients that could be followed (P less than 0.001). The mean HbAlc levels of the hypoglycemic group and the control group differed significantly (8.1 +/- 1.3% versus 8.7 +/- 1.7%, P less than 0.05). Six to 12 mo after the reaction, the mean HbAlc level in the follow-up subgroup rose from 8.1 +/- 1.3% to 9.1 +/- 1.1% (P less than 0.05). Patients' errors as a cause of the insulin reaction were not only the result of the patients' deficient knowledge but more often of lack of alertness and carelessness. We conclude that it is not possible to prevent all the severe hypoglycemic reactions in diabetic patients. However, besides avoiding overtreatment by the physician, teaching patients to respond more adequately to changing circumstances in daily life or to warning signs could also reduce the incidence of hypoglycemia.


Proinflammatory Cytokine Dysregulation and Cognitive Dysfunction Among Patients with Remitted Bipolar I and II Disorders.
Euthymic patients with bipolar disorder reportedly demonstrated increased levels of proinflammatory cytokines and cognitive function deficits. Because uncertain differences exist in cognitive function and proinflammatory cytokines between remitted bipolar I (BD1) and bipolar II (BD2) disorders, we performed this study to further investigate these differences. We enrolled 58 patients with remitted BD1 and 27 with remitted BD2, and matched them for age and sex with 51 controls. Proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), C-reactive protein, and soluble tumor necrosis factor receptor 1 (sTNFR1) were measured, and performance in the Word List Memory Task (WLMT) and Wisconsin Card Sorting Task (WCST) was assessed. Significantly elevated levels of sTNFR1 were observed among patients with BD1 (p < .001) and BD2 (p = .038) compared with the controls; however, they did not differ between patients with BD1 and BD2 (p =.130). Working memory deficit measured by the WLMT was significantly greater in patients with BD1 (p < .001) and BD2 (p < .05) compared with controls, but did not differ between patients with BD1 and BD2 (p > 0.1). Furthermore, sTNFR1 levels were negatively correlated with cognitive function measured using the WLMT and WCST (all p < .05). Our results showed that euthymic patients with BD1 and BD2 showed similar levels of sTNFR1 and cognitive function (especially working memory) impairments. Further investigation is required to explore whether a common pathophysiology may contribute to the shared inflammatory and cognitive alterations between BD1 and BD2.


Pathways to the diagnosis of epithelial ovarian cancer in Australia.
To describe the diagnostic pathways experienced by a large, representative group of Australian women with ovarian cancer, and to document the time between first presentation to a medical professional and clinical diagnosis. 1463 women with epithelial ovarian cancer from an Australia-wide population-based study (2002-2005) completed a telephone interview in which they described the events that led to the diagnosis of their cancer. Number and type of doctors consulted, investigations performed, referral patterns and the time from first presentation to diagnosis. Of the 1463 women, 145 had their cancer diagnosed incidentally and were excluded from analysis. Most of the remaining 1318 women (1222, 93%) presented first to their general practitioner. As a result of their first medical consultation, 75 women (6%) were given a diagnosis, and 484 (37%) were referred to a gynaecologist, gynaecological oncologist or oncologist for further assessment. Overall, 85% of women visited three or fewer doctors before their cancer was diagnosed; 66% of cancers were diagnosed within 1 month of the initial presentation, and 80% were diagnosed within 3 months. For 12% of women, the diagnostic process took longer than 6 months; this was more likely for women residing in remote Australia, those with lower incomes, and those presenting with abdominal pain or bowel symptoms, or with more than one symptom. Despite anecdotal suggestions to the contrary, most women with ovarian cancer in Australia are investigated and diagnosed promptly. The diagnostic process is more protracted for a minority of women, and the factors we found to be associated with diagnostic delay warrant further investigation.


Prevalence of hypertension in the adult population of Belgium: report of a worksite study, Attention Hypertension.
Hypertension remains a major cause of cardiovascular morbidity in Belgium. Information on the prevalence of hypertension in the working population is desirable. A worksite study of hypertension prevalence was carried out in Belgium where 3472 individuals were screened for 1 week. The result was that high blood pressure (> or = 140/90 mm Hg) was identified in approximately one-third of the men and one-quarter of the women even though the majority of subjects had no recorded history of hypertension. Associations were identified between age and systolic blood pressure and, in men, between systolic blood pressure and alcohol consumption. Most participants in the survey were unaware of their serum cholesterol level. The results of this survey suggest that a large proportion of subjects with high blood pressure in the Belgian working population remain unidentified and indicate a lack of awareness about other cardiovascular risk factors.


Characterization and clinical utility of different collimator shapes in accelerator-based BNCT systems for head and neck cancer.
NeuCure® is the only accelerator-based boron neutron capture therapy (BNCT) system in the world with pharmaceutical approval. Until now, only flat collimators (FCs) on the patient side have been installed. However, in some cases of head and neck cancer patients, positioning the patient close enough to the collimator when using FCs was difficult. Thus, there are concerns about the prolongation of the irradiation time and overdose to normal tissues. To address these issues, a collimator with a convex-extended section on the patient side (extended collimators [ECs]) was developed, and its pharmaceutical approval was obtained in February 2022. This study evaluated the physical characterization and usefulness of each collimator using a simple geometry water phantom model and human model. In the water phantom model, the thermal neutron fluxes at 2 cm depth on the central axis were 5.13 × 108, 6.79 × 108, 1.02 × 109, and 1.17 × 109n/cm2/s for FC(120), FC(150), EC50(120), and EC100(120), respectively, when the distance from the irradiation aperture was kept constant at 18 cm. With ECs, the relative off-axis thermal neutron flux decreased steeply. In the hypopharyngeal cancer human model, the tumor dose changes were within <2%, but the maximum oral mucosa doses were 7.79, 8.51, 6.76, and 4.57 Gy-Eq, respectively. The irradiation times were 54.3, 41.3, 29.2, and 24.8 min, respectively. In cases where positioning the patient close to the collimator is difficult, the use of ECs may reduce the dose to normal tissues and shorten the irradiation time.


Adrenergic, cholinergic and peptidergic nerve fibres in dura mater--involvement in headache?
Nerve fibres containing noradrenaline, acetylcholinesterase, vasoactive intestinal polypeptide and substance P were demonstrated in the dura mater of guinea-pigs using histochemical and immunohistochemical methods. These fibres accompanied blood vessels of all size, indicating a vasomotor role. In addition, some nerve fibres were observed without any obvious relation to the blood vessels. The rich supply of nerve fibres to the various parts of the dura mater may possibly be of importance in the pathogenesis of some types of headache.


Rectosigmoid deep infiltrating endometriosis and ureteral involvement with loss of renal function.
Endometriosis is a complex disease with unclear pathogenesis, defined as the presence of endometrial tissue (glands and stroma) outside its usual location in the uterine cavity. Ureteral involvement is rare, with an estimated frequency of 10-14% in cases of deep endometriosis with nodules of 3 cm or larger. An important complication of ureteral involvement is asymptomatic loss of renal function. In a patient with asymptomatic renal failure the relevance of extrinsic ureteral involvement by deep endometriosis has been taken to account. A 32-year-old nulliparous woman presented with chronic pelvic pain associated with severe dysmenorrhea, dyspareunia and digestive problems including diarrhea, occasional constipation and rectal bleeding. She reported no urological symptoms. Magnetic resonance imaging (MRI) identified a 4 cm nodule in the recto-vaginal septum, compressing and infiltrating the rectal wall, and chronic left hydronephrosis. Isotope renogram revealed 91% function in the right kidney and 9% in the left kidney. A multidisciplinary surgical team including consultants from the departments of digestive surgery and urology assessed the patient. The treatment recommended was a joint approach of laparoscopic surgery to perform adhesiolysis, ureterolysis, freeing of the uterus and appendages, resection of the rectovaginal septum nodule, and left nephrectomy. Diagnosis and treatment of deep endometriosis should be performed in specialized centers and in the context of multidisciplinary collaboration. We must be aware of the potential risk of ureteral involvement and the asymptomatic loss of renal function in any patient with endometriosis nodules of 3 cm or larger.


Mechanisms of organ selective tumour growth by bloodborne cancer cells.
The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats. Following intravenous (i.v.) and intraportal (i.ptl.) injection of cells tumour colonies localized in lung and liver respectively due to tumour cell arrest. Arterially injected radiolabelled cells disseminated and arrested in a similar distribution to cardiac output and did not 'home' to any organs. Following arterial injection of unlabelled tumour cells colonies grew in many organs. While the pattern of growth for a particular tumour varied with the cell dose, the 'arterial patterns' for all of the tumours studied followed a similar pattern. Some organs (eg adrenals, ovaries and periodontal ligament) were consistently preferred, others (eg skin and skeletal muscle) only supported tumour growth following the delivery of large numbers of cells, while in some tissues (eg spleen and intestines) tumour never grew. Viable tumour cells could be demonstrated by bioassay in many organs for up to 24h after i.a. injection. However tumour growth only occurred in certain organs and the pattern of this growth was not related to the number of tumour cells arrested or their rate of autolysis. This site preference could be expressed quantitatively as the probability of an arrested cell developing into a tumour and was considered a 'soil effect'. Site preference was not directly related to organ vascularity. Organ colonisation was promoted by steroid treatment but the mechanism was unclear and was not secondary to T-cell immunosuppression or prostaglandin synthesis suppression. The adrenal glands were preferred sites of tumour growth but pharmacological manipulation of adrenal function did not alter tumour growth to this organ. Sites of injury and healing were preferred sites of tumour colonisation and this could not be accounted for by increased delivery of tumour cells to these regions. The possibility that the macrophage component of the inflammatory response promoted tumour growth was suggested from studies in which the interval between trauma and inoculation of tumour cells was varied as well as by promotion of intraperitoneal (i.p.) tumour growth by a macrophage infiltrate.


Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity.
In skeletal muscle, ceramides may be involved in the pathogenesis of insulin resistance through an attenuation of insulin signalling. This study investigated total skeletal muscle ceramide fatty acid content in participants exhibiting a wide range of insulin sensitivities. The middle-aged male participants (n=33) were matched for lean body mass and divided into four groups: type 2 diabetes (T2D, n=8), impaired glucose tolerance (IGT, n=9), healthy controls (CON, n=8) and endurance-trained (TR, n=8). A two step (28 and 80 mU m(-2) min(-1)) sequential euglycaemic-hyperinsulinaemic clamp was performed for 120 and 90 min for step 1 and step 2, respectively. Muscle biopsies were obtained from vastus lateralis at baseline, and after steps 1 and 2. Glucose infusion rates increased in response to insulin infusion, and significant differences were present between groups (T2D<IGT<CON<TR). At baseline, muscle ceramide content was 108+/-7, 95+/-6, 126+/-12 and 156+/-25 nmol total ceramide fatty acids/g wet weight of tissue in the T2D, IGT, CON and TR groups, respectively, and muscle ceramide content was higher (p<0.01) in the TR than the IGT group. Muscle ceramide content was not influenced by insulin infusion. Interestingly, a positive correlation (r=0.42, p<0.05) was present between muscle ceramide content at baseline and insulin sensitivity. Total muscle ceramide content was similar between individuals showing marked differences in insulin sensitivity, and therefore does not seem to be a major factor in muscle insulin resistance. Furthermore, aerobic capacity does not appear to influence muscle ceramide content.


Distribution of particle aggregates in the internodal axolemma and adaxonal Schwann cell membrane of rodent peripheral nerve.
Freeze-fracture studies on myelinated fibres from the internodal regions of rat and mouse sciatic nerve show symmetrical particle aggregates within the adaxonal Schwann cell plasmalemma and particle clusters in the axolemma. These are mainly confined to the vicinity of the internal mesaxon and the Schmidt-Lanterman incisures. The Schwann cell particle aggregates are concentrated as bands over the cytoplasmic pockets of Schmidt-Lanterman incisures and the paramesaxonal pockets. In the axolemma there are linear rows of particle aggregates along the groove related to the inner mesaxon and in bands to either side of it. The morphological features suggest the possibility of metabolic coupling between the axoplasm and the Schwann cell cytoplasm via the periaxonal space.


Orbital involvement of an extramedullary plasmacytoma.
A patient presenting with left-sided proptosis was found to have an EMP primary to the maxillary antrum with extenion into the orbital floor. The patient was in stage II, and myeloma protein was detectable. This protein was found to be the lambda-chain of IgG.


Coculture cells that express leukemia inhibitory factor (LIF) enhance mouse blastocyst development in vitro.
Leukemia inhibitory factor is a cytokine that plays an important role in implantation and enhances mouse preimplantation embryo development in vitro. Since leukemia inhibitory factor enhances early embryo development, we tested the hypothesis that coculture cells that express leukemia inhibitory factor would enhance mouse blastocyst development in vitro. In this study, Northern analysis for leukemia inhibitory factor was performed on total RNA extracted from Vero cells, human embryonic fibroblasts, and human placental fibroblasts. Two-cell mouse embryos were cultured to blastocyst in Ham's F-10 with 15% human cord serum (control) or with the coculture cells. Northern analysis demonstrated expression of LIF mRNA in Vero cells and embryonic fibroblasts but not in placental fibroblasts. Development to blastocyst was significantly enhanced in two-cell embryos cultured with Vero cells (86%, 140/163) and embryonic fibroblasts (83%, 118/142) when compared to controls (71%, 67/94, P < 0.05) or placental fibroblasts (71%, 95/134), P < 0.05). These data suggest that coculture cells that express leukemia inhibitory factor may be superior to nonleukemia inhibitory factor expressing cells for early preimplantation embryo development.


Electrophysiological Responses of the Beech Leaf-Mining Weevil, Orchestes fagi, to Seasonally-Variant Volatile Organic Compounds Emitted by American Beech, Fagus grandifolia.
The beech leaf-mining weevil, Orchestes fagi, is a common pest of European beech, Fagus sylvatica, and has recently become established in Nova Scotia, Canada where it similarly infests American beech, F. grandifolia. We collected volatile organic compounds (VOCs) emitted by F. grandifolia leaves at five developmental stages over one growing season and simultaneously analyzed them for volatile emissions and O. fagi antennal response using gas chromatography-electroantennographic detection (GC-EAD). Volatile profiles changed significantly throughout the growing season, shifting from primarily β-caryophyllene, methyl jasmonate, and simple monoterpene emissions to dominance of the bicyclic monoterpene sabinene during maturity. Two VOCs dominant during bud burst, (R)-(+)-limonene and geranyl-p-cymene, may be of biological relevance due to the highly specific oviposition period of O. fagi at this stage though antennal responses were inconclusive. Senescence showed a decrease in blend complexity with an increase in (Z)-3-hexenyl acetate and (Z)-3-hexen-1-ol as well as a resurgence of α-terpinene and geranyl-p-cymene. We present a novel electroantennal preparation for O. fagi. Antennae of both male and female O. fagi responded to the majority of detectable peaks for host volatiles presented via GC-EAD. Females displayed greater overall sensitivities and less specificity to host volatiles and it is hypothesized that this translates to more generalist olfaction than males. It is clear that olfactory cues are important physiologically though their implications on behaviour are still unknown. The results presented in this study provide a baseline and tools on which to connect the complex and highly time-specific phenology of both F. grandifolia and the destructive pest O. fagi through which olfactory-based lures can be investigated for monitoring systems.


Presumed adverse events in health care are a frequent indication for medico-legal autopsy in Finland.
The medico-legal autopsy is an essential tool in investigating deaths caused by an adverse event in health care, for both clinical risk management and for professional liability issues. However, there are no statistics available regarding the frequency of autopsies performed due to suspected adverse events. This study aimed to determine the number of medico-legal autopsies done because of presumed adverse events, whether these events were unintentional, medical errors or cases in which malpractice was suspected. Furthermore, differences in treatment types, causes and manner of death were analyzed. The data was obtained from all medico-legal autopsies performed in Northern Finland and Lapland during 2014-2015 (n = 2027). Adverse events were suspected in 181 (8.9%) cases. The suspicions of an adverse event occurring were most often related to medication, gastrointestinal surgery and orthopedic surgery. The manner of death was classified as medical (or surgical) treatment or investigative procedure in 22 (12.2%) cases. The causes of death were completely unrelated to the suspected adverse event in 41 (22.7%) cases. In conclusion, the frequency of presumed adverse events was quite high in this data set, but in the majority of the cases, the suspicion of an adverse event causing death was disproved by an autopsy. Nonetheless, proper investigation of these cases is essential to ensure legal protection of the deceased, next of kin and health care personnel, as well as to support clinical risk management.


The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: a pooled analysis of 12 randomised controlled trials.
Plant sterols (PS) are well known for their low-density lipoprotein cholesterol-lowering effect. Until recently, they were believed to have little or no impact on blood triglycerides (TG). However, studies taken individually were possibly lacking statistical power to detect modest TG decreases. This study was performed to quantify the TG-lowering effect of PS by pooling individual subject data from 12 randomised controlled trials that investigated the effects of PS on blood lipids. The main outcome variable was the control-adjusted PS effect on relative (%) and absolute (mmol/L) changes in TG. The relative and absolute changes in high-density lipoprotein cholesterol (HDL-C) were also assessed. Differences in changes of serum lipid concentrations between PS and control treatments were estimated by an ANCOVA using a random effect model which included PS intake (active or control), study and predefined subject characteristics. The twelve randomised controlled trials included in total 935 hypercholesterolaemic subjects not preselected based on their baseline TG concentrations. In most studies, the PS dose ranged between 1.6 and 2.5 g/day. PS intake significantly lowered serum TG by 6.0% (95% CI: -10.7, -1.2) or 0.12 mmol/L (95% CI: -0.20, -0.04). No significant interaction was observed between PS intake and baseline TG concentrations on relative changes, but, on absolute changes, interaction was significant with larger TG decreases observed with higher TG concentrations at baseline. No effects were observed on HDL-C concentrations. These results show that PS exert a modest TG-lowering effect which is dependent on baseline concentrations.


Prenatal prediction of neonatal haemodynamic adaptation after maternal hyperoxygenation.
The reactivity of the pulmonary vascular bed to the administration of oxygen is well established in the post-natal circulation. The vasoreactivity demonstrated by the fetal pulmonary artery Doppler waveform in response to maternal hyperoxia has been investigated. We sought to investigate the relationship between the reactivity of the fetal pulmonary arteries to hyperoxia and subsequent neonatal cardiac function in the early newborn period. This explorative study with convenience sampling measured pulsatility index (PI), resistance index (RI), acceleration time (AT), and ejection time (ET) from the fetal distal branch pulmonary artery (PA) at baseline and following maternal hyperoxygenation (MH). Oxygen was administered for 10 min at a rate of 12 L/min via a partial non-rebreather mask. A neonatal functional echocardiogram was performed within the first 24 h of life to assess ejection fraction (EF), left ventricular output (LVO), and neonatal pulmonary artery AT (nPAAT). This study was conducted in the Rotunda Hospital, Dublin, Ireland. Forty-six women with a singleton pregnancy greater than or equal to 31 weeks' gestational age were prospectively recruited to the study. The median gestational age was 35 weeks. There was a decrease in fetal PAPI and PARI following MH and an increase in fetal PAAT, leading to an increase in PA AT:ET. Fetuses that responded to hyperoxygenation were more likely to have a higher LVO (135 ± 25 mL/kg/min vs 111 ± 21 mL/kg/min, p < 0.01) and EF (54 ± 9% vs 47 ± 7%,p = 0.03) in the early newborn period than those that did not respond to MH prenatally. These findings were not dependent on left ventricular size or mitral valve (MV) annular diameter but were related to an increased MV inflow. There was no difference in nPAAT. These findings indicate a reduction in fetal pulmonary vascular resistance (PVR) and an increase in pulmonary blood flow and left atrial return following MH. The fetal response to hyperoxia reflected an optimal adaptation to postnatal life with rapid reduction in PVR increasing measured cardiac output.


[Preimplantation embryo development: current status and perspectives in clinical embryology].
Preimplantation embryo development is one of the key features with implantation itself to achieve a pregnancy. Assisted Reproductive Technologies (ART) both in human and animal have improved our knowledge on these events, although predicting embryo potential to give a baby remains elusive. However data from the last 10 years have allowed either to hierarchize the available parameters or to open some new perspectives to predict embryo developmental potential. Both kinetics and morphological parameters belong to noninvasive quality embryo assessment for many years, although recent data on microvideographic analysis and multivariate analysis led to reduce their biological meaning. Moreover, new technical detection of meiotic spindle birefringency or zona pellucida anisotropy has improved the oocyte quality assessment with a deep impact for countries with restrictive legislation. Beyond such morphological criteria, more functional approaches concerned the oocyte (embryo) or its environment. Direct transcriptomic analysis, while invasive and therefore experimental, brought important data on embryo "quality". However, noninvasive metabolomic or proteomic analysis of embryo media gave promising results as well as respirometry. The environment of the oocyte has focused a specific attention, either based on regulatory proteins or cytokines present in follicular fluid, or involving genes or proteins from cumulus cells, as oocyte-cumulus dialog is a key factor in oocyte maturation. Whereas it is not possible for the time being to predict which parameter(s) will be implemented routinely, all data obtained underline that the ability to develop and implant is not based on embryo superlatives (more rapid, expressing more genes or proteins, larger metabolites uptake) but rather on a quiet state, as claimed by Leese some years ago, where a lot of resources would not be mobilized by any stressful situation.


Intracellular "fibrous long spacing" collagen in morbus dupuytren (Dupuytren's contracture).
Fine structural analysis of 21 surgically removed specimens of Morbus Dupuytren (Dupuytren's contracture) in the cells of the proliferative phase revealed spindle-shaped or round, periodic banded structures of 1--1.5 micron size. These intracellular structures are surrounded by trilaminar membranes of 45 A continuous with membranes of the endoplasmic reticulum. The periodic banded structures display a light-dark pattern of 750--900 A and resemble with respect to periodicity and general morphology "fibrous long spacing" collagen. To date, "fibrous long spacing" collagen in human tissue has only been observed in the extracellular space, both in normal and pathologic conditions. Its formal pathogenesis is discussed.


Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials.
Whether supplemental vitamin D reduces risk of cancer or cardiovascular disease (CVD) is relatively unexplored in randomized trial settings. The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2 × 2 factorial trial of daily vitamin D3 (2000 IU) and marine omega-3 fatty acids (1 g) in the primary prevention of cancer and CVD among 25,871 U.S. men aged ≥50 and women aged ≥55, including 5106 African Americans. Median treatment duration was 5.3 years. Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR] = 0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up. Vitamin D did not significantly reduce the co-primary endpoint of major CVD events (HR = 0.97 [0.85-1.12]), other cardiovascular endpoints, or all-cause mortality (HR = 0.99 [0.87-1.12]). Updated meta-analyses that include VITAL and other recent vitamin D trials indicate a significant reduction in cancer mortality but not in cancer incidence or CVD endpoints. Additional research is needed to determine which individuals may be most likely to derive a net benefit from vitamin D supplementation. (VITAL clinicaltrials.gov identifier: NCT01169259).


Two new steroidal compounds from starfish Asterias amurensis Lutken.
Two new sulfated steroidal compounds (1 and 2), along with three known steroidal saponins (3, 4, and 5) were isolated from the starfish Asterias amurensis Lutken. The structures of new compounds were elucidated as 3beta-O-sulfated-cholest-5-ene-7alpha-ol (1) and (E) 25-O-beta-d-xylopyranosyl-26, 27-dinor-24(S)-methyl-22-ene-15alpha-O-sulfated-5alpha-cholest-3beta,6alpha-ol (2) by extensive NMR experiments and chemical evidence. Their effects on UMR106 cell proliferation were screened by MTT method. The results indicated that compounds 2 and 2a (0.01-100 microM) significantly promoted the osteoblastic proliferation. The initial structure-activity relationship analysis suggests that the sugar moiety is the necessary group for the activity.


Improved thermoregulation caused by forced water intake in human desert dwellers.
Residents of the Negev desert in Israel sustain a mild state of dehydration. Low, concentrated urine outputs, high incidence of kidney diseases and high hematocrit ratios characterize this population. Educational programs to increase the awareness of the population to the dangers of dehydration have undoubtedly failed. It was our purpose to see whether forced increased drinking will affect the above variables. Ten healthy subjects were asked to double their normal voluntary water intake without (phase II) and with salt supplements (50 mM NaCl, 20 mM KCl) (phase III), for one week. After phases II and III significant increases in body masses, decreased concentrations of serum proteins, hemoglobin, hematocrit ratios and serum osmolalities were found. No significant changes were found in the concentrations of sodium and potassium in the serum. At the end of each phase, the subjects were asked to exercise on a bicycle ergometer for 60 min at 50% VO2max in a heated chamber at 45 degrees C, and 30%-50% relative humidity. Experiments were terminated if and when heart-rates exceeded 180 bpm or the rectal temperature increased to 39 degrees C. After both experimental phases, subjects increased their tolerance to heat, extending the exercise periods by 25% and 30%. Compared with their starting levels, hematocrit ratios, serum proteins and hemoglobin concentrations increased in phases II and III while no changes were recorded in the control period (phase I). It is suggested that spontaneous voluntary water drinking in desert dwellers is not enough to achieve a true state of "euhydration".


Independent risk factors of mortality in patients with sepsis receiving single-dose etomidate as an induction agent during rapid sequence intubation in a large tertiary emergency department in Thailand.
There is limited evidence regarding factors associated with mortality in septic patients receiving etomidate. This study aimed to determine independent pre-intubation factors predicting 28-day mortality in septic patients receiving single-dose etomidate as an induction agent during rapid sequence intubation (RSI). This single-center retrospective cohort study included intubated septic patients receiving etomidate as an induction agent during RSI in the emergency department of Siriraj hospital, Bangkok, Thailand, between January 1st, 2016 and June 30th, 2020. Pre-intubation characteristics were compared between survivors and non-survivors. Independent risk factors associated with 28-day mortality were identified using the Cox proportional hazards regression model. Association between etomidate dosage and mortality was also determined. A total of 344 patients, 238 (69%) survivors and 106 (31%) non-survivors, were included in the analyses. The initial Cox hazards model identified a pre-intubation lactate level ≥ 4 mmol/L as an independent factor associated with mortality (adjusted Hazards ratio [aHR] 2.66, 95% confidence interval [CI] 1.55-4.56). After removing lactate level from the model due to limited lactate values in the data, cancer was also predictive of 28-day mortality (aHR 1.83, 95%CI 1.10-3.04), while patients with respiratory infections and underlying chronic lung disease were associated with lower mortality (aHR 0.54, 95%CI 0.37-0.80 and aHR 0.57, 0.33-0.96, respectively). Etomidate dosage was not associated with mortality in our study. In septic patients who received a single dose of etomidate, a pre-intubation lactate level ≥ 4 mmol/L and cancer were associated with increased 28-day mortality, while respiratory infection and underlying chronic lung disease were associated with lower mortality. Physicians may take these factors into consideration when selecting induction agents for septic patients.


Expression, purification, characterization, and cytotoxic evaluation of the ML1-STxB fusion protein.
Targeted delivery of a toxin substance to cancer cells is one of the most recent cancer treatment options. Mistletoe Lectin-1 (ML1) in Viscum album L. is a Ribosome-inactivating proteins with anticancer properties. Therefore, it appears that a recombinant protein with selective permeability can be generated by fusing ML1 protein with Shiga toxin B, which can bind to Gb3 receptor that is abundantly expressed on cancer cells. In this study, we sought to produce and purify a fusion protein containing ML1 fused to STxB and evaluate its cytotoxic activities. The ML1-STxB fusion protein coding sequence was cloned into the pET28a plasmid, then was transformed into E. coli BL21-DE3 cells. Following induction of protein expression, Ni-NTA affinity chromatography was used to purify the protein. Using SDS-PAGE and western blotting, the expression and purification processes were validated. On the SkBr3 cell line, the cytotoxic effects of the recombinant proteins were evaluated. On SDS-PAGE and western blotting membrane, analysis of purified proteins revealed a band of approximately 41 kDa for rML1-STxB. Ultimately, statistical analysis demonstrated that rML1-STxB exerted significant cytotoxic effects on SkBr3 cells at 18.09 and 22.52 ng/L. The production, purification, and encapsulation of rML1-STxB fusion protein with potential cancer cell-specific toxicity were successful. However, additional research must be conducted on the cytotoxic effects of this fusion protein on other malignant cell lines and in vivo cancer models.


Amelioration of the hepatotoxic effects of nonsteroidal drugs using vitamin C and determination of their relationship with the lipid profile.
Despite the various clinical benefits of nonsteroidal anti-inflammatory drugs, their frequent and prolonged use has led to numerous health risks, including hepatotoxicity. Hepatotoxicity mediated by oxidative stress can affect the lipid profile. The objective was to investigate whether post-treatment with vitamin C can ameliorate the effects of diclofenac and naproxen in the livers of prepubertal rats and to highlight their relationship with lipid profile. Forty prepubertal female albino rats were distributed among the control group, the diclofenac-administered group (5 mg/kg/day), and the naproxen-administered group (50 mg/kg/day). This study included two phases. In Phase 1, only five rats from each group were dissected after 21 days of oral administration to assess the hepatotoxic effects of nonsteroidal drugs. In Phase 2, five of the remaining animals in each intervention group were post-treated with 25 mg/kg/day of vitamin C for an additional 21 days. After the administration and post-treatment, serum biochemical parameters and histopathological signs were evaluated. Extreme elevation in the levels of aspartate and alanine aminotransferases was observed in the diclofenac and naproxen groups compared with those in the control (p < 0.001). In addition, the levels of high- and low-density lipoproteins were significantly impacted in these drug groups (p < 0.01, p < 0.05 respectively). Several pathological signs in the liver histology were observed in both drug groups. After post-treatment with vitamin C, noticeable amelioration of these alterations was observed. There were slightly elevation in the liver enzymes and insignificant increase and decrease in the high and low-density lipoproteins respectively. Vitamin C post-treatment ameliorated the hepatotoxicity induced by diclofenac sodium and naproxen.


Erythrocyte-biomimetic nanosystems to improve antitumor effects of paclitaxel on epithelial cancers.
Chemotherapy is a difficult treatment for cancer patients because of the low effective accumulation of chemo-drugs and their detrimental side effects. Nanoparticles have shown promise as a solution to these problems. However, the known differences in the porosity and vascularization of tumor vessels, and other factors, including the potential formation of a "protein crown," the short half-life time in circulation, and the low drug distribution, often limit their application. To address these problems, biomimetic nanoparticles coated with cell membranes have been developed and shown to have advantages such as prolonged circulation, high biocompatibility, and enhanced targeting abilities in drugs and nanoparticles, thus exhibiting good application prospects in cancer therapy for liver, lung, and melanoma cancers. Accordingly, we designed a PH-sensitive biomimetic nanodrug delivery system with a delicate "core-shell" structure based on red blood cell membranes. Briefly, core nanoparticles were synthesized by the self-assembly of natural amphoteric polymers, including hydrophilic carboxymethylcellulose sodium and hydrophobic stearic acid. For the shell structure, red blood cell membranes were modified using folic acid by a lipid tether (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) to increase tumor-targeting ability, whereas polyethylene glycol was inserted to decrease lipid tether modification-induced potential sequestration by either the mononuclear phagocyte system or the reticuloendothelial system. Via a series of formulation optimizations, paclitaxel was packaged into the red blood membrane-based core-shell nanoparticles with an average size of 226.9 ± 2.75 nm and a negative Zeta potential of -14.5 ± 0.3 mV. More importantly, the examinations focusing on CD47, a representative red blood cell membrane protein, revealed not only the successful establishment of the membrane shell but also the right-side-out membrane orientation on our core-shell nanoparticles. Our nanodrug delivery system showed good biocompatibility and sensitivity to acidic tumor microenvironments while effectively prolonging the circulation time of paclitaxel and further enhancing its antitumor effects on epithelial malignancies, including liver, lung, and melanoma cancers. In particular, our nanodrug delivery system significantly alleviated paclitaxel-induced renal toxicity. Taken together, our findings highlight that the red blood membrane-based core-shell nanoparticle is a promising biomimetic nanodrug delivery system for functionally delivering chemotherapeutic drugs, and it has promise in clinical applications.


Correction: Frankincense essential oil suppresses melanoma cancer through down regulation of Bcl-2/Bax cascade signaling and ameliorates heptotoxicity via phase I and II drug metabolizing enzymes.
[This corrects the article DOI: 10.18632/oncotarget.26930.].


Preference For Cervical Cancer Education: A Multisite Cross-Sectional Survey of Female Senior High School Students in Ghana.
Cervical cancer incidence continues to rise in Ghana. To enhance knowledge and prevention of cervical cancer among young people in Ghana, there is a need to better understand their education preferences. The study aimed to describe female senior school students' preferences for receiving cervical cancer education. A cross-sectional survey of students from 17 schools in the Ashanti Region of Ghana assessed the strength of preference for receiving cervical cancer education from a range of sources, settings and delivery mediums. Of the 2400 participants (aged 16-24 years), the majority endorsed doctors (87%, 95%CI: 85-88%), nurses (80%, 95%CI: 78-82%) and credible health organisations (78%, 95%CI%: 76-79%) as their preferred source of education, and hospitals 83% (95%CI: 81-84%) as the preferred setting. Nearly all students (92%) endorsed at least three cervical cancer education delivery mediums, with at least three quarters endorsing television (78%, 95%CI: 77-80%), one-on-one health consultation in-person or online (77%, 95%CI: 75-79%; 75%, 95%CI: 73-77%), and health information websites (75%, 95%CI: 73-77%). Findings suggest that cervical cancer education efforts among female senior school students in Ghana should consider the use of a range of more resource-intensive individualised approaches to low-cost anonymous, generic approaches from credible sources and institutions.


How Does Misinformation and Capricious Opinions Impact the Supply Chain - A Study on the Impacts During the Pandemic.
Misinformation or fake news has had multifaceted ramifications with the onset of the Covid-19 pandemic, creating widespread panic amongst people. This study investigates the impact of misinformation/ fake news (on internet platforms) on consumer buying behavior, impact of fear (created by fake news) on hoarding of essential products and consumer spending and finally impact of misinformation-induced panic buying on supply chain disruptions. It draws upon the consumer decision theory and the cognitive load theory for explaining the psychological and behavioral responses of consumers. The study follows an inductive approach towards theory building using a multi-method approach. Initially, a qualitative research method based on interviews followed by text-mining has been used followed by analysis using python for topic modelling using Latent Dirichlet Allocation (LDA). The findings revealed several prominent themes like consumer shift to online buying, two contrasting spending intentions namely financial security and compensatory consumptions, irrational panic buying, uncertainty/ambiguity of government protocol and norms, social media fraudulent practices and misinformation dissemination, personalized buying experience, reduced trust on news and marketers, logistics and transportation bottlenecks, labor shortage due to migration and plant closures, and bullwhip effect in supply chains.


Arachidonic acid metabolism in platelets stored for 5 days.
(C-14)-Arachidonic acid [(C-14)-AA] metabolism was studied in platelet concentrates (PCs) stored for 5 d. There was a gradual decrease in uptake of radioactivity from day 0 to 3 (P less than 0.01). On day 0, distribution of radioactivity in platelet phospholipids (PLs), and formation of phosphatidic acid, HETE and cyclooxygenase products, when platelets were exposed to thrombin (5 U/ml), were similar to that reported for fresh platelets. On day 3 there was a change in the distribution of (C-14)-AA in platelet PLs which consisted of an increase in the percentage of radioactivity bound to phosphatidylserine, from 5.3 +/- 0.9% on day 0 to 8.8 +/- 1.5% on day 3 (P less than 0.001), and a decrease in (C-14)-AA in phosphatidylinositol (PI), from 12.4 +/- 1.5% on day 0, to 7.9 +/- 0.9% on day 3 (P less than 0.001). Phosphatidic acid generated by thrombin-stimulated platelets on day 0, comprised 2.6 +/- 0.5% of total radioactivity, but dropped to 1.4 +/- 0.3% on day 3 (P less than 0.001), and 0.9 +/- 0.2% on day 5 (P less than 0.01). These values showed a good correlation with the percentage of (C-14)-AA released from PI on the same days (r = 0.9). On day 0, 13.4 +/- 4.4% of platelet radioactivity was released from phosphatidylcholine by thrombin, but this amount was reduced to 6.8 +/- 3.4% on day 5 (P less than 0.05). Generation of radioactive 12-hydroxy-5,8,10,14-eicosatetraynoic acid (HETE) also dropped from 7.2 +/- 2.9 on day 0, to 2.1 +/- 1 on day 5 (P less than 0.01). We could not detect changes in cyclooxygenase metabolites. In conclusion, we suggest that various enzymatic pathways implicated in AA metabolism by platelets are impaired by storage.


uPAR and cathepsin B downregulation induces apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma.
Cathepsin B and urokinase plasminogen activator receptor (uPAR) are postulated to play key roles in glioma invasion. Calcineurin is one of the key regulators of mitochondrial-dependent apoptosis, but its mechanism is poorly understood. Hence, we studied subcellular localization of calcineurin after transcriptional downregulation of uPAR and cathepsin B in glioma. In the present study, efficient downregulation of uPAR and cathepsin B increased the translocation of calcineurin A from the mitochondria to the cytosol, decreased pBAD (S136) expression and its interaction with 14-3-3ζ and increased the interaction of BAD with Bcl-xl. Co-depletion of uPAR and cathepsin B induced mitochondrial translocation of BAD, activation of caspase 3 as well as PARP and cytochrome c and SMAC release. These effects were inhibited by FK506 (10 μM), a specific inhibitor of calcineurin. Calcineurin A was co-localized and also co-immunoprecipitated with Bcl-2. This interaction decreased with co-depletion of uPAR and cathepsin B and also with Bcl-2 inhibitor, HA 14-1 (20 μg/ml). Altered localization and interaction of calcineurin A with Bcl-2 was also observed in vivo when uPAR and cathepsin B were downregulated. In conclusion, downregulation of uPAR and cathepsin B induced apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma.


Risk-taking and fairness among cocaine-dependent patients in dual diagnoses: Schizophrenia and Anti-Social Personality Disorder.
This study reports experimental results from a clinical sample of patients with a cocaine-related disorder and dual diagnosis: Schizophrenia and Anti-Social Personality Disorder. Both types of patients as well as a non-clinical group of students performed two incentivized decision-making tasks. In the first part of the experiment, they performed a lottery-choice task in order to elicit their degree of risk aversion. In the second part, they decided in two modified dictator games aimed at eliciting their aversion to advantageous and disadvantageous inequality. It is found that the Anti-Social Personality Disorder group exhibits no significant differences from the non-clinical sample in either task. However, compared with the students' sample, subjects from the group with schizophrenia show more risk aversion and exhibit more aversion towards disadvantageous inequality.


Acetylsalicylic acid desensitization in patients with coronary artery disease: A comprehensive overview of currently available protocols.
Acetylsalicylic acid (ASA) represents the basis of pharmacological therapy for cardiovascular prevention. However, several patients are excluded from the benefits of ASA for hypersensitivity problems, and controversies still exist on their management. The aim of present study was to evaluate the safety and efficacy of ASA desensitization protocols in patients requiring dual antiplatelet therapy for coronary artery disease. Literature archives and main scientific sessions' abstracts were scanned for studies describing desensitization protocols for patients with ASA hypersensitivity. Primary endpoint was the tolerance of ASA maintenance therapy (protocol success). Secondary endpoints were: 1) the occurrence of hypersensitivity symptoms during the protocol, 2) the rate of ASA discontinuation at follow-up; 3) recurrent cardiovascular ischemic events. We finally selected 14 studies out of 335 initially screened citation, reporting complete data on protocol desensitization strategies, with a total of 256 patients. Among them 213 (83.2%) underwent an oral desensitization protocol, while 43 received endovenous ASA. The protocol was successfully completed in 238 out of 256 patients (92.9%), who were subsequently kept on chronic daily therapy with ASA. The weighted success proportion was wP [95%CI] = 93[89.8–96.1]%. Hypersensivity symptoms occurred during the desensitization protocol in 29 patients, with a pooled events rate of 11.3[7.5–15.2]%. All adverse reactions were safely faced with pharmacological interventions. In 11 of these patients, slowing the protocol or restarting another ASA challenge could successfully achieve the tolerance. The rate of ASA discontinuation and major cardiovascular events was extremely low (6.1 and 2.3% respectively). Aspirin desensitization protocols represent a safe and effective option for the management of patients with a cardiovascular indication to ASA and history of allergy to ASA. Future randomized trials are certainly needed to confirm present findings and provide indications for the optimization of these protocols.


Putting Meaning Back Into the Mean: A Comment on the Misuse of Elementary Statistics in a Sample of Manuscripts Submitted to Clinical Therapeutics.
Errors in the statistical presentation and analyses of data in the medical literature remain common despite efforts to improve the review process, including the creation of guidelines for authors and the use of statistical reviewers. This article discusses common elementary statistical errors seen in manuscripts recently submitted to Clinical Therapeutics and describes some ways in which authors and reviewers can identify errors and thus correct them before publication. A nonsystematic sample of manuscripts submitted to Clinical Therapeutics over the past year was examined for elementary statistical errors. Clinical Therapeutics has many of the same errors that reportedly exist in other journals. Authors require additional guidance to avoid elementary statistical errors and incentives to use the guidance. Implementation of reporting guidelines for authors and reviewers by journals such as Clinical Therapeutics may be a good approach to reduce the rate of statistical errors.


Exogenous Strigolactones alleviate KCl stress by regulating photosynthesis, ROS migration and ion transport in Malus hupehensis Rehd.
In recent years, the application of large amounts of potash fertilizer in apple orchards leads to worsening KCl stress. Strigolactone (SL), as a novel phytohormone, reportedly participates in plant tolerance to NaCl and drought stresses. However, the underlying mechanism and the effects of exogenous SL on the KCl stress of apple seedlings remain unclear. We sprayed different concentrations of exogenous SL on Malus hupehensis Rehd. under KCl stress and measured the physiological indexes like, photosynthetic parameter, content of ROS, osmolytes and mineral element. In addition, the expressions of KCl-responding genes and SL-signaling genes were also detected and analyzed. Application of exogenous SL protected the chlorophyll and maintained the photosynthetic rate of apple seedlings under KCl stress. Exogenous SL strengthened the enzyme activities of peroxidase and catalase, thereby eliminating reactive oxygen species production induced by KCl stress, promoting the accumulation of proline, and maintaining osmotic balance. Exogenous SL expelled K+ outside of the cytoplasm and compartmentalized K+ into the vacuole, increased the contents of Na+, Mg2+, Fe2+, and Mn2+ in the cytoplasm to maintain the ion homeostasis under KCl stress. Exogenous SL can regulate photosynthesis, ROS migration and ion transport in apple seedlings to alleviate KCl stress.


Complete genome sequence of a new bipartite begomovirus infecting fluted pumpkin (Telfairia occidentalis) plants in Cameroon.
The complete genome sequence was determined and characterized for a previously unreported bipartite begomovirus from fluted pumpkin (Telfairia occidentalis, family Cucurbitaceae) plants displaying mosaic symptoms in Cameroon. The DNA-A and DNA-B components were ~2.7 kb and ~2.6 kb in size, and the arrangement of viral coding regions on the genomic components was like those characteristic of other known bipartite begomoviruses originating in the Old World. While the DNA-A component was more closely related to that of chayote yellow mosaic virus (ChaYMV), at 78 %, the DNA-B component was more closely related to that of soybean chlorotic blotch virus (SbCBV), at 64 %. This newly discovered bipartite Old World virus is herein named telfairia mosaic virus (TelMV).


Effects of DK-002, a synthesized (6aS,cis)-9,10-Dimethoxy-7,11b-dihydro-indeno[2,1-c]chromene-3,6a-diol, on platelet activity.
In the present study, the mechanism of antiplatelet activity of DK-002, a synthesized (6aS,cis)-9,10-Dimethoxy-7,11b-dihydro-indeno[2,1-c]chromene-3,6a-diol, was investigated. DK-002 inhibited the thrombin, collagen, and ADP-induced rat platelet aggregation in a concentration-dependent manner, with IC50 values of 120, 27, and 47 microM, respectively. DK-002 also inhibited thrombin-induced dense granule secretion, thromboxane A2 synthesis, and [Ca2+]i elevation in platelets. DK-002 did not show any significant effect on ADP-induced inhibition of cyclic AMP elevation by prostaglandin E1, but DK-002 was confirmed to inhibit ADP-induced [Ca2+]i elevation and shape change. DK-002 inhibited 4-bromo-A23187-induced [Ca2+]i elevation in the presence of creatine phosphate/creatine phosphokinase (CP/CPK, a ADP scavenging system) and indomethacin (a specific inhibitor of cyclooxygenase). DK-002 also inhibited Ca2+ mobilization in thrombin- or 4-bromo-A23187-stimulated platelets through its inhibitory effects on both Ca2+ release from intracellular stores and Ca2+ influx, in the presence of CP/CPK and indomethacin. Taken together, the present study shows that DK-002 has inhibitory effects on stimulation of platelets, and suggests that its antiplatelet activity might be related to the inhibitory mechanism on Ca2+ mobilization in stimulated platelets.


Sensitization of T and B cells by a normally tolerogenic macromolecule: the induction of unresponsiveness and of sensitization is polymorphic.
Changes induced in B and T cells by tolerogen were experimentally defined in animals which resist down-regulation. Female A/J, C57BL/6J, MLR/MpJ-lpr/lpr, MLR/MpJ-+/+ and NZB/B1NJ mice were injected at various ages with a tolerogenic form of rabbit gamma globulin (sRGG) or were left uninjected, and all were then immunized with dinitrophenylated RGG (DNP-RGG) on alum. The degree of tolerance was estimated by measuring anti-DNP and anti-RGG spleen plaque-forming cell (PFC) numbers. In some cases, the state of T or B cells deduced from these experiments was further examined by cell transfer experiments. Four types of responsiveness to the tolerogenic form of RGG (sRGG) were distinguished: 1) persistent tolerance inducibility of T and B cells to tolerance induction (A/J); 2) T cells retaining tolerance-inducibility after initiation of age-dependent sensitization of B cells by the tolerogenic form of RGG (C57BL/6J, NZB/B1NJ); 3) age-dependent resistance of T cells to tolerance-induction and age-dependent sensitization of B cells by tolerogen, with the sensitization only manifesting itself in reactivity with T cells from immunized donors (SJL/J); and 4) sensitization of T cells by a usually tolerogenic form of RGG (MLR/MpJ-lpr-lpr). Thus, the development of resistance against tolerance induction is highly polymorphic, not only with respect to the age of onset, but also with respect to the cellular site of its first manifestation and the effect. Possible mechanisms of B-cell sensitization in sRGG-treated C57BL/6 and NZB mice are discussed in relation to the age-dependent emergence of a B-cell subpopulation and of non-specific helper T-cell factors.


Antenatal care and skilled delivery service utilisation in Somali pastoral communities of Eastern Ethiopia.
To assess maternal health care service utilisation and associated factors in Somali pastoral communities of eastern Ethiopia. Community-based cross-sectional study complemented by qualitative assessments in Adadle district, Somali region, eastern Ethiopia, among 450 women in six kebeles from August to September 2016. Logistic regression was used to assess factors associated with antenatal care use and skilled delivery care use, controlling for confounders. About 27% [95%CI 22.8-31.2%] of women used antenatal care, and 22.6% [95%CI 18.7-26.5%] received skilled delivery service. None of the respondents reported post-natal care. About 43% reported that they had no knowledge of antenatal care, and 46% did not perceive delivery at a health facility as important. Pastoral lifestyle, husband's educational status, women's attitude towards health care service and financial support from the husband were significantly associated with antenatal care utilisation. Health professionals' attitudes, perceptions of institutional delivery, antenatal care utilisation and information about exemptions from maternal health care fees were associated with skilled delivery service utilisation. Improving community awareness of antenatal care, employing female health professionals and culturally adapted guidelines could improve skilled delivery utilisation. In a patriarchal society, involving male partners in all maternal health issues is essential to increase use of maternal health services and to decrease maternal mortality.


6-O-Veratroyl catalpol suppresses pro-inflammatory cytokines via regulation of extracellular signal-regulated kinase and nuclear factor-κB in human monocytic cells.
The compound 6-O-veratroyl catalpol (6-O) is a bioactive iridoid glucoside that was originally isolated from Pseudolysimachion rotundum var. subintegrum. It has been demonstrated that catapol derivative iridoid glucosides including 6-O, possess anti-inflammatory activity in carragenan-induced paw edema mouse model as well as bronchoalveolar lavage fluid of ovalbumin-induced mouse model. In the present study, we investigated whether 6-O modulates inflammatory responses in THP-1 monocytic cells stimulated with phorbol12-myristate-13-acetate (PMA). Our data showed that 6-O inhibited PMA induced interleukin (IL)-1β and tumor necrosis factor (TNF)-α expression in THP-1 monocytic cells. Mechanistic studies revealed that 6-O suppressed the activity of protein kinase C (PKC), which further resulted in downstream inactivation of extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB) inflammatory pathway. The results implied that 6-O may protect against inflammatory responses that could be a potential compound in treating inflammatory diseases.


Effects of vanadate on ouabain binding and inhibition of (Na+ + K+)-ATPase.
Effects of vanadate on ouabain binding and inhibition of sodium and potassium adenosine triphosphatase (Na+ + K+)-ATPase) were investigated under various ionic conditions. 1. Vanadate facilitated ouabain binding to (Na+ + K+)-ATPase in the presence of Mg2+ and this facilitation was partially reversed by catechol. 2. Vanadate antagonized the ability of high concentrations of NaCl to inhibit ouabain binding in the presence of magnesium. 3. Ouabain binding to the vanadate-enzyme complex, formed from magnesium and vanadate, was more sensitive to depression by potassium than that to the phosphoenzyme formed from magnesium and inorganic phosphate. 4. Preincubation of (Na+ + K+)-ATPase with vanadate in the presence of magnesium initially formed a potassium-insensitive complex as shown by a rapid initial rate of ouabain binding. However, within 5 min potassium overcame the vanadate potentiation of ouabain binding regardless of the order in which it was added to the reaction mixture. 5. Under conditions of enzyme turnover, vanadate failed to antagonize the inhibitory power of ouabain despite the presence of a high concentration of potassium. This suggests a possible relationship between the sensitivity of the sodium pump in various tissues to the cardiac glycosides and intracellular vanadate concentrations.


Purification of five azaspiracids from mussel samples contaminated with DSP toxins and azaspiracids.
Human intoxications during toxic episodes in shellfish are a very important concern for public health, as well as for economic interests of producer regions. Although initially each toxin appeared in a determined geographical zone, nowadays many of them are found in multiple places worldwide. In addition, more toxic compounds (new toxins or new analogs of known toxins) are being isolated and identified, which bring about new risks for public health. An example of this situation is the group of azaspiracids (AZAs). Initially these toxins were concentrated in Irish coasts but today appear in many different geographic locations; in the first toxic episode only three analogs were isolated, but now it is known that the group is comprised of at least eleven identified compounds. A substantial problem associated with all these new toxins is the extreme difficulty associated with the study of their toxic effects and mechanisms of action due to the very small quantities of purified toxin available. Therefore, the study of procedures to isolate them from contaminated shellfish or to synthesize them is of tremendous importance. In this paper we design a complete procedure to obtain AZAs analogs from mussels contaminated with DSP toxins and azaspiracids by means of three consecutive steps: an extraction procedure to remove toxins from shellfish, a solid phase extraction (SPE) to clean the samples and separate DSP toxins and AZAs, and a preparative HPLC to isolate each analog. In all the steps LC/MS is used to detect and quantify the toxins. Large amounts of AZA1, AZA2, AZA3, AZA4 and AZA5 were obtained by use of this procedure, which can be utilized in future studies relating to the toxins such as the production of certified materials and standards.


Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid-Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms.
Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug product's shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.


Hyperuricemia: a novel old disorder-relationship and potential mechanisms in heart failure.
Uric acid, the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is an old emerging metabolic disorder, and interaction among uric acid and cardiovascular diseases has been clearly described. Several illness including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related with uric acid levels increase. In this review, we will discuss the pathophysiology of hyperuricemia and describe the biological plausibility for this metabolite to participate in the pathogenesis of cardiovascular disorders. In particular, we will focus on the implications of hyperuricemia in the onset and progression of heart failure, paying special attention to the pathophysiology and the possible clinical implications. We will conclude by discussing the effects of lowering plasma uric acid concentration on the prognosis of heart failure by reviewing most of available data on the different classes of drugs directly or indirectly involved in the hyperuricemia management.


A clinical evaluation of the pharmacokinetics and pharmacodynamics of intravenous alfaxalone in cyclodextrin in male and female rats following a loading dose and constant rate infusion.
To characterise, as a clinical study, the pharmacokinetics and pharmacodynamics and describe the hypnotic effect of the neurosteroid alfaxalone (3α-hydroxy-5 α-pregnane-11, 20-dione) formulated with 2-hydroxypropyl-β-cyclodextrin in male and female rats. Prospective, experimental laboratory study. A total of 12 (six male and six female) adult, aged-matched Sprague Dawley rats. Surgery and instrumentation was performed under isoflurane anaesthesia in an oxygen/nitrous oxide mixture (1:2) and local anaesthetic infiltration. All animals received a loading dose (1.67 mg kg-1 minute-1) for 2.5 minutes followed by a constant rate infusion (0.75 mg kg-1 minute-1) for 120 minutes of alfaxalone. Isoflurane and nitrous oxide was discontinued 2.5 minutes after the alfaxalone infusion started. Cardiorespiratory variables (heart rate, respiratory rate, arterial blood pressure and end tidal carbon dioxide tension) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Carotid artery blood samples were collected at strategic time points for blood gas analysis, haematology, biochemistry, and plasma concentrations of alfaxalone. Plasma samples were assayed using liquid chromatography-mass spectrometry. There were significant differences between the sexes for plasma clearance (p=0.0008), half-life (p=0.0268) and mean residence time (p=0.027). Mean arterial blood pressure was significantly higher in the male rats (p=0.0255). This study confirms that alfaxalone solubilised in 2-hydroxypropyl-β-cyclodextrin provides excellent total intravenous anaesthesia in rats. Sex-based differences in pharmacokinetics and pharmacodynamics were demonstrated and must be considered when designing biomedical research models using alfaxalone.


Evaluating the utility of the Threshold of Toxicological Concern (TTC) and its exclusions in the biocompatibility assessment of extractable chemical substances from medical devices.
The Threshold of Toxicological Concern (TTC) is a pragmatic approach used to establish safe thresholds below which there can be no appreciable risk to human health. Here, a large inventory of ~45,000 substances (referred to as the LRI dataset) was profiled through the Kroes TTC decision module within Toxtree v3.1 to assign substances into their respective TTC categories. Four thousand and two substances were found to be not applicable for the TTC approach. However, closer examination of these substances uncovered several implementation issues: substances represented in their salt forms were automatically assigned as not appropriate for TTC when many of these contained essential metals as counter ions which would render them TTC applicable. High Potency Carcinogens and dioxin-like substances were not fully captured based on the rules currently implemented in the software. Phosphorus containing substances were considered exclusions when many of them would be appropriate for TTC. Refinements were proposed to address the limitations in the current software implementation. A second component of the study explored a set of substances representative of those released from medical devices and compared them to the LRI dataset as well as other toxicity datasets to investigate their structural similarity. A third component of the study sought to extend the exclusion rules to address application to substances released from medical devices that lack toxicity data. The refined rules were then applied to this dataset and the TTC assignments were compared. This case study demonstrated the importance of evaluating the software implementation of an established TTC workflow, identified certain limitations and explored potential refinements when applying these concepts to medical devices.


The Higgs field and the resolution of the Cosmological Constant Paradox in the Weyl-geometrical Universe.
The nature of the scalar field responsible for the cosmological inflation is found to be rooted in the most fundamental concept of Weyl's differential geometry: the parallel displacement of vectors in curved space-time. Within this novel geometrical scenario, the standard electroweak theory of leptons based on the SU(2) L ⊗U(1) Y as well as on the conformal groups of space-time Weyl's transformations is analysed within the framework of a general-relativistic, conformally covariant scalar-tensor theory that includes the electromagnetic and the Yang-Mills fields. A Higgs mechanism within a spontaneous symmetry breaking process is identified and this offers formal connections between some relevant properties of the elementary particles and the dark energy content of the Universe. An 'effective cosmological potential': Veff is expressed in terms of the dark energy potential: [Formula: see text] via the 'mass reduction parameter': [Formula: see text], a general property of the Universe. The mass of the Higgs boson, which is considered a 'free parameter' by the standard electroweak theory, by our theory is found to be proportional to the mass [Formula: see text] which accounts for the measured cosmological constant, i.e. the measured content of vacuum-energy in the Universe. The non-integrable application of Weyl's geometry leads to a Proca equation accounting for the dynamics of a ϕρ -particle, a vector-meson proposed as an an optimum candidate for dark matter. On the basis of previous cosmic microwave background results our theory leads, in the condition of cosmological 'critical density', to the assessment of the average energy content of the ϕρ -excitation. The peculiar mathematical structure of Veff offers a clue towards a very general resolution of a most intriguing puzzle of modern quantum field theory, the 'Cosmological Constant Paradox' (here referred to as the 'Λ-Paradox'). Indeed, our 'universal' theory offers a resolution of the Λ-Paradox for all exponential inflationary potentials: VΛ (T,ϕ)∝e-nϕ , and for all linear superpositions of these potentials, where n belongs to the mathematical set of the 'real numbers'. An explicit solution of the Λ-Paradox is reported for n=2. The resolution of the Λ-Paradox cannot be achieved in the context of Riemann's differential geometry.This article is part of the themed issue 'Second quantum revolution: foundational questions'.


Microsurgical rat varicocele model.
A rat varicocele model using partial occlusion of the left renal vein was described previously. Reproducibility in creating this model has met with varied success. Alternate routes of testicular venous drainage may negate the effect of partial renal vein occlusion on varicocele creation. We hypothesized that varicocele induction would be more effective if microsurgical ligation of the gonadal venous drainage to the common iliac vein was combined with partial occlusion of the left renal vein. We randomly assigned a total of 36 rats to 3 groups, including sham surgery, partial renal vein occlusion alone (the classic technique) and microsurgical ligation. Half of the rats in each group were evaluated at 5 and 12 weeks, respectively. We evaluated internal gonadal vein and spermatic cord diameter, testicular weight, cauda epididymal sperm concentration and motility and testicular histology using the Johnsen score as well as serum and intratesticular testosterone and dihydrotestosterone. Five weeks after varicocele creation the microsurgical ligation group had a larger spermatic cord diameter and lower Johnsen scores than rats in the classic technique and sham surgery groups. At 12 weeks the microsurgical ligation group had a larger spermatic cord diameter, lower cauda epididymal sperm concentration, lower sperm motility and worse histology than the classic technique and sham surgery groups. There was no difference in serum androgen outcomes but the microsurgical ligation group had lower intratesticular androgens. Adding microsurgical ligation of testicular vein collaterals in the pelvis to partial renal vein occlusion appears to improve the effectiveness of creating a rat varicocele model.


Lateral preferences and performance on non-verbal laterality tests in a normal population.
The goal of the present study was to determine if, in a normal population, handedness, footedness, eyedness, earedness and overall congruency across lateral preferences were predictive of perceptual asymmetry on non-verbal tasks. In Experiment 1, subjects had to decide whether a laterally presented facial expression matched a previously presented target. In Experiment 2, subjects had to determine whether the tone of voice heard on dichotic and binaural presentations was the same or different. Eye preference was the most successful variable in predicting both visual field and ear advantages. Knowledge of a person's eye preference however, did not allow for a very accurate prediction of perceptual asymmetry. Nonetheless, the findings suggest that eye preference should be taken into account in future non-verbal laterality studies.


Interfacial properties as biophysical markers of cervical cancer.
Monolayers at air-liquid interfaces offer a convenient model for understanding the behavior of many natural systems like biological membranes. Langmuir monolayers were used to characterize the interfacial properties of tissue homogenates, organic phases and aqueous phases of tissue biopsy samples from 30 patients of cervical cancer and 15 normals. Our results reveal that the tensiometric parameters can differentiate between cancer and normal tissues obtained from human cervix and were statistically significant using t-test (P<0.05). The minimum surface tension of the cancer tissue monolayer was 52.9+/-4.4 mN/m, 1.4-folds greater than the normal cervical tissue homogenate value of 38.5+/-2.6 mN/m. The normal tissue homogenate isotherm had a hysteresis area of 90.3 microJ, which was approximately 6.2 times greater than that of the cervical cancer tissue monolayer. The total lipid and phospholipid contents of the cancerous cervical tissue were roughly double that of the normal cervical tissue and the surface activity was also in line with this observation. The difference in hysteresis of the cancerous and normal tissues indicates a decreased stability of the cancerous tissue film as compared to normal. The difference in surface activity denotes alterations in the molecular packing of the tissues in the cancerous state, which may have implications in terms of drug permeability and responsiveness. Further, differences in surface activity may play a role in altered cell adhesion and metastasis. This study is the first to evaluate surface properties of cancerous tissues and can lead to the development of a biophysical marker of cervical cancer based on interfacial properties.


Primary pulmonary hemangiopericytoma.
Hemangiopericytoma is a potentially malignant tumor of vascular origin. It usually is a solitary lesion and may arise in the chest or in extrathoracic areas. It is usually encapsulated. Microscopic features vary with the degree of differentiation of the individual tumor. The more differentiated variety exhibits abundant capillaries with open lumina surrounded by ovoid tumor cells; in the less differentiated tumors, the capillaries lack lumina and the tumor cells are spindle shaped. The prognostic significance of the microscopic pattern is controversial. However, prominent mitotic activity, necrosis, hemorrhage, and increased cellularity are ominous signs and are usually noticed in tumors that later exhibit malignant behavior. The larger the lesion, the more likely that it will be symptomatic. Treatment of choice is ample surgical resection.


Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue.
To further evaluate the mechanism of action of phosphodiesterase (PDE) inhibitors on the human prostate, the effects of PDE4 and PDE5 inhibitors on the tension induced by norepinephrine (NE) and on the intracellular levels of cyclic nucleotides in isolated human prostatic tissue were investigated. Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil and the PDE4 inhibitors rolipram and RP 73401 on the tension induced by NE (40 microM) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays. The tension induced by NE was dose dependently reversed by the drugs with the following rank order of efficacy: tadalafil greater than RP 73401 greater than rolipram greater than or equal to vardenafil greater than sildenafil. The maximal reversion of tension values ranged from 52.3% (tadalafil) to 17% (sildenafil). Of the PDE inhibitors, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP 73401 (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil, and sildenafil (28-fold, 12-fold, and 3-fold, respectively). Our results have demonstrated that drugs interfering with the cyclic nucleotide-mediated pathways can reverse the tension induced by NE in isolated prostatic tissue and elevate cyclic adenosine monophosphate and cyclic guanosine monophosphate. Our findings serve to explain how PDE inhibitors can affect symptoms of lower urinary tract symptoms and benign prostatic hyperplasia.


Ectopic functioning adrenocortico-myelolipoma in longstanding Nelson's syndrome.
A 26-year-old man with the Nelson's syndrome is described, in whom an abdominal tumour developed, accompanied by recurrent Cushing's syndrome 11 years after total adrenalectomy. Upon removal the tumour was a myelolipoma containing islands of adrenocortical-like elements. On incubation of the tumour with radioactive precursors, its capacity to produce cortisol in vitro was shown. The name adrenocortico-myelolipoma is suggested for this tumour.


Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer.
Nelfinavir induces apoptosis in liposarcoma by inhibiting site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. We postulate similar effects in castration-resistant prostate cancer because it exhibits a lipogenic phenotype. Nelfinavir inhibited androgen receptor activation in androgen-sensitive prostate cancer and the nuclear translocation of the fusion proteins sterol regulatory element binding protein-1 (SREBP-1)-enhanced green fluorescence protein (EGFP) and activating transcription factor 6 (ATF6)-EGFP in castration-resistant prostate cancer cells, viewed under confocal microscopy. Nelfinavir and site-1 protease (S1P) and S2P small interfering RNAs (siRNAs) reduced the proliferation of castration-resistant prostate cancer and induced apoptosis, which was opposed by autophagy. Inhibition of autophagy with hydroxychloroquine was additive to the apoptotic effect of nelfinavir. Western blotting of S1P and S2P siRNA knockdown and/or nelfinavir-treated cells confirmed the accumulation of precursor SREBP-1 and ATF6. 3,4-Dichloroisocoumarin, an S1P inhibitor, did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduced the nelfinavir-treated molecular and biological phenotype. Nelfinavir-mediated inhibition of regulated intramembrane proteolysis led to the accumulation of unprocessed SREBP-1 and ATF6. This resulted in sequential endoplasmic reticulum stress, inhibition of the unfolded protein response, reduced fatty acid synthase expression and apoptosis, which was countered by autophagy. Inhibition of autophagy was at least additive to this pro-apoptotic effect. These findings provide new insights into nelfinavir-induced endoplasmic reticulum stress and cancer cell death, and lead us to propose investigating its clinical activity in castration-resistant prostate cancer. This report validates S2P as a therapeutic target in castration-resistant prostate cancer.


Secure control design for nonlinear cyber-physical systems under DoS, replay, and deception cyber-attacks with multiple transmission channels.
This paper introduces the state-/output-feedback control for multi-channel nonlinear cyber-physical systems (CPSs). Many cyber-attacks are considered such as Denial-of-Service (DoS), replay and deception attacks. The deception cyber-attacks can be treated as measurement additive and multiplicative uncertainties. Both time-varying state-dependent and state-independent sensor additive attacks are considered. As DoS attack makes the CPS states unavailable, the standard modeling and control methods cannot be applied directly. Alternatively, as attackers in the replay attack re-transmit previous data and prevent the transmission of the more recent data, a delayed model is generated. To deal with these problems, a new observer at the controller side is proposed. It is used to perform two main tasks. The first is to estimate all system states at every time instant. The second is to exclude some unsecured transmitting channels from affecting the system response. Therefore, all attacks in these channels will have no effect on the system response. Using the estimated states, an anti-cyber-attacks state-feedback controller is investigated. Meanwhile, it is verified that the suggested approach certifies the convergence of all the CPSs states under different cyber-attacks. The effectiveness of the proposed secure control approach against different kinds of cyber-attacks is confirmed through two examples with simulation results.


An unusual case of anterior and posterior laryngeal cleft together: combined cleft of larynx.
Congenital clefts of the larynx are rare and usually found dorsally. An anterior or ventral cleft of the larynx is extremely rare. Only a few patients with this defect have been reported in the literature. The purpose of this paper is to present a patient having an anterior and posterior laryngeal cleft together. A 20-year-old man presented with a history of dysphonia since childhood. He did not report symptoms of swallowing or respiration, and had no history of neck trauma. Findings of videolaryngoscopy showed a grossly abnormal larynx. The anterior commissure was wider than normal, and the vocal folds did not show a fusion anteriorly. There was an interarytenoid cleft posteriorly. A neck CT with 3D reconstruction demonstrated a ventral cleft or nonfusion of the thyroid cartilage with a posterior cricoid cleft. Barium swallow study was in normal limits. Since the patient did not have any problem with swallowing or respiration, no surgical intervention was planned, and the patient was put on speech therapy, which revealed improvement in voice. To our knowledge, this is the first case of a combined laryngeal cleft. The diagnosis is established by the clinical symptoms, endoscopic evaluation, and radiographic examinations including 3D and barium studies.


Putting concepts into context.
At first glance, conceptual representations (e.g., our internal notion of the object "lemon") seem static; we have the impression that there is something that the concept lemon "means" (a sour, yellow, football-shaped citrus fruit) and that this meaning does not vary. Research in semantic memory has traditionally taken this "static" perspective. Consequently, only effects demonstrated across a variety of contexts have typically been considered informative regarding the architecture of the semantic system. In this review, we take the opposite approach: We review instances of context-dependent conceptual activation at many different timescales-from long-term experience, to recent experience, to the current task goals, to the unfolding process of conceptual activation itself-and suggest that the pervasive effects of context across all of these timescales indicate that rather than being static, conceptual representations are constantly changing and are inextricably linked to their contexts.


Boosting the activity of Prussian-blue analogue as efficient electrocatalyst for water and urea oxidation.
The design and fabrication of intricate hollow architectures as cost-effective and dual-function electrocatalyst for water and urea electrolysis is of vital importance to the energy and environment issues. Herein, a facile solvothermal strategy for construction of Prussian-blue analogue (PBA) hollow cages with an open framework was developed. The as-obtained CoFe and NiFe hollow cages (CFHC and NFHC) can be directly utilized as electrocatalysts towards oxygen evolution reaction (OER) and urea oxidation reaction (UOR) with superior catalytic performance (lower electrolysis potential, faster reaction kinetics and long-term durability) compared to their parent solid precursors (CFC and NFC) and even the commercial noble metal-based catalyst. Impressively, to drive a current density of 10 mA cm-2 in alkaline solution, the CFHC catalyst required an overpotential of merely 330 mV, 21.99% lower than that of the solid CFC precursor (423 mV) at the same condition. Meanwhile, the NFHC catalyst could deliver a current density as high as 100 mA cm-2 for the urea oxidation electrolysis at a potential of only 1.40 V, 24.32% lower than that of the solid NFC precursor (1.85 V). This work provides a new platform to construct intricate hollow structures as promising nano-materials for the application in energy conversion and storage.


Colocalization of GAD-like immunoreactivity and 3H-GABA uptake in amacrine cells of rabbit retina.
Rabbit retinas were double labeled to determine the degree of colocalization of glutamic-acid-decarboxylase-like immunoreactivity (GAD-like IR) and 3H-GABA uptake using light (LM) and electron microscopic (EM) autoradiography. Both GAD-like IR and 3H-GABA uptake were found in amacrine cell bodies in the inner nuclear layer (INL) as well as in cell bodies in the ganglion cell layer (GCL), and throughout the inner plexiform layer. GAD-like IR was found in 32% of the amacrine cells in the INL, 86% of which also showed 3H-GABA uptake; 3H-GABA uptake was observed in 38% of the amacrine cells. However, only 72% of these cells showed GAD-like IR. Labeled cells in the GCL were only 10-15% as common as similarly labeled cells in the INL. As in the INL, all GAD-positive cells in the GCL were double labeled, but only 53% of the cells taking up 3H-GABA were double labeled. We suggest that labeled cells in the GCL were ganglion cells rather than displaced amacrine cells. Cells, in both the INL and GCL, that showed 3H-GABA uptake but no GAD-like IR had a higher average grain density than double-labeled cells, indicating that uptake by these cells was specific. The relevance to GABAergic function of 3H-GABA uptake without an indication of GAD-like IR is yet to be determined. Statistical analysis at the EM level showed that one-third of the GAD-positive synaptic terminals of amacrine cells were double labeled after a 4-month exposure. Longer exposures at the EM level should reveal a higher percentage of GAD-positive terminals because at the LM level, one-half of the double-labeled cell bodies were "lightly" labeled with grains. The high degree of colocalization of GAD-like IR and 3H-GABA uptake suggests that both markers may be useful for labeling GABAergic neurons in the rabbit retina.


Role of parenting practices and digital media on beverage intake in European schoolchildren of different weight status. Feel4Diabetes-study.
Halting the rise in childhood obesity is an ongoing challenge in Europe. Sugar-sweetened beverage (SSB) and artificially sweetened beverage (ASB) consumption has become common practice at home and during family meals. The objective of this study was to investigate associations of parenting practices and home digital media availability with beverage intake in European schoolchildren of different weight groups. Cross-sectional data were derived from six countries taking part in the multicentered Feel4Diabetes-study. Anthropometric data were measured for 12 030 schoolchildren (n = 6097 girls; median age = 8.1 y). Details on sociodemographic characteristics, beverage intake, food parenting practices, and home availability of digital media were collated from questionnaires. The outcomes, daily SSB and ASB intakes, were included as dependent variables in multivariable regression models that provided odds ratios reflecting their association with parenting practices and digital media (exposures), after stratifying for children's weight status (underweight or normal versus overweight or obese). After controlling for children's sex, region, maternal body mass index, and education, the multivariate model found that in both body mass index groups, permissive parenting practices, such as rewarding and allowing consumption of unhealthy foods "very often or often," as compared with "rarely or never," were associated with a high daily intake of SSBs and ASBs in children, while parents "watching television together with their child," rewarding with screen time, and availability of television in children's rooms increased the likelihood of both beverages in the underweight or normal-weight group. Modification of permissive parenting practices and removal of television from children's rooms could effectively reduce SSB intake and curb the ongoing threat of child obesity in Europe.


A folding "framework structure" of Tetrahymena group I intron.
We have published the dynamic extended folding (DEF) method, which is a RNA secondary structure prediction approach-to simulate the in vivo RNA co-transcriptional folding process. In order to verify the reliability of the method, we selected the X-ray-determined Tetrahymena group I intron as a sample to construct the framework of its folding secondary structure. Our prediction coincides well with the secondary structure predicted by T.R. Cech and the X-ray diffraction crystal structure determined by Lehnert V. Our results show that the DEF framework structure of Tetrahymena group I intron reflects its function sites in a concise and straightforward manner, and the scope of the simulation was expanded.


Patchy cerebral white matter edema in chronic renal failure.
Bilateral patchy cerebral white matter edema was observed in two children with chronic renal failure. Uremia in one case and hypertension or hyponatremia in the other appeared to be the cause of the neurological and radiological findings.


Persistent atypical lymphocytic hyperplasia following tick bite in a child: report of a case and review of the literature.
We report a 6-year-old girl who developed a red papule on the posterior neck at the site of a previous tick bite. Initial biopsy was performed a year after the bite and the specimen showed a dense lymphoid infiltrate with admixed CD30+ cells. The patient was referred to our center because of concern about the development of a CD30+ lymphoproliferative disorder. The lesion was completely excised. Histology showed no evidence of a clonal lymphoproliferative disorder or Borrelia infection, but persistence of CD30+ cells. This case demonstrates that a tick bite reaction can persist for more than 1 year and show immunophenotypic and morphologic overlap with a CD30+ lymphoproliferative disorder. Complete history with thorough clinical and histopathologic evaluation is necessary to arrive at the correct diagnosis.


[Terra incognita of tissue donation: A systematic literature review analyzing institutional factors influencing the willingness to donate tissue].
Partly because of a lack of governmental commitment in educational work, tissue donation is largely unknown in the German population, although it has an increasing relevance for patient care. Due to the progress in research, the shortage of donor tissues in Germany is constantly increasing and has to be compensated by imports. In contrast, nations such as the USA are self-sufficient in donor tissue and can even export it. Since not only individual but also institutional factors (e.g., legal framework, allocation principles and the organization of tissue donation) can lead to these national differences in donor rates, the present systematic literature review will investigate how these factors influence the willingness to donate tissue. Relevant publications were systematically searched in seven databases. The search command consisted of English and German terms for the two search components "tissue donation" and "health care system". Papers published in English or German between 2004 and May 2021 and focusing on the analysis of institutional factors influencing the willingness to donate tissue post-mortem for transplantation were included (inclusion criteria); studies on blood and organ and living donation as well as publications not dealing with institutional factors influencing the willingness to donate tissue were excluded (exclusion criteria). In reporting, we followed the PRISMA 2020 statement. Of 1,398 hits, seven were finally included after screening. Many of the remaining studies focused on organ donation or non-institutional aspects of tissue donation. Only two studies considered the central population perspective. Furthermore, five publications originate from an Australian research group and focus on the international allocation of tissues. The results highlight the inadequate state of research and at the same time suggest that both tissue bank organization and allocation principles may influence the willingness to donate tissue. At the same time, the publications indicate that tissue donors are often not informed about a potential commercial use or an international allocation of tissues, which represents an ethical-legal conflict. The results indicate that institutional factors may influence people's willingness to donate. In particular, the lack of societal awareness of the issue results in various areas of tension for which recommendations for action have been developed. In order to prevent a slump in tissue donations because of socially unacceptable practices, further population-based studies should explore the institutional framework conditions that society demands for tissue donation.