Comparison of 3 protocols for analgesia control after cesarean delivery: a randomized controlled trial.
Proper pain control after cesarean delivery is of high clinical importance to the recovery and relief of patients after surgical delivery. We aimed to compare fixed time interval to on-demand regimens of nonopioid analgesics and to assess whether a protocol that is based on intravenous administration is superior to oral administration. This was a randomized controlled trial performed between April 2017 and May 2018. Patients who underwent elective cesarean delivery were assigned randomly to receive 1 of 3 pain relief protocols for the first 48 hours after surgery: (1) the fixed intravenous protocol included intravenous paracetamol (acetaminophen) 3 times daily with oral ibuprofen twice daily, (2) the fixed oral protocol included oral paracetamol 3 times daily with oral ibuprofen twice daily; if the patient requested additional analgesia, tramadol hydrochloride or dipyrone were given as rescue treatments, (3) the on-demand protocol included oral paracetamol or ibuprofen or dipyrone (based on visual analog scale). Pain intensity was measured and compared with the use of the visual analog scale (range, 0 ([no pain] to 10 [worst pain]). Total doses of pain relief analgesia and maternal and neonatal adverse effects were compared between the groups. The study included 127 women who were assigned randomly to the intravenous protocol group (n=41), oral protocol group (n=43), and on-demand protocol group (n=43). There were no between group differences in maternal and pregnancy characteristics, cesarean delivery indications, or surgical technique. The average visual analog scale score was 6.2±0.8 in the intravenous group, 7.0±1.1 in the oral group, and 7.5±0.7 in the on-demand group, in the first 24 hours (P=.01) and 6.4±0.7, 6.8±0.9, and 7.4±0.7 for the total 48 hours, respectively (P<.001). Mean pain score reduction was higher in the intravenous protocol compared with the fixed oral protocol group (4.7±1.2 vs 4.0±1.4; P=.02). The median doses of pain relief analgesia in the intravenous group were 5 (interquartile range, 5-7), 6 in the oral group (interquartile range, 4-6), and 4 in the on-demand group (interquartile range, 3-6; P=.001) in the first 24 hours and 9 (interquartile range, 7-10), 9 (interquartile range, 7-10), and 7 (interquartile range, 4-9), respectively, for the total 48 hours (P<.001). There were no "between group" differences in neonatal birthweight or maternal and neonatal adverse outcomes. Administration of pain relief analgesia (ibuprofen and acetaminophen) in fixed time intervals (intravenous or oral) after cesarean delivery yielded reduced visual analog scale pain scores compared with an on-demand protocol, despite fewer pain relief drugs consumed in the on-demand group.


Calculation of the relative free energy of oxidation of Azurin at pH 5 and pH 9.
Free energy calculations are described for the small copper-containing redox protein Azurin from Pseudomonas aeruginosa. A thermodynamic cycle connecting the reduced and oxidized states at pH 5 and pH 9 is considered, allowing for an assessment of convergence in terms of hysteresis and cycle closure. Previously published thermodynamic integration (TI) data is compared to Hamiltonian replica exchange TI (RE-TI) simulations using different simulation setups. The effects of varying simulation length, initial structure, position restraints on particular atoms, and the strength of temperature coupling are studied. Although the overall simulation times are too short to observe an experimentally described peptide plane rotation, it is found that RE-TI simulations do stimulate the distribution of conformational changes over the relevant values of the TI coupling parameter λ. This results in significantly improved values for hysteresis and cycle closure when compared to regular TI.


Evaluation of mean transit time in children as an indicator of airways obstruction.
Mean transit time was evaluated as a test of pulmonary function in normal and asthmatic children. It was found to be independent of body size and negatively correlated with PEFR, FEV1 and FVC in normal children. Mean transit time was less sensitive in detecting the effects of bronchodilator therapy in asthmatic children than other simpler tests of lung function. The range of normal was so wide that there was no clear demarcation between normal and abnormal. The degree of overlap makes isolated tests of mean transit time of little diagnostic value. It is therefore concluded that mean transit time though it theoretically offers the attractive advantage of being a sensitive indicator of both large and small airways obstruction, is unlikely to play a major part in the routine evaluation of lung function in asthmatic children.


Ketoconazole for successful treatment of cryptococcosis in a cat.
Cryptococcosis affecting the skin and a lymph node in a 1 1/2-year-old cat was treated successfully with ketoconazole as the sole therapeutic agent. The cat was lesion-free 1 year after treatment.


Validation and translation of the Hungarian version of the Australian Pelvic Floor Questionnaire (APFQ-H).
The aims of the study were the translation, cultural adaptation, and validation of self-administered Australian Pelvic Floor Questionnaire (APFQ) on a Hungarian population. The validation was performed in 294 women over 18 who agreed to answer the Hungarian version of the APFQ. The validation of the questionnaire included evaluation of content/face validity, internal consistency, construct validity, test-retest reproducibility, discriminant validity and convergent validity. Acceptable and good internal consistency was observed in all four dimensions [McDonald's ω (95% confidence interval) coefficients were > 0.7 for each dimension: bladder 0.888, bowel 0.790, prolapse 0.895 and sexual function 0.738]. Test-retest analyses revealed high reproducibility with intraclass correlation coefficients (bladder 0.83, bowel 0.92, prolapse 0.96 and sexual function 0.87). Prolapse symptom score correlated significantly with Pelvic Organ Prolapse Quantification (POP-Q), and bladder score correlated significantly with the results of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ UI SF) (convergent validity). Scores distinguished between patients with pelvic floor disorders and controls (high discriminant validity). Hungarian version of the self-administered APFQ is a reliable and valid instrument for evaluating symptom severity and impact of pelvic floor dysfunction on the quality of life of Hungarian women.


Family structure and birth order of patients with anorexia nervosa.
A retrospective case-notes study of 252 patients was undertaken, to focus on their birth order, and other aspects of their sibships. There is little evidence of a relationship to birth order using an established measure (Slater, 1962). Previous researchers have found a preponderance of female siblings in the families of patients with anorexia nervosa. We have not found this, neither is our sample characterised by older or younger siblings of any one sex. This is true for both female and male anorexics. These results are discussed in terms of experimental and family theories concerning the development of anorexia nervosa.


Synthesis of functionalised organochalcogenides and in vitro evaluation of their antioxidant activity.
Differently substituted β-hydroxy- and β-amino dialkyl and alkyl-aryl tellurides and selenides have been prepared through ring-opening reactions of epoxides and aziridines with selenium- or tellurium-centered nucleophiles. The antioxidant properties and the cytotoxicity of such compounds have been investigated on normal human dermal fibroblasts. Most of the studied compounds exhibited a low cytotoxicity and a number of them proved to be non-toxic, not showing any effect on cell viability even at the highest concentration used (100 μM). The obtained results showed a significant antioxidant potential of the selected organotellurium compounds, particularly evident under conditions of exogenously induced oxidative stress. The antioxidant activity of selenium-containing analogues of active tellurides has also been evaluated on cells, highlighting that the replacement of Se with Te brought about a significant increase in the peroxidase activity.


Air gun pellet injury of the heart with popliteal embolus.
An air gun pellet cardiac injury, in which there was penetration through the right ventricle, interventricular septum, and anterior papillary muscle and ejection from the left ventricle, is described. The pellet embolus was removed from the left popliteal artery with restoration of flow. The particular implications of pellet embolization are discussed and contrasted with those of bullet embolism.


Oxygen saturation in intraosseous sternal blood measured by CO-oximetry and evaluated non-invasively during hypovolaemia and hypoxia - a porcine experimental study.
This study intended to determine, and non-invasively evaluate, sternal intraosseous oxygen saturation (SsO2) and study its variation during provoked hypoxia or hypovolaemia. Furthermore, the relation between SsO2 and arterial (SaO2) or mixed venous oxygen saturation (SvO2) was investigated. Sixteen anaesthetised male pigs underwent exsanguination to a mean arterial pressure of 50 mmHg. After resuscitation and stabilisation, hypoxia was induced with hypoxic gas mixtures (air/N2). Repeated blood samples from sternal intraosseous cannulation were compared to arterial and pulmonary artery blood samples. Reflection spectrophotometry measurements by a non-invasive sternal probe were performed continuously. At baseline SaO2 was 97.0% (IQR 0.2), SsO2 73.2% (IQR 19.6) and SvO2 52.3% (IQR 12.4). During hypovolaemia, SsO2 and SvO2 decreased to 58.9% (IQR 16.9) and 38.1% (IQR 12.5), respectively, p < 0.05 for both, whereas SaO2 remained unaltered (p = 0.44). During hypoxia all saturations decreased; SaO2 71.5% (IQR 5.2), SsO2 39.0% (IQR 6.9) and SvO2 22.6% (IQR 11.4) (p < 0.01), respectively. For hypovolaemia, the sternal probe red/infrared absorption ratio (SQV) increased significantly from baseline (indicating a reduction in oxygen saturation) + 5.1% (IQR 7.4), p < 0.001 and for hypoxia + 19.9% (IQR 14.8), p = 0.001, respectively. Sternal blood has an oxygen saturation suggesting a mixture of venous and arterial blood. Changes in SsO2 relate well with changes in SvO2 during hypovolaemia or hypoxia. Further studies on the feasibility of using non-invasive measurement of changes in SsO2 to estimate changes in SvO2 are warranted.


Comparison of extracellular enzyme activities and community composition of attached and free-living bacteria in porous medium columns.
Free-living and surface-associated microbial communities in sand-packed columns perfused with groundwater were compared by examination of compositional and functional characteristics. The composition of the microbial communities was assessed by bulk DNA extraction, PCR amplification of 16S ribosomal DNA fragments, separation of these fragments by denaturing gradient gel electrophoresis, and sequence analysis. Community function was assessed by measurement of beta-glucosidase and aminopeptidase extracellular enzyme activities. Free-living populations in the aqueous phase exhibited a greater diversity of phylotypes than populations associated with the solid phase. The attached bacterial community displayed significantly greater beta-glucosidase and aminopeptidase enzyme activities per volume of porous medium than those of the free-living community. On a per-cell basis, the attached community had a significantly higher cell-specific aminopeptidase enzyme activity (1.07 x 10(-7) nmol cell(-1) h(-1)) than the free-living community (5.02 x 10(-8) nmol cell(-1) h(-1)). Conversely, the free-living community had a significantly higher cell-specific beta-glucosidase activity (1.92 x 10(-6) nmol cell(-1) h(-1)) than the surface-associated community (6.08 x 10(-7) nmol cell(-1) h(-1)). The compositional and functional differences observed between these two communities may reflect different roles for these distinct but interacting communities in the decomposition of natural organic matter or biodegradation of xenobiotics in aquifers.


Salvia officinalis and Lippia triphylla: Chemical characterization and evaluation of antidepressant-like activity.
Salvia officinalis (Lamiaceae) and Lippia triphylla (Verbenaceae) are two plants known for their therapeutic effects in conventional medicine for the treatment of a wide extent of diseases, including the ones on the central nervous system. In the present study, the impact of aqueous extract from the leaves of these two herbs for the treatment of depression was examined. The phytochemical profile highlighted the presence of eighteen and ten polyphenolic compounds in Salvia officinalis and Lippia triphylla, respectively. The antidepressant effects of such extracts were assessed using two tests: the forced swimming test (FST) and tail suspension test (TST) in swiss albino mice. Five mice were partitioned into each group: control (distilled water), standard (Imipramine hydrochloride, 25 mg/kg) and three test ones treated with increased doses of aqueous extracts (250-500-1000 mg/kg), orally administered for two weeks. The acute treatment of the mice with aqueous extracts of Salvia officinalis and Lippia triphylla reduced significantly the time of immobility in the forced swimming test (p < 0.001) as compared to control group, and also decreased significantly the time of immobility of mice in the tail suspension test (p < 0.001). The findings attained in this work show how both plants possess potential anti-depressant-like effects; however, the translation from the results presented in this work to a potential use as therapeutic agents would require the acquisition of a stronger scientific evidence.


Quality improvement project to reduce pain and distress associated with immunization visits in pediatric primary care.
This quality improvement project implemented an evidence-based immunization protocol aimed at decreasing pain and distress associated with immunizations for children ages 4 to 6 by utilizing distraction and a benzocaine-based anesthetic spray. The original protocol is used at a large, university-based pediatric primary care hospital. A convenience sample of 30 children from a community-based healthcare center was utilized to assess effectiveness in alternate settings. This quasi-experimental project collected survey information from child participants and consenting caregivers. Statistical analysis by paired t-test indicated a statistically significant decrease in reported distress by both the child and the caregiver utilizing the immunization protocol.


Combined histopathological risk score using TP53 protein expression, CD8+ T cell density and intratumoral budding is an independent predictor of neoadjuvant therapy response in rectal adenocarcinoma.
Neoadjuvant therapy is the recommended treatment for locally advanced rectal adenocarcinoma; however, there remains significant variability in response to therapy. Tumour protein 53 (TP53) has been associated with therapy response and prognosis with conflicting data. Recently, we demonstrated that immune cell density and intratumoral budding (ITB) are predictive factors in rectal cancer. We investigated the predictive value of TP53 immunohistochemistry with CD8+ T cell density and ITB on pretreatment biopsies of rectal adenocarcinoma for response to neoadjuvant therapy. Pretreatment biopsies of rectal adenocarcinoma from 117 patients with neoadjuvant therapy were analysed for TP53 expression by immunohistochemistry, ITB, CD8+ T cell density and mismatch repair protein (MMR) status. Most rectal adenocarcinomas displayed aberrant TP53 expression (86 of 117, 74%). Compared to wild-type TP53, aberrant TP53 expression was associated with proficient MMR status (P = 0.003) and low CD8+ T cell density (P = 0.001). Aberrant TP53 was significantly associated with a partial to poor response to neoadjuvant therapy [odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.04-5.62, P = 0.04]. A combined histopathological risk score (HRS) was created using CD8+ T cell density, ITB and TP53 expression. Patients were separated into low (none to one factor) and high (two to three factors) HRS categories. In the multivariable model, patients with a high HRS were 3.25-fold more likely to have a partial or poor response to neoadjuvant therapy (95% CI = 1.48-7.11, P = 0.003). Our study demonstrates that aberrant TP53 expression, high ITB and low CD8+ T cell density in pretreatment biopsies can help predict response to neoadjuvant therapy. These biomarkers may be helpful in identifying patients at risk for therapy resistance.


microRNA-26a represses pancreatic cancer cell malignant behaviors by targeting E2F7.
Dysregulation of microRNAs (miRNAs) exerts key roles in the development of pancreatic cancer (PCa). miR-26a is reportedly a tumor suppressor in cancers. However, whether miR-26a modulates PCa progression is poorly understood. Here, we found that miR-26a was down-regulated in PCa. Overexpressed miR-26a suppressed PCa cell proliferation, colony formation, and tumor stem cell properties. Mechanically, the transcription factor E2F7 is a downstream target of miR-26a. miR-26a decreased E2F7 expression through binding to the 3'-untranslated region (UTR) of E2F7. Decreased miR-26a in PCa tissues was inversely correlated with E2F7. The inhibitory effects of miR-26a in PCa were reversed by E2F7 overexpression. Consistently, the knockout of E2F7 further significantly inhibited the growth of PCa cells combined with miR-26a overexpression. Further study revealed that E2F7 bound the promoter of vascular endothelial growth factor A (VEGFA), a key factor in angiogenesis, and transcriptionally activated the expression of VEGFA. miR-26a overexpression attenuated the effects of E2F7 on VEGFA promotion. Our results uncovered the novel function of miR-26a/E2F7/VEGFA in PCa, making miR-26a a possible target for PCa treatment.


Establishing the contribution of active histone methylation marks to the aging transcriptional landscape of Drosophila photoreceptors.
Studies in multiple organisms have shown that aging is accompanied by several molecular phenotypes that include dysregulation of chromatin. Since chromatin regulates DNA-based processes such as transcription, alterations in chromatin modifications could impact the transcriptome and function of aging cells. In flies, as in mammals, the aging eye undergoes changes in gene expression that correlate with declining visual function and increased risk of retinal degeneration. However, the causes of these transcriptome changes are poorly understood. Here, we profiled chromatin marks associated with active transcription in the aging Drosophila eye to understand how chromatin modulates transcriptional outputs. We found that both H3K4me3 and H3K36me3 globally decrease across all actively expressed genes with age. However, we found no correlation with changes in differential gene expression. Downregulation of the H3K36me3 methyltransferase Set2 in young photoreceptors revealed significant changes in splicing events that overlapped significantly with those observed in aging photoreceptors. These overlapping splicing events impacted multiple genes involved in phototransduction and neuronal function. Since proper splicing is essential for visual behavior, and because aging Drosophila undergo a decrease in visual function, our data suggest that H3K36me3 could play a role in maintaining visual function in the aging eye through regulating alternative splicing.


Global, regional, and national prevalence, incidence, mortality, and risk factors for atrial fibrillation, 1990-2017: results from the Global Burden of Disease Study 2017.
To estimate the prevalence, incidence, mortality, and risk factors for atrial fibrillation (AF) in 195 countries and territories from 1990 to 2017. Following the methodologies used in the Global Burden of Disease Study 2017, the prevalence, incidence, and mortality of AF were analysed by age, sex, year, socio-demographic index (SDI), and location. The percentage contributions of major risk factors to age-standardized AF deaths were measured by population attributable fractions. In 2017, there were 37.57 million [95% uncertainty interval (UI) 32.55-42.59] prevalent cases and 3.05 million (95% UI 2.61-3.51) incident cases of AF globally, contributing to 287 241 (95% UI 276 355-304 759) deaths. The age-standardized rates of prevalent cases, incident cases, and deaths of AF in 2017 and their temporal trends from 1990 to 2017 varied significantly by SDI quintile and location. High systolic blood pressure was the leading risk factor for AF age-standardized deaths [34.3% (95% UI 27.4-41.5)] in 2017, followed by high body mass index [20.7% (95% UI 11.5-32.2)] and alcohol use [9.4% (95% UI 7.0-12.2)]. Our study has systematically and globally assessed the temporal trends of AF, which remains a major public heath challenge. Although AF mainly occurred in developed countries, the unfavourable trend in countries with lower SDI also deserves particular attention. More effective prevention and treatment strategies aimed at counteracting the increase in AF burden should be established in some countries.


Special treatment of prediction errors in autism spectrum disorder.
For autistic individuals, sensory stimulation can be experienced as overwhelming. Models of predictive coding postulate that cortical mechanisms disamplify predictable information and amplify prediction errors that surpass a defined precision level. In autism, the neuronal processing is putting an inflexibly high precision on prediction errors according to the HIPPEA theory (High, Inflexible Precision of Prediction Errors in Autism). We used an apparent motion paradigm to test this prediction. In apparent motion paradigms, the illusory motion of an object creates a prediction about where and when an internally generated token would be moving along the apparent motion trace. This illusion facilitates the perception of a flashing stimulus (target) appearing in-time with the apparent motion token and is perceived as a predictable event (predictable target). In contrast, a flashing stimulus appearing out-of-time with the apparent motion illusion is an unpredictable target that is less often detected even though it produces a prediction error signal. If a prediction error does not surpass a given precision threshold the stimulation event is discounted and therefore less often detected than predictable tokens. In autism, the precision threshold is lower and the same prediction errors (unpredictable target) triggers a detection similar to that of a predictable flash stimulus. To test this hypothesis, we recruited 11 autistic males and 9 neurotypical matched controls. The participants were tasked to detect flashing stimuli placed on an apparent motion trace either in-time or out-of-time with the apparent motion illusion. Descriptively, 66% (6/9) of neurotypical and 64% (7/11) of autistic participants were better at detecting predictable targets. The prediction established by illusory motion appears to assist autistic and neurotypical individuals equally in the detection of predictable over unpredictable targets. Importantly, 55% (6/11) of autistic participants had faster responses for unpredictable targets, whereas only 22% (2/9) of neurotypicals had faster responses to unpredictable compared to predictable targets. Hence, these tentative results suggest that for autistic participants, unpredictable targets produce an above threshold prediction error, which leads to faster response. This difference in unpredictable target detection can be encapsulated under the HIPPEA theory, suggesting that precision setting could be aberrant in autistic individuals with respect to prediction errors. These tentative results should be considered in light of the small sample. For this reason, we provide the full set of materials necessary to replicate and extend the results.


Optimization and validation of a loop-mediated isothermal amplification (LAMP) assay for detection of Giardia duodenalis in leafy greens.
Giardia duodenalis is one of the most common food and water-borne intestinal parasites of humans and animals worldwide. Fresh, ready-to-eat produce such as leafy greens and salad mixes are considered potential transmission vehicles for Giardia infection in humans. Therefore, a specific, sensitive, and reliable method for Giardia detection in leafy greens is needed. We optimized washing procedures for the recovery of Giardia cysts from leafy greens and adapted and validated an existing EF1α LAMP assay for the detection of Giardia DNA to support routine diagnostic surveillance and disease outbreak investigations. Four leafy green types (35 ± 1 g) were spiked with 100 Giardia cysts and we compared washing by shaking with 1 M glycine (n = 20) or 0.1% Alconox (n = 20). DNA was extracted from washes, tested by LAMP and melt curve analysis, and time to positive (TTP) values compared. The detection limit was determined by spiking 10 (n = 40) Giardia cysts onto these same types of leafy greens and processing as above with 0.1% Alconox. Method robustness was assessed by subjecting spring mix (n = 45 total) to aging (1, 3 or 7 days) and washes to aging and freezing conditions prior to testing. Assay repeatability and specificity were evaluated, and an artificial positive control (APC) distinguishable by melt temperature (Tm) from DNA of Giardia spiked on leafy greens was designed to rule out cross-contamination from the control. Giardia detection rates were higher and TTP was lower (P < 0.05) for 0.1% Alconox (19/20, 8.85 ± 0.3 min) compared with 1 M glycine (15/20, 14.53 ± 7.2 min). The LAMP assay detected 10 Giardia cysts spiked on leafy greens in 13-34 min in 14/40 samples tested. Robustness assessment showed that TTP was higher (P < 0.0001) when spiked produce was stored for 7 days (13.09 ± 1.14 min) compared to fresh (9.72 ± 0.43 min). No unspiked samples were positive by LAMP, and the Tm for DNA of Giardia spiked on leafy greens was higher (P < 0.0001, 87.43 ± 0.05 °C) than the APC (86.43 ± 0.12 °C). Within-assay repeatability co-efficient of variation (CV) for TTP was 5.4% and no cross-contamination occurred when spiked and un-spiked samples were processed in alternate order. The optimized sample processing procedure combined with the EF1α LAMP assay is a sensitive, specific, labour-saving, and rapid method for the detection of Giardia cysts in leafy greens.


[Effect of triiodothyronine and methylthiouracil on the enzymatic activity of biogenic amine metabolism in rat brain synaptosomes].
Triiodothyronine injections are shown to lower DOPA decarboxylation and 5-hydroxytryptophan decarboxylation activity and also to decrease the intensity of serotonin and norepinephrine oxidative deamination in the rats' brain synaptosomes. Hypothyroidism produced by 6-methylthiouracil administration was accompanied by intensification of the DOPA-decarboxylase activity and monamine oxidase transformation into serotonin and norepinephrine with no parallel occurring essential changes in the 5-hydroxytryptophan decarboxylation.


Topological differences and confounders of mental rotation in cervical dystonia and blepharospasm.
Mental rotation (mR) bases on imagination of actual movements. It remains unclear whether there is a specific pattern of mR impairment in focal dystonia. We aimed to investigate mR in patients with cervical dystonia (CD) and blepharospasm (BS) and to assess potential confounders. 23 CD patients and 23 healthy controls (HC) as well as 21 BS and 19 hemifacial spasm (HS) patients were matched for sex, age, and education level. Handedness, finger dexterity, general reaction time, and cognitive status were assessed. Disease severity was evaluated by clinical scales. During mR, photographs of body parts (head, hand, or foot) and a non-corporal object (car) were displayed at different angles rotated within their plane. Subjects were asked to judge laterality of the presented image by keystroke. Both speed and correctness were evaluated. Compared to HC, CD and HS patients performed worse in mR of hands, whereas BS group showed comparable performance. There was a significant association of prolonged mR reaction time (RT) with reduced MoCA scores and with increased RT in an unspecific reaction speed task. After exclusion of cognitively impaired patients, increased RT in the mR of hands was confined to CD group, but not HS. While the question of whether specific patterns of mR impairment reliably define a dystonic endophenotype remains elusive, our findings point to mR as a useful tool, when used carefully with control measures and tasks, which may be capable of identifying specific deficits that distinguish between subtypes of dystonia.


The case for restructuring health care in the United States: the Hawaii paradigm.
Health care in the United States is plagued by many problems. This includes excessive specialization with too few generalists, burdensome bureaucratic federal rules and regulations, and outlandish malpractice awards--all contributing to costs of care that exceeds all other nations. Cost has erroneously been identified as the cause of the problem rather than being one of many results of a failing system. Rather than repetitive unsuccessful efforts to tinker with cost as the cause, it makes far more sense to design and build a better structure of health care including expanding the existing biomedical model into a broader biomedical-psychosocial model. Hawaii, with virtually 100% of its population insured, is closer to this model than most states. It also manages to be ranked the healthiest state with one of the lowest health care costs in the nation.


Exploring the chemical space of protein-protein interaction inhibitors through machine learning.
Although protein-protein interactions (PPIs) have emerged as the basis of potential new therapeutic approaches, targeting intracellular PPIs with small molecule inhibitors is conventionally considered highly challenging. Driven by increasing research efforts, success rates have increased significantly in recent years. In this study, we analyze the physicochemical properties of 9351 non-redundant inhibitors present in the iPPI-DB and TIMBAL databases to define a computational model for active compounds acting against PPI targets. Principle component analysis (PCA) and k-means clustering were used to identify plausible PPI targets in regions of interest in the active group in the chemical space between active and inactive iPPI compounds. Notably, the uniquely defined active group exhibited distinct differences in activity compared with other active compounds. These results demonstrate that active compounds with regions of interest in the chemical space may be expected to provide insights into potential PPI inhibitors for particular protein targets.


Variant histologies in bladder cancer: Does the centre have an impact in detection accuracy?
To compare the accuracy in detecting variant histologies (VH) at transurethral resection of bladder (TURB) and radical cystectomy (RC) specimen among tertiary referral centres, in order to investigate potential reasons of discrepancies from the pathological point of view. Clinical and histopathological data of TURB specimen and subsequent cystectomy specimen of 3,445 RC candidate patients have been retrospectively collected from 24 tertiary referral centres between 1980 and 2021. VH considered in the analysis were pure squamous cell carcinoma, urothelial carcinoma with squamous differentiation, pure adenocarcinoma, urothelial carcinoma with glandular differentiation, micropapillary bladder cancer (BCa), neuroendocrine BCa, and other variants. The degree of agreement between TURB and RC concerning the identification of VH was expressed as concordance, classified according to Cohen's kappa coefficient. A VH was reported in 17% of TURB specimens, 45% of which were not confirmed in RC. The lowest concordance rate was reported for micropapillary BCa with 11 out of 18 (61%) centres reporting no agreement, whereas neuroendocrine BCa achieved the highest concordance rate with only 3 centres (17%) reporting no agreement. Our results shows that even among centres with the advantage of a referent uropathologist the micropapillary variant is characterized by scarce accuracy between TURB and RC. Differences in TURB specimen acquisition by the urologist and in sampling methods among different centres are the main limitations of the study. Accuracy of TURB in detecting VH is poor for certain VH, in particular for micropapillary BCa, with evident variation among centres. Novel diagnostic tools are required to better identify these VH and drive patients toward a personalized treatment.


Highly toxic coplanar PCB126 reduces liver peroxisomal enzyme activities in rats.
The effect of the highly toxic coplanar PCB congener, 3,4,5,3',4'-pentachlorobiphenyl (PCB126) on hepatic peroxisomes was studied in rats. The aim of this study was to investigate whether a toxic dose of the dioxin-like coplanar PCB modifies enzyme activities in peroxisomes where plays an important role in lipid metabolism. Treatment with PCB126, at a single i.p. administration of 25 mg/kg which evokes clear suppression of body weight gain, resulted in marked reduction (to about 40-50%) of catalase activity and peroxisomal fatty acyl-CoA β-oxidizing system. Immunoblotting showed that expression of catalase was greatly reduced by the treatment in parallel with the activity. Light microscopy revealed a drastic reduction in granules possessing peroxidase activity, while electron microscopy demonstrated that no apparent morphological changes had taken place. Thus the reduction in catalase activity caused by PCB126 could be attributable to suppression of protein expression. The marked reduction of these peroxisomal enzyme activities might be related to hyperlipidemia caused by dioxin-related compounds in rats and humans.


A quality assurance program for a state university student health center.
The New Mexico State University Student Health Center redesigned its quality assurance program to follow the Joint Commission's ten-step process for monitoring and evaluation. This article outlines the scopes of care in the Health Center's different units and provides case-study examples, including important aspects of care and indicators, to illustrate the monitoring and evaluation process as it is used for both retrospective studies and concurrent monitoring.


Six-month effects of the Groningen active living model (GALM) on physical activity, health and fitness outcomes in sedentary and underactive older adults aged 55-65.
To determine the effects on energy expenditure, health and fitness outcomes in sedentary older adults aged 55-65 after 6-month participation in the GALM program. In three Dutch communities, subjects from matched neighbourhoods were assigned to an intervention (n = 79) or a waiting-list control group (n = 102). The GALM program consisted of fifteen 60 min sessions once a week emphasising moderate-intensity recreational sports activities. The intervention group showed significant increases in energy expenditure for recreational sports activities, other leisure-time physical activity, health indicators, and perceived and performance-based fitness. Contrary to our expectations, the same increases were found for the control group. Consequently, only significant between-group differences, favouring the intervention group, were obtained for sleep, diastolic blood pressure, perceived fitness score and grip strength. The increases in energy expenditure for physical activity from the GALM program, especially for the more intensive recreational sports activities, look promising and are in line with the expected amounts necessary to improve health. Further research is needed to evaluate long-term effects of participation in the GALM program. These results underline that GALM can be considered successful in stimulating leisure-time physical activity and improving health and fitness in older adults.


The fight against COVID-19: Striking a balance in the renin-angiotensin system.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin-angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.


Association between pretransplant Thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors.
A matched cohort study was designed to test the efficacy of polyclonal rabbit antiserum specific for human T cells (Thymoglobulin), administered in vivo on days 1-5 (2 mg/kg/day) before T cell-replete unrelated donor marrow transplantation. Thymoglobulin was given to 52 leukemic patients at Huddinge Hospital. Control patients matched for diagnosis, disease stage, age and treated with a similar regimen, apart from the omission of Thymoglobulin, were selected in Seattle during the same period (n = 104). All received conditioning with cyclophosphamide and TBI. In the study group all patients received 10 Gy single dose TBI, while the controls were given 12-14.4 Gy fractionated TBI. GVHD prophylaxis was cyclosporine and methotrexate. Patients were treated for grade I acute GVHD in the study group, and for grade II GVHD in the control group. Multivariable analyses were adjusted for patient and donor age and CMV serology, HLA matching, donor gender and marrow cell dose. Non-relapse mortality was lower in the study patients (hazard ratio = 0.30, 95% CI 0.12-0.75, P value = 0.005). The 5-year cumulative incidence of non-relapse mortality was 19% in the study cohort, and 35% in the control cohort. Overall mortality was also lower in study patients (hazard ratio 0.51, 95% CI 0.27-0.97, P value = 0.03). No significant difference in the risk of relapse was seen (P = 0.63). This suggests that Thymoglobulin during conditioning may reduce non-relapse mortality after unrelated donor marrow transplantation.


Paradigm Shift in Gastric Cancer Prevention: Harnessing the Potential of Aristolochia olivieri Extract.
Gastric cancer, particularly adenocarcinoma, is a significant global health concern. Environmental risk factors, such as Helicobacter pylori infection and diet, play a role in its development. This study aimed to characterize the chemical composition and evaluate the in vitro antibacterial and antitumor activities of an Aristolochia olivieri Colleg. ex Boiss. Leaves' methanolic extract (AOME). Additionally, morphological changes in gastric cancer cell lines were analyzed. AOME was analyzed using HPLC-MS/MS, and its antibacterial activity against H. pylori was assessed using the broth microdilution method. MIC and MBC values were determined, and positive and negative controls were included in the evaluation. Anticancer effects were assessed through in vitro experiments using AGS, KATO-III, and SNU-1 cancer cell lines. The morphological changes were examined through SEM and TEM analyses. AOME contained several compounds, including caffeic acid, rutin, and hyperoside. The extract displayed significant antimicrobial effects against H. pylori, with consistent MIC and MBC values of 3.70 ± 0.09 mg/mL. AOME reduced cell viability in all gastric cancer cells in a dose- and time-dependent manner. Morphological analyses revealed significant ultrastructural changes in all tumor cell lines, suggesting the occurrence of cellular apoptosis. This study demonstrated that AOME possesses antimicrobial activity against H. pylori and potent antineoplastic properties in gastric cancer cell lines. AOME holds promise as a natural resource for innovative nutraceutical approaches in gastric cancer management. Further research and in vivo studies are warranted to validate its potential clinical applications.


Excision of a DNA sequence determining kanamycin resistance from a ColE1-Km recombinant plasmid.
A 4.8 X 10(6) dalton ECoRI-generated fragment of the R-factor R6-5 carrying the gene for kanamycin resistance (Km) was joined in vitro to ECoRI-treated ColE1 plasmid DNA. Transformation of E. coli with the ColE1-Km recombinant plasmid yielded clones, which were immune to colicin E1, resistant to kanamycin and failed to produce colicin E1. During multiplication of this recombinant plasmid in the presence of chloramphenicol, cells expressed an increased resistance to kanamycin. Transformation studies with the recombinant DNA molecule showed very frequent loss of Km resistance in those cells harbouring a preexisting F'gal plasmid. Since colicin immunity is not affected and the col- phenotype is still present, one has to test for a remaining DNA sequence further existing in ColE1 DNA by cleaving the plasmid DNA with the ECoRI restriction endonuclease. The full length of ColE1 DNA (6.2 kb) was restored, which confirmed that no deletion of ColE1 DNA sequences had occured. The remaining DNA sequence was identified as a 2.0 or 2.2 kb segment. On the basis of the length of the excised fragment it is proposed that the insertion sequence ISI and a part of the inverted repeat sequence with corrdinates 21.0 to 22.0 of the R6-5 DNA are recognised by a nucleolytic function.


Teratogenic effects of retinoic acid on neurulation in mice embryos.
Retinoic acids (RA) are natural chemicals that exert a hormone-like activity and a variety of biological effects on early development of mouse. In this study, the probable teratogenic effects of RA on CNS have been investigated in pregnant mice (n = 20) divided into four groups: (1) untreated controls, (2) controls which received a single dose of DMSO, (3) a group that received 40 mg/kg, and (4) a group that received 60 mg/kg of all-trans RA in DMSO, respectively on the eighth day of gestation. Embryos whose dams had received 40 and 60 mg/kg doses of RA, showed malformations and decreased size. At 40 mg/kg dosage level, 50% of the embryos had closed neural tubes while at 60 mg/kg dosage level the neural tube failed to close. The neuroblast mantle layers were disorganized in the 40 mg/kg and even more in the 60 mg/kg exposed group compared to the controls. In mitosis, the density of chromatin was increased in the 60 mg/kg dose group. Compared to controls the 40 and 60 mg/kg dose groups of RA treated dams decreases in the luminal longitudinal and internal measures were observed. Also the thickness of ventricular, mantle and marginal layers was smaller. Wide intercellular spaces due to the degenerated cells at high doses of RA as well as an accumulation of intercellular fluid were observed. Therefore, the wedge shape of neuroepithelium was abolished, preventing the elevation of the neural wall.


CXCL12-binding receptors expression in non-small cell lung cancer relates to tumoral microvascular density and CXCR4 positive circulating tumoral cells in lung draining venous blood.
Lung cancer is the main cause of cancer-related death in Western countries. Despite early diagnosis, approximately 40% of patients have undergone surgical resection for localized non-small cell lung cancer relapse within 24 months after surgery. Current prognostic criteria for patients with non-small cell lung cancer are gradually enriched by the discovery of critical biological markers in surgical samples to better stratify patients with high risk for recurrent and metastatic disease after surgical manipulation. In fact, specific biological features are needed to drive metastasis development and, among these chemokine receptors, when activated, seem to play a relevant role, promoting both neovessels formation and tumoral cell migration. To this purpose, blood samples from the closed stumps of the pulmonary veins were drawn immediately after major pulmonary surgery in 45 patients with resectable non-small cell lung cancer to evaluate the expression of chemokine CXCL12 receptor, CXCR4, in circulating tumor cells. In addition, primary tumor sections have been used to assess microvascular density (MVD) and vessels invasion and build prognostic tissue micro-array to investigate the expression of CXCL12 receptors CXCR4 and CXCR7. Cells positive for cytokeratins from tumor draining pulmonary venous blood were detectable in 11 cases (23.9%). In 8 out of 11 cases, CK positive cells coexpressed CXCR4. Moreover, in tumoral tissue high CXCR4 expression was significantly associated to high mMVD (p = 0.046), high CXCR7 expression (p = 0.001), adenocarcinoma histotype (p = 0.023), and to the presence of circulating tumoral cells in pulmonary veins (p = 0.001). Finally, vessel invasions relate to high MVD. In conclusion, the results of our study underline the significant potential role of CXCL12 receptors in determining both vessel formation and tumoral cell migration to blood stream, favoring metastasis development.


Complex dynamics of a fractional-order SIR system in the context of COVID-19.
This paper proposes and analyses a new fractional-order SIR type epidemic model with a saturated treatment function. The detailed dynamics of the corresponding system, including the equilibrium points and their existence and uniqueness, uniform-boundedness, and stability of the solutions are studied. The threshold parameter, basic reproduction number of the system which determines the disease dynamics is derived, and the condition of occurrence of backward bifurcation is also determined. Some numerical works are conducted to validate our analytical results for the commensurate fractional-order system. Hopf bifurcations for the fractional-order system are studied by taking the order of the fractional differential as a bifurcation parameter.


Inverse relationship between stigma and quality of life in India: is epilepsy a disabling neurological condition?
Stigma associated with epilepsy has negative effects on psychosocial outcomes, affecting quality of life (QOL) and increasing disease burden in persons with epilepsy (PWEs). The aim of our study was to measure the impact of stigma on the QOL of PWEs and the prevalence of neurological disability due to stigmatized epilepsy. A prospective observational study with a sample of 208 PWEs was conducted. Neuropsychological Tests used were the Indian Disability Evaluation Assessment Scale (IDEAS) to measure disability, the Dysfunctional Analysis Questionnaire (DAQ) to measure QOL, and the Stigma Scale for Epilepsy (SSE) to assess stigma. Spearman correlation was calculated, and stigma (SSE) was highly significant with QOL (DAQ) (0.019) and disability due to stigmatized epilepsy (IDEAS) (0.011). The present study supports the global perception of stigma associated with epilepsy and its negative impact on their overall QOL and its contribution to the escalation of the disease burden.


Greedy caliper propensity score matching can yield variable estimates of the treatment-outcome association-A simulation study.
Greedy caliper propensity score (PS) matching is dependent on randomness, which can ultimately affect causal estimates. We sought to investigate the variation introduced by this randomness. Based on a literature search to define the simulation parameters, we simulated 36 cohorts of different sizes, treatment prevalence, outcome prevalence, treatment-outcome-association. We performed 1:1 caliper and nearest neighbor (NN) caliper PS-matching and repeated this 1000 times in the same cohort, before calculating the treatment-outcome association. Repeating caliper and NN caliper matching in the same cohort yielded large variations in effect estimates, in all 36 scenarios, with both types of matching. The largest variation was found in smaller cohorts, where the odds ratio (OR) ranged from 0.53 to 10.00 (IQR of ORs: 1.11-1.67). The 95% confidence interval was not consistently overlapping a neutral association after repeating the matching with both algorithms. We confirmed these findings in a noninterventional example study. Caliper PS-matching can yield highly variable estimates of the treatment-outcome association if the analysis is repeated.


Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE).
Acetylcholine inhibitors (AChEIs) are currently considered as potential drugs for treating Alzheimer disease. In this work, we developed a receptor-dependent 3D-QSAR (RD-3D-QSAR) models based on a series of 60 benzylpiperidine inhibitors of human acetylcholinesterase to support the design of new AChEIs. The best two models, A-F (N = 47, q(2) = 0.736, r(2) = 0.860) and C-F (N = 47, q(2) = 0.753, r(2) = =0.900) were developed and validated by a combined GA-PLS approach, available in WOLF. Residues of the aromatic gorge (Tyr341 and Trp439) and catalytic triad (His447) are related to both equations showing the consistency of these models with the SAR. Based on those models we have proposed four new benzylpiperidine derivatives and predicted the pIC(50) for each molecule. The good predicted potency of benzylpiperidine derivative, IIa, indicates that it is a potential candidate as a new HuAChE inhibitor.


Risk assessment of local dermal effects and skin sensitisation under the EU Chemicals Regulation REACH: a proposal for a qualitative, exposure scenario specific, approach.
Within the framework of REACH, an assessment regarding local dermal effects and skin sensitisation should be performed for substances. Quantitative hazard information for these effects is often not available. Furthermore, it is difficult to relate the way in which animals are exposed in dermal toxicity studies directly to dermal exposure in practice. In the absence of quantitative information, a qualitative assessment for dermal effects is the most reasonable option. The qualitative approach as proposed in the REACH guidance recommends only general risk management measures (RMM) for three categories with a low, moderate and high identified hazard, without specifying which RMM are needed for a specific exposure scenario. We propose to differentiate frequency of exposure based on differences in activities and to compare measured and estimated local skin exposure levels with rules of thumb for evaluation of control of risks per hazard category. For workers, specific RMM regimes are assigned to each combination of hazard category and process category (PROC). For consumers, a strategy in which RMM are arranged from product-integrated measures to the use of personal protective equipment (PPE) is presented. Our approach may be transferred into automated assessment tools like Chesar and CEFIC GES.


Combining NHC bis-phenolate ligands with oxophilic metal centers: a powerful approach for the development of robust and highly effective organometallic catalysts.
The present paper describes an overview of a novel family of tridentate NHC pincer ligand in which two phenoxide moieties are directly connected to the nitrogen atoms of a central N-heterocyclic carbene. It was envisioned that such a structure might be suitable for coordination to a variety of metal centers across the periodic table, including oxophilic metals. Various metal complexes bearing such ligand are indeed readily accessible in high yields via straightforward routes. Interestingly, a robust zirconium-NHC complex was found to polymerize rac-lactide in a highly controlled, living and stereoselective manner to afford heterotactic PLA.


Investigating the use of primary adult subventricular zone neural precursor cells for neuronal replacement therapies.
With the relatively recent discovery that neurogenesis persists throughout life in restricted regions of the adult mammalian brain, including those of human beings, there has been great interest in the use of adult-derived neural stem cells for neuronal replacement. There are many great hurdles that must be overcome in order for such replacement strategies to succeed. In this review, we outline some of these hurdles and discuss recent experiments that investigate the potential of using neural precursor cells found in the subventricular zone of the adult brain for brain repair.


c-Jun regulates eyelid closure and skin tumor development through EGFR signaling.
To investigate the function of c-Jun during skin development and skin tumor formation, we conditionally inactivated c-jun in the epidermis. Mice lacking c-jun in keratinocytes (c-jun(Deltaep)) develop normal skin but express reduced levels of EGFR in the eyelids, leading to open eyes at birth, as observed in EGFR null mice. Primary keratinocytes from c-jun(Deltaep) mice proliferate poorly, show increased differentiation, and form prominent cortical actin bundles, most likely because of decreased expression of EGFR and its ligand HB-EGF. In the absence of c-Jun, tumor-prone K5-SOS-F transgenic mice develop smaller papillomas, with reduced expression of EGFR in basal keratinocytes. Thus, using three experimental systems, we show that EGFR and HB-EGF are regulated by c-Jun, which controls eyelid development, keratinocyte proliferation, and skin tumor formation.


Determination of ²³⁹Pu airborne concentration alpha correction factor for a zinc sulfide detector via ambient ²²²Rn progeny air sampling.
This research empirically determined the ²³⁹Pu airborne concentration alpha correction factor for an ADM-300 zinc sulfide detection system via ambient ²²²Rn progeny air sampling using a RADeCO high volume air sampler. Radon progeny air samples were collected on a four inch glass fiber filter and evaluated on both a high purity germanium detector and the ADMē-300 simultaneously using the three count method. These data were analyzed to obtain a loss fraction in the glass fiber filter for the ²¹⁴Bi collected. The ²¹⁴Bi response then was used to estimate a loss fraction for ²³⁹Pu. The ²³⁹Pu airborne concentration alpha correction factor for the ADM-300 detection system was found to be 445 ± 47 dpm ft³ cpm⁻¹ m⁻³ as compared to a previously published correction factor of 500 dpm ft³ cpm⁻¹ m⁻³.


WITHDRAWN: Alternative functional criteria to assess airflow-limitation reversibility in asthma.
This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.08.002. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.


Economic burden of periodontitis in the United States and Europe: An updated estimation.
The aim of this study is to estimate the direct and indirect economic burdens of periodontal disease in the US and in Europe. We used the most recent data available for the US and for Europe (32 European countries) to estimate the cost of periodontal disease. Global health, dental and periodontal expenditures were estimated. We tried to estimate the direct and the indirect costs of periodontitis. Indirect costs, those related to productivity losses, are a consequence of periodontal disease proper, plus edentulism and caries because of periodontal disease. In 2018, the aggregate cost in the US was estimated at $3.49B and €2.52B in Europe. Indirect costs because of periodontal disease amounted to $150.57B (95% confidence interval [CI]: 103.32-189.87) in the US countries and €156.12B (95% CI: 123.72-221.86) in Europe. The majority of the projected indirect costs were because of edentulism related to periodontal disease and periodontal disease. Indirect costs were the majority of the estimated economic impact with an average of 0.73% (95% CI: 0.50%-0.93%) of annual gross domestic product in the US and 0.99% (95% CI: 0.78%-1.40%) in Europe. Periodontal disease caused an estimated loss of $154.06B in the US and €158.64B in Europe, in 2018. These results show that the economic burden of periodontal disease is significant and its indirect costs are impactful.


Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care.
The reliability of a clinical diagnosis of heart failure in primary care is poor. Concentrations of natriuretic peptides are high in heart failure. This population-based study examined the predictive value of natriuretic peptides in patients with a new primary-care diagnosis of heart failure. Concentrations of plasma atrial (ANP and N-terminal ANP) and B-type (BNP) natriuretic peptides were measured by radioimmunoassay in 122 consecutive patients referred to a rapid-access heart-failure clinic with a new primary-care diagnosis of heart failure. On the basis of clinical assessment, chest radiography, and transthoracic echocardiography, a panel of three cardiologists decided that 35 (29%) patients met the case definition for new heart failure. ANP and NT-ANP results were available for 117 patients (34 with heart failure) and BNP results for 106 (29 with heart failure). Geometric mean concentrations of natriuretic peptides were much higher in patients with heart failure than in those with other diagnoses (29.2 vs 12.4 pmol/L for ANP; 63.9 vs 13.9 pmol/L for BNP; 1187 vs 410.6 pmol/L for NT-ANP; all p < 0.001). At cut-off values chosen to give negative predictive values for heart failure of 98% (ANP > or = 18.1 pmol/L, NT-ANP > or = 537.6 pmol/L, BNP > or = 22.2 pmol/L), the sensitivity, specificity, and positive predictive value for ANP were 97%, 72%, and 55%; for NT-ANP 97%, 66%, and 54%; and for BNP 97%, 84%, and 70%. Addition of ANP or NT-ANP concentration or both did not improve the predictive power of a logistic regression model containing BNP concentration alone. In patients with symptoms suspected by a general practitioner to be due to heart failure, plasma BNP concentration seems to be a useful indicator of which patients are likely to have heart failure and require further clinical assessment.


Characteristics and gelling properties of gelatin from goat skin as affected by drying methods.
Characteristics and gel properties of spray-dried goat skin gelatin (SDGG) and freeze-dried counterpart (FDGG) were determined, in comparison with commercial bovine gelatin (BG). SDGG gel had the similar gel strength to FDGG gel and their gel strengths were higher than that of BG gel. SDGG gel showed slightly higher a* and b* values as well as the higher solution turbidity than those of FDGG. Both SDGG and FDGG solutions could set at room temperature (25-28 °C) within 18.52-19.30 min and showed the gelling and melting temperatures of 25.14-25.23 and 34.09-34.18 °C, respectively. Gels from SDGG and FDGG had the denser structure with smaller voids than that from BG. Therefore, drying methods affected the characteristics and gel properties of gelatin from goat skin to some degree.


Impact of Social Distancing on the Mental Health of Parents and Children in Qatar.
This study investigated the effects of COVID-19-related social distancing practices on parents and children's mental health and explored joint parent-child activities and coping strategies among Arab families in Qatar. The sample of 308 parents answered self-reported questionnaires regarding their mental health, coping strategies, activities with their children, social distancing practices, and their children's mental health. Pearson's correlation coefficient and structural equation modeling were carried out. The results showed a significant positive correlation between social distancing and parents' activities with their children and their coping strategies, as well as between parents' mental health, activities with their children, children's mental health, and parents' coping strategies. Path analysis showed that social distancing practices influence both parents' and children's mental health through parents' activities with children and their coping strategies. Our findings revealed how living under stressful conditions, such as COVID-19, could enhance the mental health of family members.


2-[2-(1H-Imidazol-3-ium-5-yl)eth-yl]-3-(pyridin-2-yl)-2H-imidazo[1,5-a]pyridin-4-ium bis-(perchlorate).
In the title mol-ecular salt, C(17)H(17)N(5) (+)·2ClO(4) (-), the dihedral angles between the fused-ring system and the pendant five- and six-membered heterocyclic rings are 6.4 (2) and 41.29 (19)°, respectively. The O atoms of both perchlorate anions are disordered over two sets of sites with occupancy ratios of 0.614 (8):0.386 (8) and 0.591 (7):0.409 (7). An intra-molecular C-H⋯N contact occurs in the cation. In the crystal, the components are linked by N-H⋯O and C-H⋯O hydrogen bonds and π-π stacking inter-actions [centroid-centroid separation = 3.642 (3) Å].


The influence of proteases on the browning of dried squid products processed by air-drying.
To clarify why mantle meat from Japanese common squid (Todarodes pacificus) dried products discolor dramatically when processed by air-drying, the role of endogenous protease(s) on browning during the processing of dried squid products was studied. The involvement of endogenous protease(s) in the generation of Free Amino Acids (FAAs) participating in the Maillard reaction was characterized. The browning and myosin heavy chain degradation during air-drying were obviously mitigated by the addition of metalloprotease inhibitors, especially EGTA and 1,10-phenanthroline, followed by serine proteinase inhibitor, especially PMSF. The amount of total FAAs in dried products increased by only 0.17% with the addition of 1,10-phenanthroline and 5.0% with added EGTA. In autolysis models, protein autolysis was almost completely inhibited by 1,10-phenanthroline. The addition of, 1,10-phenanthroline inhibited the increase in total FAAs including arginine (Arg), followed by EGTA and PMSF. The results indicated that endogenous metalloproteases and serine proteases might influence the generation of FAAs including Arg, and contribute to product discoloration during air-drying.


Alcohol Dehydrogenases with anti-Prelog Stereopreference in Synthesis of Enantiopure Alcohols.
Biocatalytic production of both enantiomers of optically active alcohols with high enantiopurities is of great interest in industry. Alcohol dehydrogenases (ADHs) represent an important class of enzymes that could be used as catalysts to produce optically active alcohols from their corresponding prochiral ketones. This review covers examples of the synthesis of optically active alcohols using ADHs that exhibit anti-Prelog stereopreference. Both wild-type and engineered ADHs that exhibit anti-Prelog stereopreference are highlighted.


Controlled discontinuation of benzodiazepine treatment for patients with panic disorder.
The purpose of this study was to compare the effects of discontinuing treatment with intermediate- and long-acting benzodiazepines. Fifty patients with panic disorder who had taken part in a double-blind treatment study and had responded to alprazolam, diazepam, or placebo for 8 months were asked to stop taking these medications gradually. After a relatively rapid dose reduction, the majority of patients relapsed. Rebound anxiety and withdrawal symptoms were identified in a substantial minority of patients. Those who were taking alprazolam showed earlier and more intense rebound anxiety and withdrawal symptoms than did the patients who received diazepam. Both the level of pretreatment anxiety and the drug the patient was taking predicted the level of anxiety when drug treatment was discontinued. The findings indicate that withdrawal phenomena commonly occur after patients stop taking benzodiazepines and that they are more frequent after discontinuation of treatment with shorter-acting drugs.


Dietary inclusion of detoxified Jatropha curcas kernel meal: effects on growth performance and metabolic efficiency in common carp, Cyprinus carpio L.
Jatropha curcas is a multipurpose and drought-resistant shrub or small tree widespread all over the tropics and subtropics. Its seeds are rich in oil, and the Jatropha kernel meal obtained after oil extraction is rich in protein. However, presence of toxic and antinutritional constituents restricts its use in fish feed. Jatropha kernel meal was detoxified. Common carp, Cyprinus carpio, fingerlings (15; av. body mass 10.9±0.65 g) were randomly distributed in three groups with five replicates. A 6-week feeding experiment was conducted in a respirometer system to evaluate the growth performance, nutrient utilisation and energy budget. Fish were fed isonitrogenous diets (38% crude protein): control diet (Control group) containing fish meal (FM) protein based protein and two other diets replacing 75% FM protein with detoxified Jatropha kernel meal (DJKM, Jatropha group) and soybean meal (SBM, Soybean group). At the end of the experiment, body mass gain, metabolic growth rate, protein efficiency ratio, protein productive value, energy retention, efficiency of metabolised energy for growth and efficiency of energy retention were determined. These parameters were high and statistically similar for Control and Jatropha groups and significantly lower (P<0.05) for Soybean group. Whereas a reverse trend was observed for energy expenditure per g protein retained in fish body. No significant differences were found in heat released, gross energy uptake, metabolised energy intake, metabolisability, energy expenditure, energy expenditure per g protein fed and apparently unmetabolised energy. Conclusively, common carp-fed plant protein (DJKM and SBM) and FM protein-based diets exhibited equal average metabolic rate.


A resource for cell line authentication, annotation and quality control.
Cell line misidentification, contamination and poor annotation affect scientific reproducibility. Here we outline simple measures to detect or avoid cross-contamination, present a framework for cell line annotation linked to short tandem repeat and single nucleotide polymorphism profiles, and provide a catalogue of synonymous cell lines. This resource will enable our community to eradicate the use of misidentified lines and generate credible cell-based data.


Changes in preferred postural patterns following stroke during intentional ankle/hip coordination.
We compared the spatio-temporal postural organization between stroke patients and healthy controls in a bipedal standing task where participants had to intentionally produce two specific ankle/hip coordination patterns: in-phase and anti-phase. The pattern to reproduce was visually represented by a ankle-hip Lissajous figure, and a real-time biofeedback displayed the current coordination sur-imposed to the expected coordination. Contrary to the healthy participants who were successful at reproducing the two patterns, stroke patients were unable to produce the in-phase pattern. In addition, when the anti-phase pattern was required, a reduction of stability was observed for the stroke group. The impairment of postural capacities following stroke was thus accompanied by a disappearance of one of the two preferred patterns found in healthy participants, a result that have consequences for understanding the etiology of postural pattern formation and the elaboration of rehabilitation programs.


Destructive strategies in treating cerebrovascular pathology: Review and treatment algorithm.
The goal of cerebrovascular pathology treatment is most often to angiographically eradicate a lesion with the lowest probability of morbidity. Destructive strategies using parent vessel occlusion are less commonly considered in the modern era. We review principles of parent vessel occlusion for treatment of cerebrovascular pathology and select cases to demonstrate these principles. Many common cerebrovascular conditions have been safely and effectively treated with destructive strategies including intracranial aneurysms, traumatic craniocervical vascular injuries, and oncologic indications such as carotid blowout. Avoiding procedural morbidity in these procedures involves assessment of collaterals distal to a planned parent vessel occlusion, determination of this arterial segment's eloquence, prevention of distal migration of endovascular devices or thrombus, and prevention of stump emboli. An algorithm for case selection and method of destructive technique versus a reconstructive approach can be used. Destructive strategies for treating cerebrovascular pathology are still relevant and can be applied safely in appropriately selected cases.


Solidified liquid layer model makes quartz crystal microbalance a convenient molecular ruler.
The applications of quartz crystal microbalance (QCM) in biointerfaces are limited by its quantitative ambiguities caused by viscoelasticity and solution effects. Although many studies clearly indicated that the quantitative interpretation of QCM data needed caution, none of those studies provided a practical solution that enabled general and quantitative interpretation of QCM data. Recently we proposed a "solidified liquid layer" model that enabled QCM to be used as a biomolecular ruler. Here we applied five kinds of proteins with significant differences in their sizes and shapes to further validate this model. The effective thickness (T(eff)) of surface immobilized, hydrated proteins were 10.2, 4.7, 1.8 and 4.8 nm for rabbit IgG, streptavidin, lysozyme, and bovine serum albumin, respectively. The critical number of stakes needed for the formation of a solidified liquid layer was found to be protein dependent. We believed this "solidified liquid layer" model will facilitate the popularization of QCM as a valuable tool in biointerface studies, such as protein adsorption process or the conformational change on surface.


[Results of 68 revascularizations of the arteries of the leg].
Results with 68 infra popliteal revascularization inversed autogenous grafts are subjected to life table analysis. The patency rate at 1, 3 and 5 years are 63.8%, 53.5% and 43.7%. This procedure allowed limb salvage in 78.5% (13 years follow up).


Rational design of copper encapsulated within nitrogen-doped carbon core-shell nanosphere for efficiently photocatalytic peroxymonosulfate activation.
Photocatalysis utilizing solar energy is a promising strategy for mitigating energy crisis and environmental pollution. Exploring a cost-effective, stable, eco-friendly, and efficient photocatalytic system is extremely urgent. Herein, copper encapsulated within nitrogen-doped carbon nanosphere (Cu@NC) possessing a unique core-shell structure with high catalytic activity was prepared by ion-exchange and pyrolysis using resin as support. The protective carbon shell can prevent the leaching of metal ions and deactivation of the catalyst. Benefiting from the special structure, Cu@NC exhibited excellent activity and durability toward the degradation of tetracycline by the activation of peroxymonosulfate (PMS). The radical trapping experiments and electron spin resonance analyses were applied to elucidate the main reactive species. This work highlights the great potential of Cu@NC core-shell nanosphere as photocatalyst, which provides a new opportunity for the remediation of environmental pollution.


KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia.
Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector beta-catenin and deregulated beta-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for beta-catenin in mast cell leukemia has not been described. Nuclear accumulation of beta-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by deregulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and beta-catenin signaling in mast cell leukemia. Beta-catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. Beta-catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of beta-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and beta-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of beta-catenin directly. Aberrant beta-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia.


Special considerations for Mohs micrographic surgery on the eyelids, lips, genitalia, and nail unit.
Although skin cancers on the eyelids, lips, genitalia, and the nail unit are infrequent, some skin cancers can have higher recurrence rates in these anatomic locations. Intrinsic to Mohs micrographic surgery (MMS) is maximal tissue preservation and high cure rates, making it a worthwhile procedure for these sensitive anatomic areas to ameliorate any functional or aesthetic compromise. The Mohs surgeon can provide a great service to patients by being aware of the anatomy, specialized instruments, unique histology, and potential complications when performing MMS on these areas.


Phosphate transfer between acetate kinase and enzyme I of the bacterial phosphotransferase system.
Interactions between homogeneous acetate kinase and proteins of the phosphoenolpyruvate:glucose phosphotransferase system (PTS) were studied. The phosphorylation of D-glucose was followed spectrophotometrically using a coupled assay system, and acetate kinase and GTP were found to substitute for phosphoenolpyruvate provided that each of the PTS proteins was present in the mixture. To further define the phosphoryl transfer reaction pathway, the system was simplified to include only the homogeneous, soluble PTS proteins. 32P was transferred from [gamma-32P]ATP to the protein IIIGlc, but this transfer reaction required acetate kinase, and the PTS proteins Enzyme I and HPr. These results suggested that acetate kinase interacts with the first protein in the PTS sequence, Enzyme I. Acetate kinase was therefore incubated with [32P] phospho-Enzyme I, and a direct transfer of the phosphoryl group was observed without the addition of any other protein. These results show that there is a reversible transfer of the phosphoryl group between Enzyme I and acetate kinase. The possible role of this interaction in regulating sugar uptake by the Krebs cycle is discussed.


Ultrastructural studies of experimental acute pancreatitis.
Acute pancreatitis was studied by electron microscopy after retrograde infusion of either trypsin, and/or beta-glucuronidase into the canine pancreatic duct. Marked changes were induced by the mixture of trypsin and beta-glucuronidase. (1) The acinar cells were initially excavated from the acinar lumen and formed cystic bodies in themselves. The cystic bodies were then disrupted at their marginal membranes, and the acinar cells were filled with a large amount of fibrillar materials which originated from the contents of the cystic bodies. At this time, the luminal margin of the acinar cells completely disappeared. (2) The cellular organellas and the intracellular fibrillar materials in the acinar cells were discharged into the interstitial space through the disrupted basal lamina. Infection in the pancreatic ductal system was considered to play an important role in the pathogenesis of acute hemorrhagic pancreatitis.


[The operating room, a place of training with multiple benefits for future professionals].
The importance of internships, as part of the alternating training of nursing students, is no longer in question. Thus, to obtain their diploma, out of the 180 European credits expected, 60 come from these placements. Although very specific and not very much involved in the training of students in initial training, an internship in the operating room is very instructive and contributes to the development of multiple nursing knowledge and skills.


Activation of partially purified rat liver lipid methyltransferase by phosphorylation.
Incubation of partially purified rat liver lipid methyltransferase with MgATP and the catalytic subunit of the cyclic AMP dependent protein kinase results in up to 4-fold activation of the methylation reaction. When (gamma-32p) MgATP is included in the assay mixture, the analysis of the phosphoprotein products by electrophoresis shows the incorporation of 32p into a single protein band of about 50K and pI 4.75. It is concluded that rat liver lipid methyltransferase can be converted from a low activity dephosphorylated form to a high activity phosphorylated form.


Central heating devices cause childhood injuries but rarely burns: a study in Greece.
Injuries related to central heating devices represent a non-negligible fraction of all indoor injuries among children with mechanical lesions, outnumbering burns. Prevention strategies refer mainly to modifications or safer use of the appliances and improvements in building design.


Age-related causes of emergency department visits after pediatric adenotonsillectomy at a tertiary pediatric referral center.
The complications of tonsillectomy and adenoidectomy (T&A) are well-described and include bleeding, dehydration, nausea, respiratory complications, and pain. After the immediate postoperative phase, the overall 30-day emergency department (ED) return rate is as high as 13.3%. However, few studies have examined the types and rates of late post-operative complications for children undergoing T&A stratified base on patient age. Herein, we aim to better characterize ED return visits for children of all ages, with special attention to those patients under three years of age. This is a retrospective case series at a tertiary academic pediatric medical center. All patients 18 years of age or younger who underwent T&A over eighteen months were included. Data including ED return diagnosis, post-operative day of presentation, and need for surgical intervention was recorded for patients who presented to the ED within 30 days of their original surgery. 5,225 patients were identified, with an overall late complication rate of 12.8%. There was no difference in the 30-day ED readmission rate for children under the age of three, although children under the age of two were more likely to present to the ED. There was a significantly higher risk of dehydration for children under the age of four years, and a significantly higher bleeding risk and need for reoperation for control of post-tonsillectomy hemorrhage (PTH) for children over the age of six. The overall ED visit rate in this study is 12.8%, with no difference based on age. Patients younger than three years of age are more likely to return to ED for dehydration, while bleeding and need for control of oropharyngeal hemorrhage is more common in older children. Knowledge of the age-related late complications of T&A may direct appropriate anticipatory peri-operative counseling of risks and return precautions.


Atmospheric science: early peak in Antarctic oscillation index.
The principal extratropical atmospheric circulation mode in the Southern Hemisphere, the Antarctic oscillation (or Southern Hemisphere annular mode), represents fluctuations in the strength of the circumpolar vortex and has shown a trend towards a positive index in austral summer in recent decades, which has been linked to stratospheric ozone depletion and to increased atmospheric greenhouse-gas concentrations. Here we reconstruct the austral summer (December-January) Antarctic oscillation index from sea-level pressure measurements over the twentieth century and find that large positive values, and positive trends of a similar magnitude to those of past decades, also occurred around 1960, and that strong negative trends occurred afterwards. This positive Antarctic oscillation index and large positive trend during a period before ozone-depleting chemicals were released into the atmosphere and before marked anthropogenic warming, together with the later negative trend, indicate that natural forcing factors or internal mechanisms in the climate system must also strongly influence the state of the Antarctic oscillation.


Analysis of factors contributing to occupational health inequality in Korea: a cross-sectional study using nationally representative survey data.
Despite the consensus that higher occupational classes tend to have better health and lower mortality rates, one study has reported reversed occupational gradients in mortality rates among Korean men after the economic crisis in the late 2000s. To examine these patterns of health inequality in more detail, we investigated the tendency of occupational gradients in socioeconomic position and multiple pathway indicators known to affect mortality in Korea. We used data from 4176 men aged 35-64 in Korea derived from the 2007-2009 and 2013-2015 Korean National Health and Nutrition Examination Surveys. We compared the age-standardized prevalence and age-adjusted mean values of each contributing factor to health inequality among occupational groups, which are divided into upper non-manual workers, lower non-manual workers, manual workers, and others. Contributing factors included childhood and adulthood socioeconomic position indicators, biological risk factors, health behaviors, psychosocial factors, and work environment. Upper non-manual workers had prominently higher levels of education, income, parental education, and economic activity than lower non-manual and manual workers. The rates of smoking and high-risk alcohol consumption were lower, and the rate of weight control activities was higher, in the non-manual classes. Further, the rates of depression and suicidal ideation were lower, and perceptions of the work environment were more favorable, among non-manual workers than among their manual counterparts. We detected occupational inequality in a wide range of socioeconomic positions and pathway indicators in Korea with consistently favorable patterns for upper non-manual workers. These occupational gradients do not support the previously reported reversed pattern of higher mortality rates in non-manual groups versus in the manual job class in Korea.


Morphology of microvascular changes and endothelial regeneration in experimental ozone-induced parathyroiditis. III. Some pathologic considerations.
Proliferation of the vascular endothelium of the parathyroid glands of dogs exposed to ozone inhalation was studied. Direct observation of mitoses in the endothelial cells were made. Focal hemorrhages in the form of the presence of erythrocytes, clotting, and fibrin deposition in the extravascular spaces were seen. Ultrastructural analysis of transverse section of blood vessels showed intravascular platelet aggregation. Lymphoid cells were observed in the lumen of the blood vessels as well as in the perivascular areas as infiltrates. The possibility is discussed that present vascular reactions signify the morphologic equivalent of an immunologic response.


Conjugated linoleic acid inhibits peritoneal metastasis in human gastrointestinal cancer cells.
The effect of conjugated linoleic acid (CLA) on peritoneal metastasis was examined by in vitro treatment of cancer cells and mouse peritoneal metastasis models. First, cell growth of MKN28 human gastric cancer cells and Colo320 human colon cancer cells was suppressed by CLA in a dose-dependent manner with an increment in apoptosis. CLA significantly inhibited invasion into type IV collagen-coated membrane of MKN28 and Colo320 cells (p < 0.05). CLA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor (PPAR)-gamma in both cell lines. BALB/c nu-nu mice were inoculated with MKN28 and Colo320 cells into their peritoneal cavity, and administrated with CLA intraperitoneally (weekly, 4 times). CLA treatment did not affect food intake or weight gain of mice. CLA treatment significantly decreased metastatic foci of both cells in the peritoneal cavity (p < 0.005). Survival rate in mice inoculated with MKN28 or Colo320 cells was significantly recovered by CLA treatment (p = 0.0025 and 0.0052, respectively). Protein production in MKN28 and Colo320 cells treated with CLA showed a decrease in epidermal growth factor receptor and transforming growth factor-alpha and an increase in Bax. These findings suggest that CLA inhibits metastasis of human gastric and colon cancer cells.


Tumor Size Predicts Muscle-invasive and Non-organ-confined Disease in Upper Tract Urothelial Carcinoma at Radical Nephroureterectomy.
Pathological stage and grade of renal pelvis urothelial carcinoma (RPUC) are difficult to estimate before radical nephroureterectomy (RNU). To examine tumor size as an independent predictor of muscle-invasive and/or non-organ-confined rates of RPUC at RNU. Within the Surveillance, Epidemiology and End Results (SEER) database (2004-2016), we identified nonmetastatic RPUC at RNU. First, we examined stage and grade distributions. Second, two separate univariable and subsequent multivariable logistic regression models (LRMs) were fitted to test the association between tumor size and the rate of (1) muscle-invasive or higher (pT2-4N0-2) and (2) non-organ-confined (pT3-4N0-2) RPUC at RNU. Of 4657 patients, 3052 (65.5%) had pT2-4N0-2 and 2382 (51.2%) pT3-4N0-2 RPUC at RNU. The median tumor size was 3.7 cm (interquartile range 2.5-5.0). The high-grade RPUC rate ranged from 71.1% to 87.2% (p < 0.001) among SEER registries. Conversely, no differences were recorded for stage (p > 0.05) or tumor size (p = 0.1) across all registries. Rates of pT2-4N0-2 and pT3-4N0-2 RPUC increased with tumor size. Specifically, for tumor size intervals from 0.1-1.0 cm to 9.1-10.0 cm, the pT2-4N0-2 rate ranged from 45% to 83% and the pT3-4N0-2 rate ranged from 23% to 75%, respectively (both p < 0.001). In multivariable LRMs, tumor size (in 1-cm units) was an independent predictor of pT2-4N0-2 (odds ratio [OR] 1.25; p < 0.001) and pT3-4N0-2 (OR 1.30; p < 0.001) disease at RNU. Tumor size is a key predictor of muscle-invasive or non-organ-confined RPUC. Greater tumor size directly and virtually linearly predicts a higher rate of invasive or non-organ-confined RPUC at RNU. For patients with cancer in urinary tract cells lining the kidney, larger tumor size predicts worse stage of the disease at surgery.


Illustration of a fatal radiation-induced lung aneurysm: Is central lung stereotactic radiotherapy to be banned?
Stereotactic body radiation therapy is still controversial for inoperable patients with central lung lesion. We report the case of a 59-year-old woman with previous history of head and neck squamous cell carcinoma who was treated by lung stereotactic body irradiation for an inoperable lymph node in station 10R. One year after, a fibroscopy showed a necrosis of the right main bronchus mucosae and the CT showed a radio-induced aneurysm protruding into the right inferior lobular bronchus. The patient eventually died a few hours later with a massive haemoptysis. This case highlights the potential toxicity of central lung stereotactic body radiation therapy and raises the question of its legitimacy.


The community structure of Methanomassiliicoccales in the rumen of Chinese goats and its response to a high-grain diet.
The newly proposed methanogenic order 'Methanomassiliicoccales' is the second largest archaeal population in the rumen, second only to the Methanobrevibacter population. However, information is limited regarding the community of this new order in the rumen. This study used real-time PCR and 454 pyrosequencing to explore the abundance and community composition of Methanomassiliicoccales in the rumen of Chinese goats fed a hay (0% grain, n = 5) or a high grain (65% grain, n = 5) diet. Real-time PCR analysis showed that the relative abundance of Methanomassiliicoccales (% of total archaea) in the goat rumen was significantly lower in the high-grain-diet group (0.5% ± 0.2%) than that in the hay-diet group (8.2% ± 1.1%, P < 0.05). The pyrosequencing results showed that a total of 208 operational taxonomic units (OTUs) were formed from ten samples at 99% sequence identity. All the sequences were identified as Methanomassiliicoccaceae at the family level, and most of the sequences (96.82% ± 1.64%) were further classified as Group 8, 9, and 10 at the Methanomassiliicoccales genus level in each sample based on the RIM-DB database. No significant differences were observed in the number of OTUs or Chao1's, Shannon's or Pielou's evenness indexes between the hay- and high-grain-diet groups (P ≥ 0.05). PCoA analysis showed that diet altered the community of Methanomassiliicoccales. At the genus level, the relative abundances of Group 10 (67.25 ± 12.76 vs. 38.13 ± 15.66, P = 0.012) and Group 4 (2.07 ± 1.30 vs. 0.27 ± 0.30, P = 0.035) were significantly higher in the high-grain-diet group, while the relative abundance of Group 9 was significantly higher in the hay-diet group (18.82 ± 6.20 vs. 47.14 ± 17.72, P = 0.020). At the species level, the relative abundance of Group 10 sp. (67.25 ± 12.76 vs. 38.13 ± 15.66, P = 0.012) and Group 4 sp. MpT1 (2.07 ± 1.30 vs. 0.27 ± 0.30, P = 0.035) were significantly higher in the high-grain-diet group, while the relative abundance of Group 9 sp. ISO4-G1 was significantly higher in the hay-diet group (12.83 ± 3.87 vs. 42.44 ± 18.47, P = 0.022). Only a few highly abundant phylogenetic groups dominated within the Methanomassiliicoccales community in the rumens of Chinese goats, and these were easily depressed by high-grain-diet feeding. The relatively low abundance suggests a small contribution on the part of Methanomassiliicoccales to the rumen methanogenesis of Chinese goats.


Steroid hormone regulation of ovalbumin and conalbumin gene transcription. A model based upon multiple regulatory sites and intermediary proteins.
Changes in rates of ovalbumin and conalbumin gene transcription and mRNA levels were monitored during an entire cycle of estrogen withdrawal and restimulation. Correlations of transcription rates with nuclear estrogen receptor levels in this experiment and in dose-response experiments reveal that conalbumin gene transcription is directly proportional to nuclear receptor levels, whereas ovalbumin gene transcription is related to receptor levels in a way that suggests cooperative interactions among receptors. Conalbumin mRNA accumulation and transcription are transiently inhibited by administration of progesterone to estrogen-stimulated chicks, whereas ovalbumin gene transcription is stimulated by this regimen. This puzzling observation can be rationalized if a single receptor binding site is involved in conalbumin gene regulation and multiple sites are involved in ovalbumin gene regulation. These ideas are combined with our recent observations that protein synthesis inhibitors and butyrate selectively, but reversibly, inhibit ovalbumin and conalbumin gene transcription. We describe a new hypothesis of how steroid hormones regulate egg white gene transcription in the chick oviduct.


A nationwide cohort study of educational background and major causes of death among the elderly population in Japan.
This prospective cohort study examined the association between educational level and major causes of death in Japan. A baseline survey was conducted between 1988 and 1990 among 110,792 inhabitants of 45 areas aged 40-79 years. Follow-up surveys were conducted annually and causes of death were identified from death certificates. The analysis was restricted to 16,715 men and 23,284 women. During the follow-up period (377,139 person-years), 6628 deaths were recorded. Individuals with low levels of education had an increased overall risk of death [relative risk (RR)=1.16, 95% confidence interval (CI): 1.08, 1.25, in men; RR=1.26, 95% CI: 1.14, 1.39, in women], cancers (RR=1.17, 95% CI: 1.04, 1.32, in men; RR=1.10, 95% CI: 0.93, 1.30, in women), and death from external causes (RR=1.81, 95% CI: 1.29. 2.54, in men; RR=1.78, 95% CI: 1.18, 2.70, in women). Ischemic heart disease risk was marginally reduced in men with low levels of education (RR=0.77, 95% CI: 0.58, 1.01). These results show that health inequalities exist in Japan, even though wealth inequalities are relatively low. Social and political initiatives will be needed to correct these inequities between different socioeconomic statuses.


Ventral pallidum DRD3 potentiates a pallido-habenular circuit driving accumbal dopamine release and cocaine seeking.
Drugs of abuse induce persistent remodeling of reward circuit function, a process thought to underlie the emergence of drug craving and relapse to drug use. However, how circuit-specific, drug-induced molecular and cellular plasticity can have distributed effects on the mesolimbic dopamine reward system to facilitate relapse to drug use is not fully elucidated. Here, we demonstrate that dopamine receptor D3 (DRD3)-dependent plasticity in the ventral pallidum (VP) drives potentiation of dopamine release in the nucleus accumbens during relapse to cocaine seeking after abstinence. We show that two distinct VP DRD3+ neuronal populations projecting to either the lateral habenula (LHb) or the ventral tegmental area (VTA) display different patterns of activity during drug seeking following abstinence from cocaine self-administration and that selective suppression of elevated activity or DRD3 signaling in the LHb-projecting population reduces drug seeking. Together, our results uncover how circuit-specific DRD3-mediated plasticity contributes to the process of drug relapse.


Detection and characterization of hyperfine-shifted resonances in the proton nuclear magnetic resonance spectrum of Anabaena 7120 ferredoxin at high magnetic fields.
This paper presents previously unobserved signals in the 1H NMR spectra of oxidized and reduced [2Fe-2S]-ferredoxin from Anabaena 7120 detected at 400, 500, and 600 MHz. The signals shifted to low field exhibited longitudinal relaxation (T1) values in the range of 100-400 microseconds and line widths in the range of 1-10 kHz (at 400 MHz), and the chemical shifts of all signals showed strong temperature dependence. Although the line widths were smaller at lower magnetic fields, the resolution was better at higher magnetic fields. In the oxidized state, a broad signal was detected at 37 ppm, which corresponds to at least 6 protons, and whose chemical shift exhibits positive temperature dependence. This signal also was found in oxidized ferredoxin reconstituted in 2H2O, which excludes the signal as arising from solvent-exchangeable amide protons. In the reduced state, four signals detected between 90 and 140 ppm exhibited negative temperature dependence. These consisted of two pairs of signals, each pair having one component with half the linewidth of the other. On the basis of their chemical shifts, linewidths, longitudinal relaxation properties, and temperature dependence we assigned these resonances to four of the beta hydrogens of the ligated cysteines. Two solvent-exchangeable hyperfine-shifted signals were found in the reduced state; these are located upfield of the diamagnetic region. The low-field hyperfine resonances of half-reduced ferredoxin in the presence of sodium dithionite showed a self electron transfer exchange rate that was slow on the NMR scale as observed earlier (Chan, T., and Markley, J. L. (1983) Biochemistry 22, 5982-5987), but the exchange rate was accelerated in the presence of methyl viologen.


Electrical status epilepticus in sleep: The role of thalamus in etiopathogenesis.
In patients diagnosed with epilepsy, decreased ratio of N-acetyl aspartate to creatine (NAA/Cr) measured in magnetic resonance spectroscopy (MRS) has been accepted as a sign of neuronal cell loss or dysfunction. In this study, we aimed to determine whether a similar neuronal cell loss is present in a group of encephalopathy with electrical status epilepticus in sleep (ESES) patients METHODS: We performed this case-control study at a tertiary pediatric neurology center with patients with ESES. Inclusion criteria for the patient group were as follows: 1) a spike-wave index of at least 50%, 2) acquired neuropsychological regression, 3) normal cranial MRI. Eventually, a total of 21 patients with ESES and 17 control subjects were enrolled in the study. MRI of all control subjects was also within normal limits. 3D Slicer program was used for the analysis of thalamic and brain volumes. LCModel spectral fitting software was used to analyze single-voxel MRS data from the right and left thalamus of the subjects. The mean age was 8.0 ± 1.88 years and 8.3 ± 1.70 years in ESES patients and the control subjects. After correcting for the main potential confounders (age and gender) with a linear regression model, NAA/Creatine ratio of the right thalamus was significantly lower in the ESES patient group compared to the healthy control group (p = 0.026). Likewise, the left thalamus NAA/Cr ratio was significantly lower in the ESES patient group than the healthy control group (p = 0.007). After correcting for age and gender, right thalamic volume was not statistically significantly smaller in ESES patients than in healthy controls (p = 0.337), but left thalamic volume was smaller in ESES patients than in healthy controls (p = 0.024). In ESES patients, the NAA/Creatine ratio, which is an indicator of neuronal cell loss or dysfunction in the right and left thalamus, which appears regular on MRI, was found to be significantly lower than the healthy control group. This metabolic-induced thalamic dysfunction, which was reported for the first time up to date, may play a role in ESES epileptogenesis.