[Alterations in the histostructure of the pancreas in experimental diabetes caused by quinoline derivatives].
Administration of chinoline derivatives, with a capacity to form stable complexes with metals (zinc?), was accompanied by a selective damage of the pancreatic islands with development of diabetes mellitus. Changes in the histostructure of the tissue caused by chinoline compounds of various chemical structure were unitypical. Their severity chiefly depended on the severity and duration of diabetes. Diabetes under study arising after the administration of chinoline derivatives were good models for detailed ascertaining of histostructure of the islet tissue and of the pancreatic duct in diabetes.


Advance in methods studying the pharmacokinetics of polyphenols.
Significant advances have been achieved during the past decade concerning the metabolism of polyphenol compounds in vitro, but scarce data has been presented about what really happens in vivo. Many studies on polyphenols to date have focused on the bioactivity of one specific molecule in aglycone form, often at supraphysiological doses, whereas foods contain complex, often poorly characterized mixtures with multiple additive or interfering activities. Whereas most studies up to the middle-late 1990s measured total aglycones in plasma and urine, after chemical or enzymatic deconjugation, or both, several recent works now report the polyphenol conjugate composition of plasma, urine, feces and/or tissues, after the administration of pure polyphenols or polyphenol-rich matrices. HPLC methods with electrochemical, mass spectrometric and fluorescence detection have adequate sensitivity. LC/UV-Vis methods have also been widely reported, but they are much less sensitive. Compared with electro-chemical and fluorescence detection, MS can quantify analytes without chromatographic separation, which leads to high throughput, presenting itself as the best choice to date. Regarding the experimental model to monitor the bioavailability of phenolic compounds, most published studies are based on human and animal models, with the majority using rodents, primates and recently the nematode Caenorhabditis elegans. This review focuses on the fundamentals of pharmacokinetic methods from the last 15 years and how the results are evaluated and validated. The types of analytical methods, animal models and biological matrices were used to better elucidate pharmacokinetics of polyphenols.


Effects of sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium on QTc prolongation: a thorough QTc study.
Sugammadex reverses the effects of rocuronium- and vecuronium-induced neuromuscular blockade, which are achieved by encapsulation. It is known that some non-antiarrhythmic drugs have the potential to delay cardiac repolarization and it is therefore recommended that the effects of all new drugs on the QT interval are assessed. This thorough corrected QT (QTc) study evaluated the effect of sugammadex alone and in combination with rocuronium or vecuronium on the individually corrected QTc interval (QTcI). This was a randomized, double-blind, six-period crossover, placebo-controlled study, with an open-label active-controlled component (moxifloxacin). The study was designed according to International Conference on Harmonization (ICH) E14 guidelines. The study was conducted in a clinical research unit from November 2006 to April 2007. Healthy male and female subjects (n = 84) were enrolled in the study. Subjects were randomized to six treatment sequences comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control), sugammadex 4 mg/kg, sugammadex 32 mg/kg, sugammadex 32 mg/kg with rocuronium 1.2 mg/kg and sugammadex 32 mg/kg with vecuronium 0.1 mg/kg. Triplicate ECGs were recorded at 13 timepoints up to 23.5 hours after study drug administration and QT intervals were evaluated manually under blinded conditions. The primary outcome was the largest time-matched mean difference in QTcI change from baseline compared with placebo across the 13 timepoints up to 23.5 hours after study drug administration. Blood samples were also collected for pharmacokinetic analysis. Of the 84 randomized healthy subjects, 80 completed the study. After moxifloxacin, QTcI prolongations were observed compared with placebo; the lower limit of the one-sided 95% confidence interval (CI) for the largest time-matched mean difference in QTcI change compared with placebo was 20.8 msec (90% CI 18.5, 23.1), thus exceeding the ICH E14 safety margin of 5 msec and demonstrating assay sensitivity. In contrast, the largest time-matched mean difference in QTcI (msec) from placebo with sugammadex treatments ranged from 2.1 (sugammadex 4 mg/kg alone) to 4.3 (sugammadex 32 mg/kg with vecuronium 0.1 mg/kg). For the largest time-matched mean difference in QTcI change compared with placebo the corresponding upper limit of the one-sided 95% CI was well below the 10 msec margin for both sugammadex doses. Telemetry results revealed that one subject experienced a non-sustained ventricular tachycardia 4 hours after sugammadex 32 mg/kg, which was self-terminating after 20 beats and considered unlikely to be drug related. Pharmacokinetic-QTc analysis showed a statistically significant (p < 0.01) relationship between sugammadex plasma concentration and QTcI; however, at mean maximum plasma concentrations of the therapeutic and supra-therapeutic sugammadex dose, the predicted one-sided upper 95% CI for the largest time-matched QTcI difference from placebo was below 10 msec. Rocuronium or vecuronium co-administration did not affect the relationship between sugammadex concentrations and QTc. Based on the results of this study of healthy subjects, it can be concluded that sugammadex alone or in combination with rocuronium or vecuronium is not associated with QTc prolongation.


Women with intellectual disabilities--a study of sexuality, sexual abuse and protection skills.
Sexual abuse and abusive relationships are known to be especially common in people with intellectual disability. This study explored how women with intellectual disability understand sex, relationships and sexual abuse, the effects of sexual abuse on their lives, and how successfully they protect themselves from abuse. Semistructured narrative interviews with nine women with mild intellectual disability in Queensland, Australia. Interviews were audio recorded, transcribed, coded and analysed qualitatively. Major themes that emerged were: sexual knowledge and sources of knowledge; negotiating sexual relationships; declining unwanted sexual contact; self protection strategies; sexual abuse experiences; and sequelae of sexual abuse. Most participants reported unwanted or abusive sexual experiences. They described sequelae such as difficulties with sex and relationships, and anxiety and depression. They described themselves as having inadequate self protection skills and difficulty reporting abuse and obtaining appropriate support. Their understanding of sex was limited and they lacked the literacy and other skills to seek information independently. It is important for general practitioners to be aware of the possibility of sexual abuse against women with intellectual disability, and to offer appropriate interventions.


Ejection Fraction Pros and Cons: JACC State-of-the-Art Review.
Ejection fraction (EF) reflects both cardiac function and remodeling, and is widely recognized as a valuable diagnostic and prognostic tool. Its use in a variety of settings, ranging from heart failure and myocardial infarction to valvular heart disease, has made it a cornerstone of modern cardiology, pervading guidelines and practice. However, the development of the test was in another era, with younger patients and a lower prevalence of heart failure with preserved EF. The performance expectations of EF in the current era are also demanding-in relation to detection of subclinical LV dysfunction, and especially relating to recognition of changes in LV function on sequential testing-for example in patients taking cardiotoxic drugs. This review discusses whether the impressive evidence base for EF justifies its ongoing use in the context of newer markers of LV function, and the sophisticated questions posed by modern cardiology.


ASSESSING BURNOUT AMONG HEALTHCARE PROFESSIONALS IN A PRIVATE HOSPITAL IN ABUJA, NIGERIA: PREVALENCE, PATTERNS, AND IMPLICATIONS.
A current worrisome global trend is the emigration of health workers from resource-constrained areas especially Africa, with 1 in 4 doctors, and 1 in 20 nurses leaving for developed countries. This phenomenon has resulted in a shortfall of over 1.5 million health workers in the region. The factors contributing to the trend remain multifaceted, with provider burnout playing a crucial role in this phenomenon. Several studies have highlighted the burden of burn out among health workers in public facilities. However, there still exists a gap in research, particularly in the context of private healthcare facilities in Nigeria. The aim of this study was to determine the prevalence and pattern of burnout in healthcare professionals working at a private hospital in Abuja, Nigeria. A descriptive cross-sectional study involving 100 healthcare professionals (doctors, nurses, and pharmacists) was conducted using a multistage sampling method. Data collection included socio-demographic information, occupational details, and the Burnout Clinical Subtype Questionnaire (BCSQ-12). Statistical analysis employed Pearson's Chi-square with a significance level of p < 0.05. The study revealed 85% prevalence of burnout, with 71% experiencing overload, 61% lacking development opportunities, and 18% feeling neglected. No significant associations were found between burnout and socio-demographic or occupational characteristics. This study highlights the high prevalence of burnout among healthcare professionals. This emphasizes the urgent need for integrating burnout screening into routine health assessments for healthcare workers. Doing so can protect their well-being, which may be a vital step in addressing the healthcare workforce crisis in Africa.


Dissipative Particle Dynamics Investigation of the Transport of Salicylic Acid through a Simulated In Vitro Skin Permeation Model.
Permeation models are often used to determine diffusion properties of a drug through a membrane as it is released from a delivery system. In order to circumvent problematic in vivo studies, diffusion studies can be performed in vitro, using (semi-)synthetic membranes. In this study salicylic acid permeation was studied, employing a nitrocellulose membrane. Both saturated and unsaturated salicylic acid solutions were studied. Additionally, the transport of salicylic acid through the nitrocellulose membrane was simulated by computational modelling. Experimental observations could be explained by the transport mechanism that was revealed by dissipative particle dynamics (DPD) simulations. The DPD model was developed with the aid of atomistic scale molecular dynamics (AA-MD). The choice of a suitable model membrane can therefore, be predicted by AA-MD and DPD simulations. Additionally, the difference in the magnitude of release from saturated and unsaturated salicylic acid and solutions could also be observed with DPD. Moreover, computational studies can reveal hidden variables such as membrane-permeant interaction that cannot be measured experimentally. A recommendation is made for the development of future model permeation membranes is to incorporate computational modelling to aid the choice of model.


Economic growth and health progress in Italy: 30 years of National Health Service.
On December 23 of 1978, during first Italian recession since the end of World War II, Parliament voted for Law 833 that gives birth to the Italian National Public Health Services (SSN) as the new and alternative model of health care system. It was the beginning of the match of Italian health care with the world class level of the public health care. Each crisis requires solidarity and actions. Maintaining levels of health and other social expenditures is critical to protect life and livelihood and to boost productivity. The purpose of the present study is to establish an alternative point of view to demonstrate that Gross Domestic Product, is a function of health care expenditure. The chronology of the events was created by using the laws published on "Gazzetta Ufficiale" (GU). In order to analyze the corporate effectiveness and efficiency, we have divided the SSN into its three main components, namely resources (input), services (output) and performances (outcome). Health services have certainly been pioneers and are still today standard-bearers of a challenge which has borne its fruits. According to the "Organization for Economic Co-operation and Development", SSN ranks second in the world classification of the return on the health care services in 2000. The World Health Organization has published in 2005 the same result: SSN ranks second in the world for ability and quality of the health care in relationship to the resources invested The continuous reforms of health care system introduced stability to the Italian system more than others countries. Success of SSN function rooted in the ability of system to adapt assuring mechanism of positive feed-back correction. In the future SSN, will required new set of reforms, such as redefinition of structures and mechanisms of governance, strategic plans, clinical administrations.


MUC1 stimulates EGFR expression and function in endometrial cancer.
The current standard of care for endometrial cancer patients involves hysterectomy with adjuvant radiation and chemotherapy, with no effective treatment for advanced and metastatic disease. MUC1 is a large, heavily glycosylated transmembrane protein that lubricates and protects cell surfaces and increases cellular signaling through the epidermal growth factor receptor (EGFR). We show for the first time that MUC1 stimulates EGFR expression and function in endometrial cancer. siRNA knockdown and CRISPR/Cas knockout of MUC1 reduced EGFR gene expression, mRNA, protein levels and signaling. MUC1 bound strongly to two regions of the EGFR promoter: -627/-511 and -172/-64. MUC1 knockout also reduced EGFR-dependent proliferation in two dimensional culture, as well as growth and survival in three dimensional spheroid cultures. MUC1 knockout cells were more sensitive to the EGFR inhibitor, lapatinib. Finally, MUC1 and EGFR co-expression was associated with increased cellular proliferation in human endometrial tumors. These data demonstrate the importance of MUC1-driven EGFR expression and signaling and suggest dual-targeted therapies may provide improved response for endometrial tumors.


Neonate with haemophagocytic lymphohistiocytosis secondary to dengue infection: a case report.
We report the first case of haemophagocytic lymphohistiocytosis (HLH) in a neonate secondary to primary Dengue virus infection. This neonate presented in the third week of life with fever, shock and hepatosplenomegaly and was diagnosed to have Dengue infection by serology and HLH was confirmed on bone marrow.


Adaptable Hydrogels Mediate Cofactor-Assisted Activation of Biomarker-Responsive Drug Delivery via Positive Feedback for Enhanced Tissue Regeneration.
The targeted and simultaneous delivery of diverse cargoes with vastly different properties by the same vehicle is highly appealing but challenging. Here, a bioactive nanocomposite hydrogel based on hyaluronic acid and self-assembled pamidronate-magnesium nanoparticles for the localized elution and on-demand simultaneous release of bioactive ions and small molecule drugs is described. The obtained nanocomposite hydrogels exhibit excellent injectability and efficient stress relaxation, thereby allowing easy injection and consequent adaptation of hydrogels to bone defects with irregular shapes. Magnesium ions released from the hydrogels promote osteogenic differentiation of the encapsulated human mesenchymal stem cells (hMSCs) and activation of alkaline phosphatase (ALP). The activated ALP subsequently catalyzes the dephosphorylation (activation) of Dex phosphate, a pro-drug of Dex, and expedites the release of Dex from hydrogels to further promote hMSC osteogenesis. This positive feedback circuit governing the activation and release of Dex significantly enhances bone regeneration at the hydrogel implantation sites. The findings suggest that these injectable nanocomposite hydrogels mediate optimized release of diverse therapeutic cargoes and effectively promote in situ bone regeneration via minimally invasive procedures.


The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK.
The positive transcription elongation factor, P-TEFb, is required for the production of mRNAs, however the majority of the factor is present in the 7SK snRNP where it is inactivated by HEXIM1. Expression of HIV-1 Tat leads to release of P-TEFb and HEXIM1 from the 7SK snRNP in vivo, but the release mechanisms are unclear. We developed an in vitro P-TEFb release assay in which the 7SK snRNP immunoprecipitated from HeLa cell lysates using antibodies to LARP7 was incubated with potential release factors. We found that P-TEFb was directly released from the 7SK snRNP by HIV-1 Tat or the P-TEFb binding region of the cellular activator Brd4. Glycerol gradient sedimentation analysis was used to demonstrate that the same Brd4 protein transfected into HeLa cells caused the release of P-TEFb and HEXIM1 from the 7SK snRNP in vivo. Although HEXIM1 binds tightly to 7SK RNA in vitro, release of P-TEFb from the 7SK snRNP is accompanied by the loss of HEXIM1. Using a chemical modification method, we determined that concomitant with the release of HEXIM1, 7SK underwent a major conformational change that blocks re-association of HEXIM1. Given that promoter proximally paused polymerases are present on most human genes, understanding how activators recruit P-TEFb to those genes is critical. Our findings reveal that the two tested activators can extract P-TEFb from the 7SK snRNP. Importantly, we found that after P-TEFb is extracted a dramatic conformational change occurred in 7SK concomitant with the ejection of HEXIM1. Based on our findings, we hypothesize that reincorporation of HEXIM1 into the 7SK snRNP is likely the regulated step of reassembly of the 7SK snRNP containing P-TEFb.


Polysaccharide production by kefir grains during whey fermentation.
Fermentation of deproteinised whey with kefir grains CIDCA AGK1 was studied focusing on polysaccharide production from lactose. Kefir grains were able to acidify whey at different rates depending on the grain/whey ratio. During fermentation, kefir grains increased their weight and a water-soluble polysaccharide was released to the media. Exopolysaccharide concentration increased with fermentation time, reaching values of 57.2 and 103.4 mg/l after 5 days of fermentation in cultures with 10 and 100 g kefir grains/l, respectively. The polysaccharide fraction quantified after fermentation corresponded to the soluble fraction, because part of the polysaccharide became a component of the grain. Weight of kefir grains varied depending on the time of fermentation. Polysaccharide production was affected by temperature. Although the highest concentration of polysaccharide in the media was observed at 43 degrees C at both grain/whey ratios, the weight of the grains decreased in these conditions. In conclusion, kefir grains were able to acidify deproteinised whey, reducing lactose concentration, increasing their weight and producing a soluble polysaccharide.


Interlay Cartilage Rim Augmented Fascia Tympanoplasty: An Effective Graft Model in Mucosal Chronic Otitis Media.
To study the efficacy of interlay cartilage rim augmented fascia tympanoplasty in mucosal chronic otitis media. A retrospective, observational study was conducted in a tertiary care hospital including charts of patients spanning a duration of one year, where 15 patients diagnosed with chronic otitis media-mucosal disease with large and subtotal perforations (with or without ossicular erosion), and had undergone interlay cartilage rim augmented fascia tympanoplasty, were analysed for morphological and functional improvement following surgery. Pre- and post-operative otomicroscopic examination and pure tone audiometry findings were the parameters considered. 86.6% had a well-healed, non-retracted, undisplaced mobile neotympanum, 6.7% who underwent a type III (minor columella) tympanoplasty had a medialised neotympanum and 1 subject (6.7%) who underwent a type I tympanoplasty had a residual pinpoint perforation which healed with conservative management. The overall morphological success rate was 93.3%. The mean hearing gain following surgery was 20.84 dB with a minimum gain of 10 dB and a maximum gain of 30 dB. The mean air-bone gap closure gain achieved was 19.2 dB with a minimum gain of 6.4 dB and a maximum gain of 30 dB. The interlay cartilage-fascia rim augmentation tympanoplasty is a novel, effective graft model suggested for large and sub-total central perforations. Future randomized studies with a larger sample size could be performed with longer follow-up to assess the outcome of this technique.


Enzymic capacities of amyloplasts from wheat (Triticum aestivum) endosperm.
Lysates of protoplasts from the endosperm of developing grains of wheat (Triticum aestivum) were fractionated on density gradients of Nycodenz to give amyloplasts. Enzyme distribution on the gradients suggested that: (i) starch synthase and ADP-glucose pyrophosphorylase are confined to the amyloplasts; (ii) pyrophosphate: fructose-6-phosphate 1-phosphotransferase and UDP-glucose pyrophosphorylase are confined to the cytosol; (iii) a significant proportion (23-45%) of each glycolytic enzyme, from phosphoglucomutase to pyruvate kinase inclusive, is in the amyloplast. Starch synthase, ADP-glucose pyrophosphorylase and each of the glycolytic enzymes showed appreciable latency when assayed in unfractionated lysates of protoplasts. No activity of fructose-1,6-bisphosphatase was found in amyloplasts or in homogenates of endosperm. Antibody to plastidic fructose-1,6-bisphosphatase did not react positively, in an immunoblot analysis, with any protein in extracts of wheat endosperm. It is argued that wheat endosperm lacks significant plastidic fructose-1,6-bisphosphatase and that carbon for starch synthesis does not enter the amyloplast as a C-3 compound but probably as hexose phosphate.


The role of APOE-epsilon4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging.
While a genetic risk factor for late-onset AD, the effects of the epsilon4 allele of the APOE gene on cognitive functioning more generally remain unclear. To assess the role of the epsilon4 allele of the APOE gene in longitudinal cognitive decline. Multiple measures of cognitive function were assessed longitudinally in the MacArthur Successful Aging Study, a population-based cohort free of frank impairment at baseline. Subjects were 965 Caucasian and African American men and women from Durham NC, East Boston, MA, and New Haven, CT, aged 70 to 79 years, recruited in 1988 through 1989, who completed two follow-up evaluations, one at 3 years and another at 7 years. At the first follow-up, modest but significant declines in naming and spatial ability were associated with the APOE-epsilon4 genotype. By the second follow-up, more pronounced and significant associations were noted between the APOE-epsilon4 genotype and cognitive decline from six of the eight cognitive outcomes. After 7 years, APOE-epsilon4 allele carriers were twice as likely to have declined on a global cognitive score (odds ratio = 2.0; 95% CI: 1.1, 3.6) as noncarriers. APOE-epsilon4 is associated with cognitive decline among a high-functioning elderly cohort, with effects most pronounced after 7 years of follow-up. Hence, the epsilon4 allele either may function as a risk factor for cognitive impairment in normal aging across a broad spectrum of domains or may exert detectable effects early in a long prodromal AD trajectory.


Is monitoring of gastric residual volume for critically ill patients with enteral nutrition necessary? A meta-analysis and systematic review.
There are many controversies over the necessity of monitoring gastric residual volume in the nursing care of enteral nutrition. We aimed to conduct an updated meta-analysis to evaluate the effects of monitoring or not monitoring gastric residual volume on patients' outcomes and complications. We searched the Cochrane Library database to 15 April 2021 for randomized controlled trials (RCTs) on the effects of gastric residual volume and no gastric residual volume monitoring. Review Manager software was used for data analysis. A total of seven RCTs involving 1240 enteral nutrition patients were included. Gastric residual volume monitoring was associated with reduced incidence of vomiting (OR2.33, 95% CI:1.68-3.24), whereas no gastric residual volume monitoring was associated with reduced incidence of unnecessary interruptions of enteral nutrition (OR0.38,95% CI:0.26-0.55). There were no significant differences on the incidence of abdominal distention (OR1.87, 95% CI:0.82-4.28), diarrhoea (OR1.03,95% CI:0.74-1.43), VAP (OR0.83, 95%CI:0.37-1.89), duration of mechanical ventilation (MD -0.06,95% CI:-1.22-1.10), length of ICU stay (MD -1.33, 95% CI:-3.58-0.91) and mortality (OR0.90,95% CI:0.61-1.34). Not monitoring gastric residual volume is associated with reduced unnecessary interruptions of enteral nutrition related to inadequate feeding and increased risk of vomiting.


Effect of Community-Based Group Exercise Interventions on Standing Balance and Strength in Independent Living Older Adults.
Many interventions to improve mobility in older adults often include exercises to address underlying impairments such as strength deficits. Task-oriented exercise interventions that focus more on walking and stepping tasks that may be encountered in the community have been considered for improving mobility in older adults. The main purpose was to examine the effect of task-oriented and impairment-based group exercise interventions on standing balance and lower extremity muscle strength. This is an ancillary study to a cluster-randomized clinical trial. Participants included 107 older adults. Participants were randomized by facility to 1 of 2 different interventions, or a waitlist control group. The On the Move (OTM) task-oriented intervention consisted of warm-up, timing and coordination (stepping and walking patterns), strengthening, and stretching exercises. The standard of care impairment-based exercise intervention (STD) consisted of warm-up, strength, endurance, and stretching exercises. Postural sway and balance measures were recorded before and after the 12-week interventions. An accelerometer was used to collect postural sway for 6 different standing balance conditions. A portable load cell was used to assess lower extremity muscle strength for 3 muscle groups. The OTM group had a significant reduction in sway acceleration during most of the balance conditions over the 12-week period, whereas the STD had smaller, nonsignificant reductions. Both exercise interventions had a significant reduction in sway compared with the waitlist control group in at least 1 balance condition. The OTM and STD groups had significant increases in hip abduction strength during the intervention and the STD group also had an increase in knee extension strength. The waitlist group had a significant reduction in strength in all muscle groups during the 12-week period. Strength changes in both exercise groups were significantly different from the waitlist group but not from each other. Both exercise intervention groups had an improvement in standing balance and lower extremity strength when compared with a waitlist group that did not receive exercise. Although the exercise groups did not significantly differ from each other, the OTM exercise group showed a trend toward improvement in static standing balance conditions.


Electron paramagnetic resonance reveals altered topography of the active center gorge of acetylcholinesterase after binding of fasciculin to the peripheral site.
Fasciculin, a peptidic toxin from snake venom, inhibits mammalian and fish acetylcholinesterases (AChE) by binding to the peripheral site of the enzyme. This site is located at the rim of a narrow, deep gorge which leads to the active center triad, located at its base. The proposed mechanisms for AChE inhibition by fasciculin include allosteric events resulting in altered conformation of the AChE active center gorge. However, a fasciculin-induced altered topography of the active center gorge has not been directly demonstrated. Using electron paramagnetic resonance with the spin-labeled organophosphate 1-oxyl-2,2,6, 6-tetramethyl-4-piperidinylethylphosphorofluoridate (EtOSL) specifically bound to the catalytic serine of mouse AChE (mAChE), we show that bound fasciculin on mAChE slows down, but does not prevent phosphorylation of the active site serine by EtOSL and protects the gorge conformation against thermal denaturation. Most importantly, a restricted freedom of motion of the spin label bound to the fasciculin-associated mAChE, compared to mAChE, is evidenced. Molecular models of mAChE and fasciculin-associated mAChE with tethered EtOSL enantiomers indicate that this restricted motion is due to greater proximity of the S-EtOSL nitroxide radical to the W86 residue in the fasciculin-associated enzyme. Our results demonstrate a topographical alteration indicative of a restricted conformation of the active center gorge of mAChE with bound fasciculin at its rim.


Effect of reactor operation modes on mitigating antibiotic resistance genes (ARGs) and methane production from hydrothermally-pretreated pig manure.
Numerous efforts have been made to enhance the performance of anaerobic digestion (AD) for accelerating renewable energy generation, however, it remains unclear whether the intensified measures could enhance the proliferation and transmissions of antibiotic resistance genes (ARGs) in the system. This study assessed the impact of an innovative pig manure AD process, which includes hydrothermal pretreatment (HTP) and a two-stage configuration with separated acidogenic and methanogenic phases, on biomethane (CH4) production and ARGs dynamics. Results showed that HTP significantly increase CH4 production from 0.65 to 0.75 L/L/d in conventional single-stage AD to 0.82 and 0.91 L/L/d in two-stage AD. This improvement correlated with a rise in the relative abundance of Methanosarcina, a key methanogenesis microorganism. In the two-stage AD, the methanogenic stage offered an ideal environment for methanogens growth, resulting in substantially faster and higher CH4 production by about 10% compared to single-stage AD. Overall, the combined use of HTP and the two-stage AD configuration enhanced CH4 production by 40% compared to traditional single-stage AD. The abundance and diversity of ARGs were significantly reduced in the acidogenic reactors after HTP. However, the ARGs levels increased by about two times in the following methanogenesis stage and reached similar or higher levels than in single stage AD. The erm(F), erm(G), ant(6)-Ia, tet(W), mef(A) and erm(B) were the six main ARGs with significant differences in relative abundances in various treatments. The two-stage AD mode could better remove sul2, but it also had a rebound which elevated the risk of ARGs to the environment and human health. Network analysis identified pH and TVFAs as critical factors driving microbial communities and ARG proliferation in the new AD process. With the results, this study offers valuable insights into the trade-offs between AD performance enhancement and ARG-related risks, pinpointing essential areas for future research and practical improvements.


A comparison of bleomycin-induced damage in lymphocytes and primary oral fibroblasts and keratinocytes in 30 subjects.
The number of chromatid breaks in peripheral blood lymphocytes (PBL) after exposure to bleomycin in the S/G2 phase of the cell cycle (in the literature referred to as 'mutagen sensitivity') is associated with an increased risk of environmentally related cancers, including oral cancer. The aim of this study was to elucidate whether mutagen sensitivity measured in lymphocytes actually reflects chromosomal instability of normal cells in the areas in which tumors develop. Therefore, bleomycin-induced chromosomal damage in and growth inhibition of cultured oral fibroblasts and oral keratinocytes from 30 persons were compared with the standard mutagen sensitivity score in PBL. A correlation was found for the percentage of aberrant metaphases between PBL and oral fibroblasts but not for the number of breaks per cell. These data do not allow a conclusion to be drawn on the use of fibroblasts to study cancer risk. Within the fibroblasts it was found that a high number of breaks per cell was associated with less growth inhibition, indicative of damage-resistant growth. Oral keratinocytes were extremely sensitive to bleomycin, as indicated by a strong cell cycle block which resulted in a mitotic index too low to determine chromosomal breaks. Moreover, in the cell proliferation assay keratinocytes were found to be 100 times more sensitive as compared with fibroblasts. There was no correlation between bleomycin sensitivity of keratinocytes compared with fibroblasts from a single patient as measured by growth inhibition. This may be due to the strong influence of alcohol consumption by the subjects, which was found to increase the sensitivity of keratinocytes but not of PBL and fibroblasts. In conclusion, oral fibroblasts but not keratinocytes can be used to measure sensitivity for chromatid breaks. The apparent influence of environmental factors on keratinocytes makes them a useful source to study exposure characteristics but limits their application for the determination of genetic factors.


Soft tissue composition, axial bone mineral density, and grip strength in postmenopausal Turkish women with early rheumatoid arthritis: Is lean body mass a predictor of bone mineral density in rheumatoid arthritis?
To study bone mineral density and body composition in patients with early rheumatoid arthritis to determine the relationship of lean mass, fat mass and hand grip strength to bone mineral density. Fifty-one female patients who fulfilled the American College of Rheumatology (ACR) for RA were recruited. Fifty-one (51) female RA patients, age matched female control subjects and 53 osteoporotic patients (WHO criteria) were included in the study. All subjects were at postmenopausal period. Early RA is defined as the disease duration <10 years. Whole body composition and BMD were estimated by DEXA (Norland XR-46). Hand grip strength was measured by JAMAR hand dynamometer. Body mass index (BMI) and anthropometric measures (skinfold thickness and waist-hip ratio) were also assessed. The mean age of patients and controls was 55.4 +/- 9.5, 56.9 +/- 7.4, and 55.2 +/- 7.6, respectively. There was no statistically significant difference in age, BMI, and years since menopause between RA patients, OP patients, and controls (p < 0.05). Bone mineral density of lumbar and femoral neck regions, total bone mineral density, and bone mineral content in RA patients were significantly lower than in controls but not in osteoporotic patients. Lean body mass was also significantly lower in RA patients than controls but not in osteoporotic patients. However, hand grip strength was significantly lower in RA patients than in osteoporotic patients and controls (p < 0.05). Total lean mass was correlated with body mass index, waist-hip ratio, femoral neck BMD, and total bone mineral content, total BMD in RA patients (p < 0.05). Grip strength was correlated with duration of disease (RA) and age negatively, and also correlated with total BMD in RA patients. These results indicate that lean mass was associated with BMD. To preserve BMD, maintaining or increasing lean mass would appear to be an appropriate strategy for avoiding hip fracture and its complications.


anthocyanin1 of petunia encodes a basic helix-loop-helix protein that directly activates transcription of structural anthocyanin genes.
The petunia loci anthocyanin1 (an1), an2, an4, and an11 are required for the transcription of anthocyanin biosynthetic genes in floral organs. The an2 and an11 loci were recently cloned and shown to encode a MYB-domain transcriptional activator and a cytosolic WD40 protein, respectively. Here, we report the isolation of an1 by transposon tagging. an1 encodes a new member of the basic helix-loop-helix family of transcription factors that is functionally and evolutionarily distinct from JAF13, the apparent petunia ortholog of maize RED1 and snapdragon DELILA. We provide genetic evidence that the transcription factors encoded by an1, an2, and an4 operate in an unexpectedly complex regulatory hierarchy. In leaves, ectopic expression of AN2 induces an1 expression, whereas in anthers, an1 expression depends on an4, encoding (or controlling) a MYB protein that is paralogous to AN2. Experiments with transgenic plants expressing a post-translationally controlled AN1-GLUCOCORTICOID RECEPTOR fusion protein indicated that independent of protein synthesis, AN1 directly activates the expression of the dfrA gene encoding the enzyme dihydroflavonol 4-reductase and of Pmyb27 encoding a MYB-domain protein of unknown function.


Spousal Concordance of Hypertension Among Middle-Aged and Older Heterosexual Couples Around the World: Evidence From Studies of Aging in the United States, England, China, and India.
Health concordance within couples presents a promising opportunity to design interventions for disease management, including hypertension. We compared the concordance of prevalent hypertension within middle-aged and older heterosexual couples in the United States, England, China, and India. Cross-sectional dyadic data on heterosexual couples were used from contemporaneous waves of the HRS (US Health and Retirement Study, 2016/17, n=3989 couples), ELSA (English Longitudinal Study on Aging, 2016/17, n=1086), CHARLS (China Health and Retirement Longitudinal Study, 2015/16, n=6514), and LASI (Longitudinal Aging Study in India, 2017/19, n=22 389). Concordant hypertension was defined as both husband and wife in a couple having hypertension. The prevalence of concordant hypertension within couples was 37.9% (95% CI, 35.8-40.0) in the United States, 47.1% (95% CI, 43.2-50.9) in England, 20.8% (95% CI, 19.6-21.9) in China, and 19.8% (95% CI, 19.0-20.5) in India. Compared with wives married to husbands without hypertension, wives married to husbands with hypertension were more likely to have hypertension in the United States (prevalence ratio, 1.09 [95% CI, 1.01- 1.17), England (prevalence ratio, 1.09, 95% CI, 0.98-1.21), China (prevalence ratio, 1.26 [95% CI, 1.17-1.35), and India (prevalence ratio, 1.19 [95% CI, 1.15-1.24]). Within each country, similar associations were observed for husbands. Across countries, associations in the United States and England were similar, whereas they were slightly larger in China and India. Concordance of hypertension within heterosexual couples was consistently observed across these 4 socially and economically diverse countries. Couple-centered interventions may be an efficient strategy to prevent and manage hypertension in these countries.


Estimating National Trends in Inpatient Antibiotic Use Among US Hospitals From 2006 to 2012.
The rising threat of antibiotic resistance and other adverse consequences resulting from the misuse of antibiotics requires a better understanding of antibiotic use in hospitals in the United States. To use proprietary administrative data to estimate patterns of US inpatient antibiotic use in recent years. For this retrospective analysis, adult and pediatric in-patient antibiotic use data was obtained from the Truven Health MarketScan Hospital Drug Database (HDD) from January 1, 2006, to December 31, 2012. Data from adult and pediatric patients admitted to 1 of approximately 300 participating acute care hospitals provided antibiotic use data for over 34 million discharges representing 166 million patient-days. We retrospectively estimated the days of therapy (DOT) per 1000 patient-days and the proportion of hospital discharges in which a patient received at least 1 dose of an antibiotic during the hospital stay. We calculated measures of antibiotic usage stratified by antibiotic class, year, and other patient and facility characteristics. We used data submitted to the Centers for Medicare and Medicaid Services Healthcare Cost Report Information System to generate estimated weights to apply to the HDD data to create national estimates of antibiotic usage. A multivariate general estimating equation model to account for interhospital covariance was used to assess potential trends in antibiotic DOT over time. During the years 2006 to 2012, 300 to 383 hospitals per year contributed antibiotic data to the HDD. Across all years, 55.1% of patients received at least 1 dose of antibiotics during their hospital visit. The overall national DOT was 755 per 1000 patient-days. Overall antibiotic use did not change significantly over time. The multivariable trend analysis of data from participating hospitals did not show a statistically significant change in overall use (total DOT increase, 5.6; 95% CI, -18.9 to 30.1; P = .65). However, the mean change (95% CI) for the following antibiotic classes increased significantly: third- and fourth-generation cephalosporins, 10.3 (3.1-17.5); macrolides, 4.8 (2.0-7.6); glycopeptides, 22.4 (17.5-27.3); β-lactam/β-lactamase inhibitor combinations, 18.0 (13.3-22.6); carbapenems, 7.4 (4.6-10.2); and tetracyclines, 3.3 (2.0-4.7). Overall DOT of all antibiotics among hospitalized patients in US hospitals has not changed significantly in recent years. Use of some antibiotics, especially broad spectrum agents, however, has increased significantly. This trend is worrisome in light of the rising challenge of antibiotic resistance. Our findings can help inform national efforts to improve antibiotic use by suggesting key targets for improvement interventions.


Serological reactivity in cancer patients to human and mouse fetal liver cells.
The occurrence of antibodies to human and mouse fetal liver cells has been quantitated in the sera from patients with carcinoma of breast, colon, and lung and with malignant melanoma. Also, we have demonstrated cross-reacting murine antibodies in the sera from multiparous, antifetal, and pregnant mice, which bind to mouse fetal liver cells and/or several types of human tumor cells. A comparative evaluation of these antibodies with two immunological techniques has demonstrated a greater number of positive sera from cancer patients assayed by isotopic antiglobulin (25 of 27, or 92%) than by membrane immunofluorescence (12 of 17, or 71%). In the non-cancer control group, positive reactions were found in 11 and 31% by the two techniques, respectively. The specificity of such serologically reactivity has been demonstrated by adsorption with fetal liver cells. These detected antibodies are not restricted to a particular type of human neoplasm, but rather to the presence of cancer. Because of their relative capacity of discrimination between benign and malignant conditions and because the assay for their detection is relatively simple, these techniques may provide alternative methods for diagnosis or monitoring of cancer patients.


[99mTc-HYNIC-N-dodecylamide]: a new hydrophobic tracer for labelling reconstituted high-density lipoproteins (rHDL) for radioimaging.
Despite the widespread use of nanotechnology in radio-imaging applications, lipoprotein based delivery systems have received only limited attention so far. These studies involve the synthesis of a novel hydrophobic radio-imaging tracer consisting of a hydrazinonicotinic acid (HYNIC)-N-dodecylamide and 99mTc conjugate that can be encapsulated into rHDL nanoparticles (NPs). These rHDL NPs can selectively target the Scavenger Receptor type B1 (SR-B1) that is overexpressed on most cancer cells due to excess demand for cholesterol for membrane biogenesis and thus can target tumors in vivo. We provide details of the tracer synthesis, characterization of the rHDL/tracer complex, in vitro uptake, stability studies and in vivo application of this new radio-imaging approach.


Model-averaging of ab initio spectra for the absolute configuration assignment via vibrational circular dichroism.
Vibrational absorption and vibrational circular dichroism spectra (VA and VCD) have been recorded for two hybrid isoindolinone-phtalide stereoisomers dissolved in CDCl3. Density-functional calculations have been performed to determine their absolute configuration. A comparison of calculated and measured values has been made using several goodness-of-fit indicators, and also introducing a model-averaging technique, taking into account the variation of calculated spectra with the details of the computational method. The model-averaging technique, preliminarily tested on two VCD spectra already assigned to two diastereomers of tadalafil, gives higher credibility to the ab initio calculations, and should be useful for other molecules with high flexibility and/or more than one stereogenic center.


Correspondence between electronic structure calculations and simulations: nonadiabatic dynamics in CS2.
The choice of ab initio electronic structure method is an important factor in determining the fidelity of nonadiabatic dynamics simulations. We present an in-depth comparison of two simulations of photodissociation in the CS2 molecule following excitation to the 11B2 state. The simulations account for nonadiabatic and spin-orbit coupling, and are performed using the SHARC surface-hopping approach combined with state-averaged SA8-CASSCF(8,6)/SVP and SA8-CASSCF(10,8)/SVP ab initio calculations, with additional reference calculations at the MRCI(14,10)/aug-cc-pvTZ level. The relative performance and veracity of the simulations can be assessed by inspection of the potential energy curves along specific coordinates. The simulations demonstrate direct competition between internal conversion and intersystem crossing, with strong correlation between molecular geometry, electronic state density, and dynamics.


Protective Effect of Cyanidin-3-O-Glucoside against Ultraviolet B Radiation-Induced Cell Damage in Human HaCaT Keratinocytes.
Ultraviolet radiation is the major environmental harmful factor that has emotional impact on human skin. The aim of the present study was to determine the mechanism of protection of cyanidin-3-O-glucoside against ultraviolet B (UVB)-induced damage to human HaCaT keratinocytes. Our results show that cyanidin-3-O-glucoside decreased the levels of intracellular reactive oxygen species generated by UVB treatment. Cyanidin-3-O-glucoside also decreased the UVB-augmented levels of the DNA damage indicators phospho-p53 and phospho-ATM/ATR. In addition, cyanidin-3-O-glucoside protected keratinocytes from UVB-induced injury by overturning the disruption of mitochondrial membrane potential and reversing apoptosis. The expression of anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) was attenuated in UVB-exposed cells but restored in UVB/cyanidin-3-O-glucoside-treated cells. Furthermore, expression of the proapoptotic proteins Bcl-2-associated X (Bax) and the key apoptosis executer cleaved caspase-3 were increased in UVB-irradiated cells and decreased in UVB/cyanidin-3-O-glucoside-treated cells. For these reasons, the results demonstrate that cyanidin-3-O-glucoside protects human keratinocytes against UVB-induced oxidative stress and apoptosis. Our study provides a theoretical basis for the use of cyanidin-3-O-glucoside in the fight against light damage.


Phototaxic foraging of the archaepaddler, a hypothetical deep-sea species.
An autonomous agent (animat, hypothetical animal), called the (archae) paddler, is simulated in sufficient detail to regard its simulated aquatic locomotion (paddling) as physically possible. The paddler is supposed to be a model of an animal that might exist, although it is perfectly possible to view it as a model of a robot that might be built. The agent is assumed to navigate in a simulated deep-sea environment, where it forages for autoluminescent prey. It uses a biologically inspired phototaxic foraging strategy, while paddling in a layer just above the bottom. The advantage of this living space is that the navigation problem--and hence our model--is essentially two-dimensional. Moreover, the deep-sea environment is physically simple (and hence easy to simulate): no significant currents, constant temperature, completely dark. A foraging performance metric is developed that circumvents the necessity to solve the traveling salesman problem. A parametric simulation study then quantifies the influence of habitat factors, such as the density of prey, and body geometry (e.g., placement, direction and directional selectivity of the eyes) on foraging success. Adequate performance proves to require a specific body geometry adapted to the habitat characteristics. In general, performance degrades gracefully for modest changes of the geometric and habitat parameters, indicating that we work in a stable region of "design space." The parameters have to strike a compromise between, on the one hand, to "see" as many targets at the same time as possible. One important conclusion is that simple reflex-based navigation can be surprisingly efficient. Additionally, performance in a global task (foraging) depends strongly on local parameters such as visual direction tuning, position of the eyes and paddles, and so forth. Behavior and habitat "mold" the body, and the body geometry strongly influences performance. The resulting platform enables further testing of foraging strategies or vision and locomotion theories stemming either from biology or from robotics.


Toxoplasma gondii pneumonia in a pancreas transplant patient.
A 41-year-old woman had fever of 3 days' duration. She had had pancreas transplantation 2 years previously and had recently completed a course of antirejection medication. Temperature spikes occurred during treatment with broad spectrum antibiotics. No obvious cause for the fever was found. The patient's condition worsened, with development of shortness of breath, bilateral pulmonary infiltrates on chest radiographs, sepsis, and shock. Fiberoptic bronchoscopy with bronchoalveolar lavage showed the presence of Toxoplasma gondii. Pyrimethamine and clindamycin were started, and the patient improved. Toxoplasma gondii occurs in contaminated food containing oocysts or cysts. Organ transplantation and blood transfusions are other routes of transmission. Most recent cases have occurred in human immunodeficiency virus (HIV) patients with reactivation of previous infection. Serology and tissue biopsies are used for diagnosis. Treatment includes a combination of pyrimethamine and sulfadiazine or trisulfapyrimidines.


Cytotoxic effects of basic FGF and heparin binding EGF conjugated with cytotoxin saporin on vascular cell cultures.
Vascular smooth muscle cell (SMC) proliferation is an integral component of intimal lesion formation. In this study we compared the mitogenic effects of basic fibroblast growth factor (bFGF) and heparin binding epidermal growth factor (HBEGF) and the cytotoxic effects of bFGF and HBEGF conjugated with plant cytotoxin saporin (SAP) on vascular cell cultures. Human vascular SMCs and endothelial cells were cultured and FGF receptor-1 (FGFR-1) and EGF receptor (EGFR) expression were detected by immunohistochemical staining. Cells were grown in 24-well plates. Variable amounts of testing drugs (bFGF, HBEGF, SAP, bFGF-SAP, or HBEGF-SAP) were added to quadruplicate wells after 24 h. Cells without drugs were used as control. The total number of cells was counted at 72 h using a hemocytometer. The cultured human vascular SMCs and endothelial cells expressed both FGFR-1 and EGFR with predominant perinuclear localization. bFGF and HBEGF demonstrated equally potent mitogenic effects on SMC proliferation. SAP alone showed a limited cytotoxic effect on both SMCs and endothelial cells. bFGF had a more potent effect on endothelial cell proliferation than HBEGF. bFGF-SAP was equally cytotoxic for both SMCs and endothelial cells, while HBEGF-SAP had a more selectively cytotoxic effect on SMCs than on endothelial cells. These data suggest that the mitogenic effects of bFGF and HBEGF and the cytotoxic effects of bFGF-SAP and HBEGF-SAP may both be mediated by their corresponding growth factor receptors. Because of its selective cytotoxic effect on SMCs, HBEGF-SAP may become a more attractive agent for controlling intimal lesion formation.


Combined effects of 17 common genetic variants on type 2 diabetes risk in a Han Chinese population.
The recent advent of genome-wide association studies has considerably accelerated the identification of type 2 diabetes loci. We aimed to investigate the combined effects of multiple genetic variants, alone or in combination with conventional risk factors, on type 2 diabetes and diabetes-related traits in Han Chinese. We genotyped 17 variants in 17 loci in a population-based Han Chinese cohort including 3,210 unrelated individuals. A genetic risk score (GRS) was calculated on the basis of these variants. The discriminatory ability was assessed by the area under the receiver operating characteristics curve. The odds ratio for type 2 diabetes and hyperglycaemia with each GRS point (per risk allele) was 1.18 (95% CI 1.12-1.23, p = 1.3 x 10(-12)) and 1.12 (95% CI 1.09-1.16, p = 7.5 x 10(-14)), respectively. Compared with participants with GRS < or =11.0 (7.63%), those with GRS > or =19.0 (8.87%) had a 4.58-fold higher risk (95% CI 2.49-8.42) of type 2 diabetes. The GRS also showed a significant association with lower beta cell function estimated by HOMA of beta cell function (p = 8.4 x 10(-10)). In addition, we observed significant interactive effects between GRS and BMI on fasting glucose and HbA(1c) levels (p = 0.04 and p = 0.03 for interaction, respectively). Discrimination of diabetes risk was improved (p < 0.001) when the GRS was added to a model including clinical risk factors. The AUCs were 0.62 and 0.77, respectively, for the GRS and conventional clinic risk factors alone, and 0.79 when the GRS was added. In this Han Chinese population, the GRS of 17 combined variants modestly but significantly improved discrimination of the conventional risk factors for type 2 diabetes.


Folliculotropic mycosis fungoides: single-center study and systematic review.
To clarify clinicopathologic features and reconcile discrepancies in previous studies of folliculotropic mycosis fungoides (FMF). A single-center retrospective clinicopathologic study and a systematic review of FMF. Tertiary referral center in the midwestern United States. Patients with clinical and histopathologic evidence of FMF seen at the tertiary referral center during a 12(1/2)-year period. Clinicopathologic features of FMF. Fifty patients (32 male [64%] and 18 female [36%]) met study criteria for the clinicopathologic review. Pruritic patches, plaques, and folliculocentric lesions (milia, cysts, and alopecia) on the head, neck, and trunk were common clinical findings. The mean time to diagnosis of FMF was 5.0 years. Diagnostic latency did not affect risk of death. One-year and 5-year overall survival rates were 96% and 62%, respectively. Frequent microscopic features were follicular mucinosis (74%) and epidermotropism (54%). Systematic review of 186 additional patients confirmed male predominance (ratio of men to women, 3.2:1.0), prevalent pruritus (73%), frequent follicular mucinosis (69%) and epidermotropism (37%) microscopically, and common head, neck, and trunk involvement. Combined data demonstrated that 6% of patients with FMF had concurrent non-mycosis fungoides hematologic malignant neoplasms and that the 5-year overall survival rate was 62% to 64%. Folliculotropic mycosis fungoides has distinct clinical and microscopic features and is associated with a poor 5-year overall survival rate.


Spinal X-ray screening of high performance fighter pilots.
Neck pain and neck injury are common complaints among military aviators flying high performance (HPF) aircraft. Since all candidates for military flying training with the Royal Norwegian Air Force have to meet HPF medical standards, medical selection procedures include a radiological examination of the spine. Nine films of the vertebral column are made with emphasis put on cervical structures. Among 232 applicants, 527 deviations from normal conditions were described--anomalies, degenerative changes and deviations of posture--which average 2.27 diagnoses per spine X-rayed. Of the candidates, 80 were considered entirely within normal limits; 20 were rejected due to the roentgen findings; and five candidates were excluded on final evaluation, their radiological diagnoses contributing to the decision. Although most changes are slight, many significant conditions are demonstrated among young healthy individuals. Since the population is highly selected, the figures we present may be minimum numbers in a western industralized society.


The evolution of phylogeographic data sets.
Empirical phylogeographic studies have progressively sampled greater numbers of loci over time, in part motivated by theoretical papers showing that estimates of key demographic parameters improve as the number of loci increases. Recently, next-generation sequencing has been applied to questions about organismal history, with the promise of revolutionizing the field. However, no systematic assessment of how phylogeographic data sets have changed over time with respect to overall size and information content has been performed. Here, we quantify the changing nature of these genetic data sets over the past 20 years, focusing on papers published in Molecular Ecology. We found that the number of independent loci, the total number of alleles sampled and the total number of single nucleotide polymorphisms (SNPs) per data set has improved over time, with particularly dramatic increases within the past 5 years. Interestingly, uniparentally inherited organellar markers (e.g. animal mitochondrial and plant chloroplast DNA) continue to represent an important component of phylogeographic data. Single-species studies (cf. comparative studies) that focus on vertebrates (particularly fish and to some extent, birds) represent the gold standard of phylogeographic data collection. Based on the current trajectory seen in our survey data, forecast modelling indicates that the median number of SNPs per data set for studies published by the end of the year 2016 may approach ~20,000. This survey provides baseline information for understanding the evolution of phylogeographic data sets and underscores the fact that development of analytical methods for handling very large genetic data sets will be critical for facilitating growth of the field.


Ecological function and interaction of different bacterial groups during alginate processing in coastal seawater community.
The degradation of high molecular weight organic matter (HMWOM) is a core process of oceanic carbon cycle, which is determined by the activity of microbial communities harboring hundreds of different species. Illustrating the active microbes and their interactions during HMWOM processing can provide key information for revealing the relationship between community composition and its ecological functions. In this study, the genomic and transcriptional responses of microbial communities to the availability of alginate, an abundant HMWOM in coastal ecosystem, were elucidated. The main degraders transcribing alginate lyase (Aly) genes came from genera Alteromonas, Psychrosphaera and Colwellia. Meanwhile, some strains, mainly from the Rhodobacteraceae family, did not transcribe Aly gene but could utilize monosaccharides to grow. The co-culture experiment showed that the activity of Aly-producing strain could promote the growth of Aly-non-producing strain when alginate was the sole carbon source. Interestingly, this interaction did not reduce the alginate degradation rate, possibly due to the easily degradable nature of alginate. This study can improve our understanding of the relationship between microbial community activity and alginate metabolism function as well as further manipulation of microbial community structure for alginate processing.


A mechanistic model for understanding root-induced chemical changes controlling phosphorus availability.
Plant nutrition models do not properly account for the effects of root-induced chemical changes in the rhizosphere, e.g. pH changes, on the availability of nutrients such as phosphorus (P). As a result, they underestimate the actual P uptake, i.e. P bioavailability to the plant, in low-P soils. The present study aims at simulating root-induced chemical mechanisms controlling P nutrition in a P-limited soil. In this work a mechanistic description for the adsorption of cations and anions by soil constituents (1pK-Triple Plane Model, ion-exchange and Nica-Donnan) was used to simulate changes induced by durum wheat (Triticum durum turgidum) in the P availability of the soil, as measured by water and CaCl2 extraction. Calcium (Ca) availability was also measured and simulated. The simulations were found to be in close agreement with experimental data. In the rhizosphere, the goodness-of-fit required to account for the measured uptake of Ca by plants, in addition to the measured uptake of P and root-induced alkalization, were satisfactory. Calcium uptake significantly increased P availability, as assessed through water extraction, by decreasing the promoting effect of Ca adsorption on P adsorption. The study thus enabled P and Ca availability to be related to their bioavailability for durum wheat under experimental conditions. It was also shown that P was primarily adsorbed onto Fe oxides and clay minerals (kaolinite and illite) depending on soil pH. The major source of P for durum wheat nutrition was P desorbed from goethite and kaolinite. In addition to confirming the validity of our approach to model P availability, the present investigation suggested that in the studied soil, a novel root-induced chemical process was controlling P nutrition under P-deficient conditions, namely the uptake of Ca.


Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.
Type-1 cannabinoid receptors (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB1R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB1R on GABAergic neurons (GABA-CB1R-KO) showed exacerbated alterations of sEPSC duration in GABAergic medium spiny neurons (MSN). On the other hand, EAE-induced alterations of corticostriatal sEPSC frequency were exacerbated only in mice lacking CB1R on glutamatergic neurons (Glu-CB1R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity was enhanced in whole CB1R-KO mice, GABA-CB1R-KO and Glu-CB1R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. Our results provide further evidence that CB1R are involved in EAE pathophysiology, and suggest that both pre- and postsynaptic alterations of glutamate transmission are important to drive excitotoxic neurodegeneration typical of this disorder.


Quantum clocks and the temporal localisability of events in the presence of gravitating quantum systems.
The standard formulation of quantum theory relies on a fixed space-time metric determining the localisation and causal order of events. In general relativity, the metric is influenced by matter, and is expected to become indefinite when matter behaves quantum mechanically. Here, we develop a framework to operationally define events and their localisation with respect to a quantum clock reference frame, also in the presence of gravitating quantum systems. We find that, when clocks interact gravitationally, the time localisability of events becomes relative, depending on the reference frame. This relativity ia a signature of an indefinite metric, where events can occur in an indefinite causal order. Even if the metric is indefinite, for any event we can find a reference frame where local quantum operations take their standard unitary dilation form. This form is preserved when changing clock reference frames, yielding physics covariant with respect to quantum reference frame transformations.


mRNA technology as one of the promising platforms for the SARS-CoV-2 vaccine development.
After the genome sequence of SARS-CoV-2 (Severe acute respiratory syndrome-related coronavirus 2) was published and the number of infected people began to increase rapidly, many global companies began to develop a vaccine. Almost all known approaches to vaccine design were applied for this purpose, including inactivated viruses, mRNA and DNA-vaccines, vaccines based on various viral vectors, synthetically generated peptides and recombinant proteins produced in cells of insects and mammals. This review considers one of the promising vaccine platforms based on messenger RNA. Until recent years, mRNA-vaccination was out of practical implementation due to high sensitivity to nuclease degradation and consequent instability of drugs based on mRNA. Latest technological advances significantly mitigated the problems of low immunogenicity, instability, and difficulties in RNA-vaccine delivery. It is worth noting that mRNA-vaccines can efficiently activate both components of the immune system, i. e. T-cell and humoral responses. The essential advantage of mRNAvaccines includes fast, inexpensive, scalable and uniform production providing a large output of desirable products in vitro. Synthesis and purification processes significantly simplify the process technology of mRNA drugs with injectable purity. Thus, mRNA production via in vitro transcription is more advantageous as compared with DNA-vaccines since it is a chemical process without the use of cells. mRNA techniques make it possible to pass all the phases of vaccine development much faster in comparison with the production of vaccines based on inactivated viruses or recombinant proteins. This property is critically important when designing vaccines against viral pathogens as the main problem of disease control includes a time gap between an epidemic and vaccine development. This paper discusses studies on the development of vaccines against coronaviruses including SARS-CoV-2 with special attention to the mRNA technique.


Empyema management: twelve years' experience since the introduction of video-assisted thoracoscopic surgery.
We reviewed empyema management at our center since video-assisted thoracoscopic surgery (VATS) was introduced. Between 1991 and 2003, 58 patients (34 male, 24 female) ages 1 day to 17 years (median, 6 years) were identified. The median interval from the onset of symptoms to presentation was 7 days; 31% of patients received inpatient care at another hospital, and 24% were from northern communities, including the Arctic. Symptoms included fever (100%), cough (66%), shortness of breath (46%), chest pain (38%), and abdominal pain (17%). Most patients (96%) had pneumonia. The most common organisms were Streptococcus pneumoniae (22%), group A streptococcus (8%), and Mycobacterium tuberculosis (3%). No organisms were identified in 31% of patients. One empyema was trauma-related and one was due to complications of esophageal stricturoplasty. All patients received intravenous antibiotics (median, 17 days). Three patients had thoracentesis, 17 had chest tubes, 3 had thoracentesis and chest tubes, 26 had VATS, 6 had thoracotomy, and 3 had minithoracotomy. Median operative times were 86 minutes for VATS, 90 minutes for thoracotomy, and 75 minutes for minithoracotomy. Median total length of stay (LOS) was 15 days for VATS, 20.5 days for thoracotomy, and 21 days for minithoracotomy. The median preoperative LOS was longer for thoracotomy (10 days) than for VATS (5 days) or minithoracotomy (1 day). The median postoperative LOS was 14 days for VATS, 9.5 days for thoracotomy, and 8 days for minithoracotomy. Our experience shows that VATS is a safe and effective approach to managing children with empyema. The shorter preoperative LOS for VATS is likely due to earlier surgical referral and intervention using less invasive surgical procedures.


Comprehensive quantification of triacylglycerols in soybean seeds by electrospray ionization mass spectrometry with multiple neutral loss scans.
Soybean seeds are an important source of vegetable oil and biomaterials. The content of individual triacylglycerol species (TAG) in soybean seeds is difficult to quantify in an accurate and rapid way. The present study establishes an approach to quantify TAG species in soybean seeds utilizing an electrospray ionization tandem mass spectrometry with multiple neutral loss scans. Ten neutral loss scans were performed to detect the fatty acyl chains of TAG, including palmitic (P, 16:0), linolenic (Ln, 18:3), linoleic (L, 18:2), oleic (O, 18:1), stearic (S, 18:0), eicosadienoic (20:2), gadoleic (20:1), arachidic (20:0), erucic (22:1), and behenic (22:0). The abundance of ten fatty acyl chains at 46 TAG masses (mass-to-charge ratio, m/z) were determined after isotopic deconvolution and correction by adjustment factors at each TAG mass. The direct sample infusion and multiple internal standards correction allowed a rapid and accurate quantification of TAG species. Ninety-three TAG species were resolved and their levels were determined. The most abundant TAG species were LLL, OLL, LLLn, PLL, OLLn, OOL, POL, and SLL. Many new species were detected and quantified. This shotgun lipidomics approach should facilitate the study of TAG metabolism and genetic breeding of soybean seeds for desirable TAG content and composition.


Insertion of membrane proteins into discoidal membranes using a cell-free protein expression approach.
We report a cell-free approach for expressing and inserting integral membrane proteins into water-soluble particles composed of discoidal apolipoprotein-lipid bilayers. Proteins are inserted into the particles, circumventing the need of extracting and reconstituting the product into membrane vesicles. Moreover, the planar nature of the membrane support makes the protein freely accessible from both sides of the lipid bilayer. Complexes are successfully purified by means of the apoplipoprotein component or by the carrier protein. The method significantly enhances the solubility of a variety of membrane proteins with different functional roles and topologies. Analytical assays for a subset of model membrane proteins indicate that proteins are correctly folded and active. The approach provides a platform amenable to high-throughput structural and functional characterization of a variety of traditionally intractable drug targets.


An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three-generation family at serious risk for aortic dissection.
Several genes involved in the familial appearance of thoracic aortic aneurysms and dissections (FTAAD) have been characterized recently, one of which is SMAD3. Mutations of SMAD3 cause a new syndromic form of aortic aneurysms and dissections associated with skeletal abnormalities. We discovered a small interstitial deletion of chromosome 15, leading to disruption of SMAD3, in a boy with mild mental retardation, behavioral problems and revealed features of the aneurysms-osteoarthritis syndrome (AOS). Several family members carried the same deletion and showed features including aortic aneurysms and a dissection. This finding demonstrates that haploinsufficiency of SMAD3 leads to development of both thoracic aortic aneurysms and dissections, and the skeletal abnormalities that form part of the aneurysms-osteoarthritis syndrome. Interestingly, the identification of this familial deletion is an example of an unanticipated result of a genomic microarray and led to the discovery of important but unrelated serious aortic disease in the proband and family members.


[Implementation and use of an electronic medical record in a department of cardiology: ten-year experience].
The rising of healthcare and hospital efficiency has underlined the necessity of clinical information systems. Hospitals represent complex organizations requiring control of different types of data for the management of patients and resources. A project was developed at the CNR Institute of Clinical Physiology of Pisa to produce an integration system to manage healthcare in its technological, administrative and clinical aspects, in respect of high quality in healthcare and cost-effectiveness evaluation. A networked computer-based information system was implemented to integrate different heterogeneous sources of patient data, both administrative and clinical (texts, signals, images), reaching a total integration. Data are stored into a relational database, processed and presented to healthcare personnel by network-connected clinical workstations. Epidemiological components are integrated to continuously offer evaluation processes to clinical components. From 1998 to August 2007 more than 300 stations were connected. The electronic medical records of more than 20 000 patients were recorded; more than 100 000 procedures were digitally integrated and the entire health file record and cost calculation could be obtained for each patient. In conclusion, the use of electronic medical records allowed a complete clinical data integration with improvement of overall structure efficiency and healthcare quality.


Dry Needling and Antithrombotic Drugs.
Many clinicians increasingly use dry needling in clinical practice. However, whether patients' intake of antithrombotic drugs should be considered as a contraindication for dry needling has not been investigated to date. As far as we know, there are no publications in analyzing the intake of antiplatelet or anticoagulant agents in the context of dry needling techniques. A thorough analysis of existing medications and how they may impact various needling approaches may contribute to improved evidence-informed clinical practice. The primary purpose of this paper is to review the current knowledge of antithrombotic therapy in the context of dry needling. In addition, reviewing guidelines of other needling approaches, such as electromyography, acupuncture, botulinum toxin infiltration, and neck ultrasound-guided fine-needle aspiration biopsy, may provide specific insights relevant for dry needling. Based on published data, taking antithrombotic medication should not be considered an absolute contraindication for dry needling techniques. As long as specific dry needling and individual risks are properly considered, it does not change the risk and safety profile of dry needling. Under specific circumstances, the use of ultrasound guidance is recommended when available.


Co-ordinated expression of connexins 26 and 32 in human endometrial glandular epithelium during the reproductive cycle and the influence of hormone replacement therapy.
Hormones are involved in the regulation of intercellular communication, and gap junction intercellular communication may play an important role in the prevention of endometrial cancer. We have investigated changes in the expression of the gap junction proteins connexin 26 (Cx26) and Cx32 in human endometrial glandular epithelium during the reproductive cycle as well as the influence of hormone replacement therapy. Frozen sections from 71 endometrial tissue samples (53 taken from women who had undergone hysterectomy during the menstrual cycle, 3 early pregnancy deciduae and 15 from menopausal women, some of whom were receiving estrogen alone or estrogen plus progesterone) were analyzed by immunofluorescence and confocal laser scanning microscopy. Cx26 and Cx32 were expressed weakly in the proliferative phase, markedly during ovulation and most strongly in the mid-secretory phase; by the late secretory phase, they decreased drastically. Cx26 and Cx32 also were expressed in early pregnancy. Women who had received estrogen and progesterone expressed the Cxs, but those who had received estrogen only or no therapy did not. These results were confirmed by Western blot analysis. They indicate that expression of Cx26 and Cx32 is correlated with cell differentiation and with the glandular function of the endometrial epithelium and suggest that expression of Cxs is controlled by serum progesterone.


V-ATPase V1 sector is required for corpse clearance and neurotransmission in Caenorhabditis elegans.
The vacuolar-type ATPase (V-ATPase) is a proton pump composed of two sectors, the cytoplasmic V(1) sector that catalyzes ATP hydrolysis and the transmembrane V(o) sector responsible for proton translocation. The transmembrane V(o) complex directs the complex to different membranes, but also has been proposed to have roles independent of the V(1) sector. However, the roles of the V(1) sector have not been well characterized. In the nematode Caenorhabditis elegans there are two V(1) B-subunit genes; one of them, vha-12, is on the X chromosome, whereas spe-5 is on an autosome. vha-12 is broadly expressed in adults, and homozygotes for a weak allele in vha-12 are viable but are uncoordinated due to decreased neurotransmission. Analysis of a null mutation demonstrates that vha-12 is not required for oogenesis or spermatogenesis in the adult germ line, but it is required maternally for early embryonic development. Zygotic expression begins during embryonic morphogenesis, and homozygous null mutants arrest at the twofold stage. These mutant embryos exhibit a defect in the clearance of apoptotic cell corpses in vha-12 null mutants. These observations indicate that the V(1) sector, in addition to the V(o) sector, is required in exocytic and endocytic pathways.


Photographic but not line-drawn faces show early perceptual neural sensitivity to eye gaze direction.
Our brains readily decode facial movements and changes in social attention, reflected in earlier and larger N170 event-related potentials (ERPs) to viewing gaze aversions vs. direct gaze in real faces (Puce et al., 2000). In contrast, gaze aversions in line-drawn faces do not produce these N170 differences (Rossi et al., 2014), suggesting that physical stimulus properties or experimental context may drive these effects. Here we investigated the role of stimulus-induced context on neurophysiological responses to dynamic gaze. Sixteen healthy adults viewed line-drawn and real faces, with dynamic eye aversion and direct gaze transitions, and control stimuli (scrambled arrays and checkerboards) while continuous electroencephalographic (EEG) activity was recorded. EEG data from 2 temporo-occipital clusters of 9 electrodes in each hemisphere where N170 activity is known to be maximal were selected for analysis. N170 peak amplitude and latency, and temporal dynamics from Event-Related Spectral Perturbations (ERSPs) were measured in 16 healthy subjects. Real faces generated larger N170s for averted vs. direct gaze motion, however, N170s to real and direct gaze were as large as those to respective controls. N170 amplitude did not differ across line-drawn gaze changes. Overall, bilateral mean gamma power changes for faces relative to control stimuli occurred between 150-350 ms, potentially reflecting signal detection of facial motion. Our data indicate that experimental context does not drive N170 differences to viewed gaze changes. Low-level stimulus properties, such as the high sclera/iris contrast change in real eyes likely drive the N170 changes to viewed aversive movements.


Skyline-plot methods for estimating demographic history from nucleotide sequences.
Estimation of demographic history from nucleotide sequences represents an important component of many studies in molecular ecology. For example, knowledge of a population's history can allow us to test hypotheses about the impact of climatic and anthropogenic factors. In the past, demographic analysis was typically limited to relatively simple population models, such as exponential or logistic growth. More flexible approaches are now available, including skyline-plot methods that are able to reconstruct changes in population sizes through time. This technical review focuses on these skyline-plot methods. We describe some general principles relating to sampling design and data collection. We then provide an outline of the methodological framework, which is based on coalescent theory, before tracing the development of the various skyline-plot methods and describing their key features. The performance and properties of the methods are illustrated using two simulated data sets.


The usefulness of fleet rectal enemas on high-dose-rate intracavitary cervical cancer brachytherapy. A prospective trial.
To evaluate the effects of rectal enemas on rectal doses during radical high-dose-rate (HDR) intracavitary cervical brachytherapy (BT). Twenty patients suffering from cervical cancer and treated with external beam radiotherapy and HDR-BT were included in a prospective trial. The first brachytherapy fraction was considered the basal status, and patients were instructed to self-administer two rectal cleansing enemas before the second fraction. Dose-volume histogram (DVH) values were generated for the rectum and correlated with rectal volume variation. Brachytherapy was carried out with a Fletcher or Utrecht applicator. No significant rectal volume differences were observed between fractions with or without rectal enemas (without, 52.64 ± 15.92 cc; with, 53.16 ± 19.28 cc). There was a significant correlation between both rectal volumes (r = 0.722, p = 0.001). No significant differences were observed in analyzed DVH parameters (median values: ΔD0.1cc, 4.17 vs. 3.61 Gy; ΔD1cc, 3.23 vs. 2.87 Gy; ΔD2cc, 2.9 vs. 2.54 Gy; ΔD5cc, 2.35 vs. 2.05 Gy, for no enema and enema fraction, respectively). No significant rectal volume differences nor DVH parameter differences were observed according the applicator type. Our rectal enemas protocol prior to HDR-BT was ineffective in significantly modifying rectal DVH parameters. No differences were observed according to the type of applicator used.


Prevalence and Associated Factors of Medication Non-Adherence in CRS Patients following Endoscopic Sinus Surgery.
This study aimed to evaluate factors that may predispose patients to not adhere to prescribed medication after endoscopic sinus surgery (ESS) and to compare SNOT-22 scores at 0-12 months post-operatively between adherent and non-adherent patients. CRS patients who underwent ESS between 2012 and 2016 were recruited to this retrospective cohort study. Adherence was assessed through a questionnaire and review of medical notes. Ninety-four participants were included (61% male, mean age 60). Of those, 66% did not adhere to their prescribed post-operative CRS medication timing or dosage. The most common reason for non-adherence was improvement of symptoms (17%), followed by deterioration of symptoms (11%) and side effects (10%). Post-operative SNOT-22 scores were lowest for non-intentionally non-adherent (NINA) participants with a mean of 10.5 [95% CI: 7.47-13.5], compared to 25.0 for intentionally non-adherent (INA) [95% CI: 17.6-32.4] and 17.7 for adherent patients [95% CI: 13.7-21.7], p = 0.01. This study identifies that almost two-thirds of patients are not compliant with CRS medications after ESS. NINA participants reported lower post-operative SNOT-22 scores compared to INA and adherent participants. Future studies should focus on educating patients to continue with medications post-operatively despite an initial improvement in symptoms.


Ectopic Expression of Mulberry G-Proteins Alters Drought and Salt Stress Tolerance in Tobacco.
Heterotrimeric guanine-nucleotide-binding proteins (G-proteins) play key roles in responses to various abiotic stress responses and tolerance in plants. However, the detailed mechanisms behind these roles remain unclear. Mulberry (Morus alba L.) can adapt to adverse abiotic stress conditions; however, little is known regarding the associated molecular mechanisms. In this study, mulberry G-protein genes, MaGα, MaGβ, MaGγ1, and MaGγ2, were independently transformed into tobacco, and the transgenic plants were used for resistance identification experiments. The ectopic expression of MaGα in tobacco decreased the tolerance to drought and salt stresses, while the overexpression of MaGβ, MaGγ1, and MaGγ2 increased the tolerance. Further analysis showed that mulberry G-proteins may regulate drought and salt tolerances by modulating reactive oxygen species' detoxification. This study revealed the roles of each mulberry G-protein subunit in abiotic stress tolerance and advances our knowledge of the molecular mechanisms underlying G-proteins' regulation of plant abiotic stress tolerance.


Unusual fracture-dislocation of the great toe: case report.
An unusual fracture-dislocation of the great toe is presented and discussed. A review of the literature is included and a possible mechanism discussed. The lack of information in the literature relative to this injury led us to report this case.


Neospora caninum: specific oligonucleotide primers for the detection of brain "cyst" DNA of experimentally infected nude mice by the polymerase chain reaction (PCR).
Both tachyzoites and bradyzoites in tissue cysts of Neospora caninum are morphologically difficult to distinguish from those of other cyst-forming apicomplexan parasites such as Toxoplasma gondii. Thus, molecular tools may contribute to easy identification of the parasite. Based upon an N. caninum-specific DNA fragment that we have recently cloned, 5 sense (Np1, Np3, Np5, Np7, Np21) and 4 antisense (Np2, Np4, Np6, Np8) oligonucleotides were designed for a sensitive and specific polymerase chain reaction (PCR). Among 19 combinations of sense and antisense primers, the Np21/Np6, Np21/Np4, and Np7/Np6 primer pairs were found to generate specific single bands in the presence of at least 10 pg genomic parasite DNA as a template. The primer pair Np21/Np6 was able to detect a single tachyzoite in the background of DNA derived from 2 mg of brain tissue. In experimentally infected athymic ICR:nu/nu mice, N. caninum-DNA was detected consistently from brain tissue at days 13 and 18 after subcutaneous inoculation of tachyzoites. The presence or absence of the organisms in the cerebrum in either proliferative or cystic form was examined by immunohistological staining. The results indicate that PCR with the primer pair Np21/Np6 could provide an efficient tool for large-scale epidemiological studies using brain tissue obtained at necropsy.


Mistreatment of older people in the United Kingdom: findings from the first National Prevalence Study.
There have been few national studies of the prevalence of elder mistreatment (abuse and neglect) in private households. This article provides an overview of the UK National Prevalence Study of Elder Mistreatment that took place in 2006. It addressed 2,111 respondents in four countries who answered a face-to-face survey questionnaire. The achieved sample was weighted to be representative of the UK older population. Of respondents, 2.6% reported mistreatment by family members, close friends, or care workers. The predominant type of reported mistreatment was neglect (1.1%) followed by financial abuse (0.6%), with 0.4% of respondents reporting psychological abuse, 0.4% physical abuse, and 0.2% sexual abuse. Women were significantly more likely to have experienced mistreatment than men, but there were gender differences according to type of abuse and perpetrator characteristics. Divergent patterns were found for neglect, financial, and interpersonal abuse. Further analysis of the data indicated that the likelihood of mistreatment varied with socioeconomic position and health status.


Co-Players in Chronic Pain: Neuroinflammation and the Tryptophan-Kynurenine Metabolic Pathway.
Chronic pain is an unpleasant sensory and emotional experience that persists or recurs more than three months and may extend beyond the expected time of healing. Recently, nociplastic pain has been introduced as a descriptor of the mechanism of pain, which is due to the disturbance of neural processing without actual or potential tissue damage, appearing to replace a concept of psychogenic pain. An interdisciplinary task force of the International Association for the Study of Pain (IASP) compiled a systematic classification of clinical conditions associated with chronic pain, which was published in 2018 and will officially come into effect in 2022 in the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization. ICD-11 offers the option for recording the presence of psychological or social factors in chronic pain; however, cognitive, emotional, and social dimensions in the pathogenesis of chronic pain are missing. Earlier pain disorder was defined as a condition with chronic pain associated with psychological factors, but it was replaced with somatic symptom disorder with predominant pain in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) in 2013. Recently clinical nosology is trending toward highlighting neurological pathology of chronic pain, discounting psychological or social factors in the pathogenesis of pain. This review article discusses components of the pain pathway, the component-based mechanisms of pain, central and peripheral sensitization, roles of chronic inflammation, and the involvement of tryptophan-kynurenine pathway metabolites, exploring the participation of psychosocial and behavioral factors in central sensitization of diseases progressing into the development of chronic pain, comorbid diseases that commonly present a symptom of chronic pain, and psychiatric disorders that manifest chronic pain without obvious actual or potential tissue damage.


A cancer center's approach to engaging African American men about cancer: the men's fellowship breakfast, Southeastern Michigan, 2008-2014.
Despite disproportionate rates of cancer morbidity and mortality among African American men, few community-based efforts have been developed and sustained to educate African American men about cancer. The University of Michigan Comprehensive Cancer Center implemented a series of breakfasts to improve cancer awareness, screening, and education among African American men. This article describes the rationale for and history of the community intervention. The 21 breakfasts were held from 2008 through mid-2014 in Ypsilanti and Ann Arbor, Michigan. Ypsilanti ranks below Michigan and the nation on most socioeconomic indicators, although most residents are high school graduates (88% in Ypsilanti and 96.5% in Ann Arbor). African American men in Ypsilanti have higher death rates for diseases associated with poor diet and inadequate physical activity compared with Ypsilanti whites and general populations in Michigan and the nation. We conducted a multicomponent qualitative process evaluation including staff meetings, conversations with participants, and focus groups. We collected 425 post-event surveys to evaluate the breakfasts quantitatively. Participants were African American (85%), were aged 51 to 70 years (54%), had health insurance (89%), and had some college education (38%). Fifty-three percent of participants reported interest in the breakfast topics including nutrition; 46%, prostate cancer; 34%, colorectal cancer, and 32%, pain management; 62% reported willingness to participate in a clinical trial. African American men are interested in learning about health and are willing to attend a health-focused breakfast series. The Men's Fellowship Breakfast is a promising strategy for bringing men together to discuss cancer screening and risk reduction.


Description of Lunatimonas salinarum sp. nov.
A Gram-stain-negative, crescent-shaped, non-motile, aerobic bacterium was isolated from a saltern at Nari along the Bhavnagar coast, Gujarat, India. The strain designated JC344T was oxidase- and catalase-positive. The 16S rRNA gene sequence analysis and sequence comparison data indicated that JC344T represented a member of the genus Lunatimonas and was closely related to the only species of the genus, Lunatimonas lonarensis AK24T (95.5 %). The DNA G+C content of JC344T was 43 mol%. JC344T has phosphatidylethanolamine (PE) and four unidentified polar lipids. MK-7 is the only respiratory quinone. The major (>10 %) fatty acids of strain JC344T are iso-C15 : 0, anteiso-C15 : 0 and summed feature 9 (iso-C17 : 1ω9c and/or C16 : 0 10-methyl). On the basis of physiological, genotypic, phylogenetic and chemotaxonomic analyses, we conclude that JC344T represents a novel species of the genus Lunatimonas, for which the name Lunatimonas salinarum sp. nov. is proposed. The type strain is JC344T (=KCTC 42988T=LMG 29259T).


Electrocochleographic study of Ménière's disease.
Auditory nerve action potential (AP), cochlear microphonics (CM), and summating potential (SP) were recorded from 32 patients with Ménière's disease. Patients were classified into three groups according to the degree of their hearing impairment. The group of patients that had a mild to moderate hearing loss and whose hearing was reversible showed notably satisfactory responses for AP, CM, and negative SP (-SP), and also showed a high incidence of positive SP (+SP). Low responses for AP and CM with an increase of detection thresholds and a high -SP/AP ratio were obtained from patients with moderate hearing impairment, whose hearing fluctuated slightly. These electrocochleographic findings were suggestive of the pathophysiologic differences at the various stages of Ménière's disease.


Psychometrics and validation of a screening instrument for sickness absence.
Absence from work due to psychosocial health complaints has considerable negative effects for employees, employers and society. A better and more effective strategy would be early identification of employees at risk for psychosocial sickness absence and early intervention to prevent sickness absence as far as possible. To assess psychometric characteristics and the external validation of a recently developed screening instrument, called 'Werkwijzer', for the identification of employees at risk for sickness absence due to psychosocial health complaints. Exploratory factor analysis was applied on items of the instrument. Cronbach's alpha coefficient was used to determine internal consistency of the subscales. Sum scores on the screening instrument were correlated to absenteeism data to determine their potential for predicting sickness absence. Predictive value was investigated, using objective sickness absence data as criterion measure. Sensitivity and specificity rates were calculated for external validation. For both men and women, three interpretable factors were found. Sum scores on the instrument showed low correlations with sickness absence. The association between 'being at risk' (yes/no) and sickness absence (yes/no) was odds ratio (OR) 3.1 (95% CI 1.5-6.5) for men and OR 2.0 (95% CI 1.4-2.7) for women. Sensitivity scores were rather low, whereas specificity scores were remarkably high. The results of this study provide the screening instrument a theoretic and scientific basis. Predictive value is promising, when absence is treated as a dichotomous measure. Sensitivity and specificity were unvarying during the development and validation phases of the instrument.


Metal-Organic Frameworks as Platforms for the Controlled Nanostructuring of Single-Molecule Magnets.
The prototypical single-molecule magnet (SMM) molecule [Mn12O12(O2CCH3)16(OH2)4] was incorporated under mild conditions into a highly porous metal-organic framework (MOF) matrix as a proof of principle for controlled nanostructuring of SMMs. Four independent experiments revealed that the SMM clusters were successfully loaded in the MOF pores, namely synchrotron-based powder diffraction, physisorption analysis, and in-depth magnetic and thermal analyses. The results provide incontrovertible evidence that the magnetic composite, SMM@MOF, combines key SMM properties with the functional properties of MOFs. Most importantly, the incorporated SMMs exhibit a significantly enhanced thermal stability with SMM loading advantageously occurring at the periphery of the bulk MOF crystals with only a single SMM molecule isolated in the transverse direction of the pores.


Cholesterol feeding alters the metabolism of thoracic-duct lymph lipoprotein cholesterol in rabbits but not in rats.
1. Labelled thoracic-duct lymph was collected from rats and rabbits after test meals containing [(14)C]cholesterol and [2-(3)H]glyceryl trioleate. 2. The metabolism of labelled cholesterol and triglyceride was studied in normally fed and cholesterol-fed rats and rabbits injected with radioactive lymph from the same species. 3. In normally fed animals of both species, 10min after intravenous administration, about 80% of lymph cholesteryl ester but only about 10% of triglyceride was recovered in the liver after clearance from the plasma. This distribution is consistent with participation of ;remnant' particles in the metabolism of dietary lymph particles. 4. The metabolism of cleared lymph lipoprotein constituents was unchanged in cholesterol-fed rats, but the recovery of cholesteryl ester in the livers of the cholesterol-fed rabbits was decreased to 30% of the cleared dose. 5. The low recovery in cholesterol-fed rabbits was accounted for mainly by increased hydrolysis of cholesteryl ester. 6. It is proposed that differences between rats and rabbits in metabolism of dietary cholesterol might be partly due to the observed enhancement of hydrolysis of lymph lipoprotein cholesteryl ester in rabbits.