Sulfated polysaccharides of Laetiporus sulphureus fruiting bodies exhibit anti-breast cancer activity through cell cycle arrest, apoptosis induction, and inhibiting cell migration.
Laetiporus sulphureus has long been used as an edible and medicinal mushroom in Asia, America, and Europe. Its fruiting bodies are widely used in folk medicine for treating cancer, gastric diseases, cough, and rheumatism. Polysaccharides are an important bioactive component of mushrooms. In nature, sulfated polysaccharides have never been reported in mushrooms. Furthermore, there is no information on differences in physicochemical properties and anti-breast cancer activities between polysaccharides (PS) and sulfated polysaccharides (SPS) of L. sulphureus. This study aimed to investigate the physicochemical properties of PS and SPS isolated from fruiting bodies of L. sulphureus and examine their anti-proliferative effects and mechanism(s) of action on MDA-MB-231 breast cancer cells. Polysaccharides (PS) were isolated using hot water and ethanol precipitation methods. Sulfated polysaccharides (SPS) were isolated by the papain-assisted hydrolysis method. Physicochemical properties comprising sugar, protein, uronic acid, and sulfate contents, and molecular weight, monosaccharide composition, and structural conformation were analyzed on PS and SPS. In the anti-cancer study, a triple-negative breast cancer cell line (MDA-MB-231) and a normal human mammary epithelial cell line (H184B5F5/M10) were used to evaluate the anti-proliferative activity of PS and SPS, and their mechanism(s) of action. The results showed that SPS, which had higher sulfate and protein contents and diversified monosaccharide composition, exhibited more potent anti-proliferative activity against MDA-MB-231 cells than PS. Furthermore, it had a selective cytotoxic effect on breast cancer cells but not the normal cells. SPS induced cell cycle arrest at G0/G1 phase via down-regulating CDK4 and cyclin D1 and up-regulating p21 protein expression. Breast cancer cell apoptosis was not observed until 72 h after SPS treatment. In addition, SPS also markedly inhibited breast cancer cell migration. This study demonstrates that SPS exhibited selective cytotoxicity and was more potent than PS in inhibiting MDA-MB-231 cell proliferation. The contents of sulfate and protein, and monosaccharide composition could be the main factors affecting the anti-breast cancer activity of L. sulphureus SPS.


[Nutritional therapy in gastrointestinal disease].
Gastrointestinal tract is an organ for digestion, absorption and utilization of nutrients. Also it functions as an immunological organ in the human body. Patients with gastrointestinal disease are at increased risk for nutritional problem due to dietary restriction during the treatment or diagnostic examinations, anorexia or altered nutritional requirement. Clinically, it is important for gastroenterologists to be aware of the principles of nutritional therapy and the relationship between gastrointestinal diseases and the combined nutritional abnormalities. Removal of enteral feeding causes mucosal atrophy and leads to increased mucosal permeability to bacteria and endotoxin. The intestinal endotoxemia results from the translocation of bacteria and endotoxin to systemic circulation, may triggers off systemic inflammatory response syndrome. Therefore, it is crucial in critically ill patients to maintain the gastrointestinal mucosal integrity along with the intestinal flora that enables the host immunity to be maintained or enhanced. Immunonutrition is a therapeutic approach to enhance the gastrointestinal mucosal barrier with various specific nutrients. The intestinal endotoxemia and immunonutrition will also be reviewed briefly.


Mental illness and psychotropic drug use among prescription drug overdose deaths: a medical examiner chart review.
Between 1999 and 2006, there was a 120% increase in the rate of unintentional drug overdose deaths in the United States. This study identifies the prevalence of mental illness, a risk factor for substance abuse, and chronic pain among prescription drug overdose deaths in West Virginia and ascertains whether psychotropic drugs contributing to the deaths were used to treat mental illness or for nonmedical purposes. In 2007, we abstracted data on mental illness, pain, and drugs contributing to death from all unintentional prescription drug overdose deaths in 2006 recorded by the West Virginia Office of the Chief Medical Examiner. Decedent prescription records were obtained from the state prescription drug monitoring program. Histories of mental illness and pain were documented in 42.7% and 56.6% of 295 decedents, respectively. Psychotropic drugs contributed to 48.8% of the deaths, with benzodiazepines involved in 36.6%. Benzodiazepines contributing to death were not associated with mental illness (adjusted odds ratio [AOR] = 1.1; 95% CI, 0.6-1.8), while all other psychotropic drugs were (AOR = 3.9; 95% CI, 2.0-7.6). Of decedents with contributory benzodiazepines, 46.3% had no prescription for the drug. Mental illness may have contributed to substance abuse associated with deaths. Clinicians should screen for mental illness when prescribing opioids and recommend psychotherapy as an adjunct or an alternate to pharmacotherapy. Benzodiazepines may have been used nonmedically rather than as a psychotropic drug, reflecting drug diversion. Restricting benzodiazepine prescriptions to a 30-day supply with no refills might be considered.


Can assignment tests measure dispersal?
Individual-based assignment tests are now standard tools in molecular ecology and have several applications, including the study of dispersal. The measurement of natal dispersal is vital to understanding the ecology of many species, yet the accuracy of assignment tests in situations where natal dispersal is common remains untested in the field. We studied a metapopulation of the grand skink, Oligosoma grande, a large territorial lizard from southern New Zealand. Skink populations occur on isolated, regularly spaced rock outcrops and are characterized by frequent interpopulation dispersal. We examined the accuracy of assignment tests at four replicate sites by comparing long-term mark-and-recapture records of natal dispersal with the results of assignment tests based on microsatellite DNA data. Assignment tests correctly identified the natal population of most individuals (65-100%, depending on the method of assignment), even when interpopulation dispersal was common (5-20% dispersers). They also provided similar estimates of the proportions of skinks dispersing to those estimated by the long-term mark-and-recapture data. Fully and partially Bayesian assignment methods were equally accurate but their accuracy depended on the stringency applied, the degree of genetic differentiation between populations, and the number of loci used. In addition, when assignments required high confidence, the method of assignment (fully or partially Bayesian) had a large bearing on the number of individuals that could be assigned. Because assignment tests require significantly less fieldwork than traditional mark-and-recapture approaches (in this study < 3 months vs. > 7 years), they will provide useful dispersal data in many applied and theoretical situations.


Transcriptomic Analysis of the Porcine Endometrium during Embryo Implantation.
In pigs, successful embryo implantation is an important guarantee for producing litter size, and early embryonic loss occurring on day 12-30 of gestation critically affects the potential litter size. The implantation process is regulated by the expression of numerous genes, so comprehensive analysis of the endometrium is necessary. In this study, RNA sequencing (RNA-Seq) technology is used to analyze endometrial tissues during early pregnancy. We investigated the changes of gene expression between three stages (day 12, 18, and 25) by multiple comparisons. There were 1557, 8951, and 2345 differentially expressed genes (DEGs) revealed between the different periods of implantation. We selected several genes for validation by the use of quantitative real-time RT-PCR. Bioinformatic analysis of differentially expressed genes in the endometrium revealed a number of biological processes and pathways potentially involved in embryo implantation in the pig, most noticeably cell proliferation, regulation of immune response, interaction of cytokine-cytokine receptors, and cell adhesion. These results showed that specific gene expression patterns reflect the different functions of the endometrium in three stages (maternal recognition, conceptus attachment, and embryo implantation). This study identified comprehensive transcriptomic profile in the porcine endometrium and thus could be a foundation for targeted studies of genes and pathways potentially involved in abnormal endometrial receptivity and embryo loss in early pregnancy.


Disease pattern and chronic illness in rural China: the Hong Kong Red Cross basic health clinic after 2008 Sichuan earthquake.
Medical teams might have difficulties preparing for deployment to rural towns due to a lack of prior information. The study objective was to identify the health needs and chronic disease prevalence of rural Chinese following a major earthquake. Hong Kong Red Cross organised a basic healthcare team to Yanmen town, Jiangyou 3 weeks after the 2008 Sichuan earthquake. A cross-sectional records-based study of all patients treated by the Hong Kong Red Cross basic healthcare team from 1 June to 19 June 2008 was conducted. Two thousand and thirty-four individual patient encounters occurred during the 19-day period. Musculoskeletal, respiratory and gastrointestinal problems were the top three categories and accounted for 30.4%, 17.4% and 12.7%, respectively. The 43.4% of the 762 patients with blood pressure measurements were above the recognised criteria for hypertension. We identified that the management of chronic diseases was an important issue, especially with the high prevalence of hypertension found in our study. Medical responders need to be aware of the potential pre-existing disease burden in the community, with the possible exacerbation in post-disaster situations. Careful planning on the use of treatment guidelines with particular focus on the local health resources available and issues with continuation of care will provide better care for the patients.


Ginger Extract-Loaded Solid Dispersion System with Enhanced Oral Absorption and Antihypothermic Action.
The aim of this study is to enhance the antihypothermic action of ginger extract (GE) employing a solid dispersion (SD) approach. The prepared SD of GE (GE/SD) was characterized in terms of physicochemical and pharmacokinetic properties. The antihypothermic action of GE samples was evaluated in a rat model of hypothermia. GE/SD exhibited improved dissolution behavior of the major active ingredients in GE, 6-gingerol (6G) and 8-gingerol (8G), with levels of dissolution 12- and 31-fold higher than that of GE, respectively. Even after storage under accelerated conditions, limited degradations of 6G and 8G were observed in GE/SD, although 6G and 8G were slightly degraded in GE. After oral administration of GE (300 mg/kg) and GE/SD (100 mg of GE/kg), the relative bioavailabilities of 6G and 8G in GE/SD were 5.0- and 5.8-fold higher than those in GE, respectively. Orally administered GE/SD (30 mg of GE/kg) inhibited ethanol-evoked hypothermia because of improved oral absorption of 6G and 8G. From these observations, the SD approach might be efficacious for enhancing the nutraceutical potentials of GE.


Role of the monocyte chemoattractant protein and eotaxin subfamily of chemokines in allergic inflammation.
Allergic inflammation is characterized by the tissue accumulation and activation of leukocytes rich in eosinophils. During these responses, there is marked induction of specific chemokines that are involved in regulating the recruitment and activation of these inflammatory cells. A subfamily of CC (or beta) chemokines composed of macrophage chemoattractant proteins (MCP) and eotaxin have emerged as cytokines involved in the recruitment and activation of the cells seen in allergic reactions. We now show that these chemokines are strikingly related in chromosomal location, gene structure, primary protein sequence, biological activity, and receptor usage. We also show that these chemokines are differentially regulated in human and animal models of allergic disease and perform distinct roles in vivo. We propose that this subfamily of chemokines plays a fundamental role in the development of allergic responses.


Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.
Increasingly, metabolic potential is proving to be a critical determinant governing a pathogen's virulence as well as its capacity to expand its host range. To understand the potential contribution of metabolism to strain-specific infectivity differences, we present a constraint-based metabolic model of the opportunistic parasite, Toxoplasma gondii. Dominated by three clonal strains (Type I, II, and III demonstrating distinct virulence profiles), T. gondii exhibits a remarkably broad host range. Integrating functional genomic data, our model (which we term as iCS382) reveals that observed strain-specific differences in growth rates are driven by altered capacities for energy production. We further predict strain-specific differences in drug susceptibilities and validate one of these predictions in a drug-based assay, with a Type I strain demonstrating resistance to inhibitors that are effective against a Type II strain. We propose that these observed differences reflect an evolutionary strategy that allows the parasite to extend its host range, as well as result in a subsequent partitioning into discrete strains that display altered virulence profiles across different hosts, different organs, and even cell types.


Design control--the ultimate protection?
Over the last decade or so, medical device manufacturers with customers in the United States and the United Kingdom should have discovered the benefits of using quality systems in their manufacturing process. Both the American GMP Regulations (21 CFR-820)--enforced by the U.S. Food and Drug Administration (FDA)--and the U.K. Department of Health Guides to Good Manufacturing Practice based upon BS 5750: Part I (1979)--enforced through the National Health Service supply chain-- have been applied with the objective of ensuring the availability of safe and effective medical devices. This article examines the design control aspects of a quality system and asks whether the medical device industry should be suspicious of third-party assessments of confidential documentation.


Kinetic studies on cytochrome c oxidase inserted into liposomal vesicles. Effect of ionophores.
Cytochrome c oxidase from ox heart was inserted into artificial liposomal vesicles obtained by sonication of purified soya-bean phospholipids. The cytochrome oxidase vesicles showed a respiratory control ratio of about 2. Spectroscopic properties in the visible and Soret regions and kinetics of CO binding are similar to those of the soluble oxidase. The catalytic efficiency of the cytochrome oxidase vesicles in oxidizing cytochrome c increases as a result of the formation of the 'pulsed' form of the oxidase and of the presence in the reaction mixture of carbonyl cyanide p-trifluoromethoxy-phenylhydrazone and nonactin. Analysis of the experimental results obtained under several conditions supports the conclusions that: (i) the alkalinization of the internal microenvironment in the liposomal vesicle is not by itself responsible for the decrease in catalytic activity; (ii) the electrical potential difference created during turnover by proton consumption and/or pumping through the liposome wall is an important mechanism of control in the chain of events leading to the oxidation of external cytochrome c.


Radiographic evaluation of non-syndromic third molar agenesis in two Mediterranean populations.
Third molar agenesis is a common finding across the world. Many studies have assessed third molar agenesis in different ethnicities and populations. However, there are no such studies in the Italian and Lebanese populations. Our study aims to evaluate the prevalence of third molar agenesis and study the pattern and distribution of agenesis in between genders in Italian and Lebanese Mediterranean populations and compare these findings with other global and Mediterranean populations' studies. Retrospective chart review was conducted based on the history and orthopantomograms of adolescents aged 12 to 21 years to assess the agenesis of third molars in a sample of Italian and Lebanese populations by two experienced dental surgeons twice within 1 month. Descriptive and comparative tests were used to analyze the patterns of ageneses and make comparisons between the two samples. 23.4% of the studied sample had at least one third molar agenesis; females were more likely to have two or more third molar agenesis than males, but neither sex predisposition for single third-molar agenesis was recorded. Both the Italian and Lebanese subgroups seemed to have similar results. The maxillary right third molar was the most common third molar to be absent. Two or more ageneses were more common than one third molar agenesis. Our Mediterranean population results fall within the range reported in the literature and corroborate with the global average prevalence.


Measurement of NO Concentration in Water Saturated Nitrogen.
The equivalent Raman scattering cross section of NO (nitric oxide) referred to O(2) (oxygen) and N(2) (nitrogen) was obtained experimentally. Furthermore, it is shown that it is possible, using the Raman effect, not only to detect small concentrations of nitric oxide in water saturated nitrogen but also to obtain quantitative measurements of NO independent of the presence of other species.


Synthesis, characterization and the formation mechanism of magnesium- and strontium-substituted hydroxyapatite.
Magnesium (Mg) and strontium (Sr) have been widely used in the field of implanted devices because of their excellent bioactivity. However, the local high ion concentration caused by the implant affects the growth of hydroxyapatite (Ca10(PO4)6(OH)2, HA), which is the main inorganic component of bone and teeth. Many studies have investigated the effect of Mg2+ and Sr2+ on the growth of HA, but no systematic research has been conducted to compare these two ions in terms of the growth of HA. In this study, the substitution of a series of Sr- and Mg-substituted HA was conducted through a conventional hydrothermal method. Comprehensive characterization techniques, including X-ray diffraction, inductive coupled plasma, field emission scanning electron microscopy, transmission electron microscopy, selected-area electron diffraction, thermo gravimetric-differential scanning calorimetry, and Fourier transform infrared spectroscopy, were used to examine the effects of Sr2+ and Mg2+ on the phase, morphology, crystallinity, chemical composition, thermal stability, and lattice parameters of HA. The results indicated that Mg ions partially substituted for calcium (Ca) ions in the apatite structure, thus decreasing the lattice parameters, partially adsorbing on the apatite surface that formed the amorphous phase, and inhibiting the crystal growth. By contrast, Sr ions fully substituted for Ca ions and increased the lattice parameters. Both Mg and Sr ions affected the morphology of HA. Crystallinity decreased with the addition of Mg ions (transition from the crystal to amorphous phase was between 30% and 40% Mg), but it was not affected by Sr ions. Thermostability decreased with the addition of Mg (a total weight loss from 8.06 wt% for 10% Mg to 25.81 wt% for 50% Mg), but it had no significant changes in the Sr-substituted samples.


Visualizing DNA domains and sequences by microscopy: a fifty-year history of molecular cytogenetics.
This short review presents a historical perspective of chromosome research during the last 50 years. It shows how molecular knowledge and technology of DNA entered cytogenetics step by step making it now daily practice in almost every modern chromosome lab. A crucial milestone in these decades has been the development of in situ protocols by Pardue and Gall, among others, initially only with isotopic labels, and without fluorescence microscopy and sophisticated detection systems. But these very first in situ hybridizations played a decisive role in the discovery of chromosome banding profiles, which were obtained under specific chemical, physical, or enzymatic conditions, thus effecting stainability of specific chromosome regions. In the decades thereafter, numerous technical improvements were achieved leading to complex multi-colour fluorescence in situ hybridization (FISH) protocols for mammals, plants, and insects. Highly improved detection systems of the FISH signals further allowed detection of DNA targets of up to 50 bp, whereas other protocols, which were developed to stretch chromatin fibres to the full length of native DNA, improved spatial resolution of adjacent targets in the light microscope to 1 kb.


Beyond Ussing's chambers: contemporary thoughts on integration of transepithelial transport.
In the mid-20th century, Hans Ussing developed a chamber that allowed for the simultaneous measurement of current and labeled probe flux across epithelia. Using frog skin as a model, Ussing used his results to propose mechanisms of transcellular Na(+) and K(+) transport across apical (exterior/luminal) and basolateral (interior) membranes that is essentially unchanged today. Others took advantage of Ussing's chambers to study mucosal tissues, including bladder and intestines. It quickly became clear that, in some tissues, passive paracellular flux, i.e., across the tight junction, was an important component of overall transepithelial transport. Subsequent work demonstrated that activation of the apical Na(+)-glucose cotransporter SGLT1 regulated paracellular permeability such that intestinal paracellular transport could coordinate with and amplify transcellular transport. Intermediates in this process include activation of p38 MAPK, the apical Na(+)/H(+) exchanger NHE3, and myosin light chain kinase (MLCK). Investigators then focused on these processes in disease. They found that TNF induces barrier dysfunction via MLCK activation and downstream caveolin-1-dependent endocytosis of the tight junction protein occludin. TNF also inhibited NHE3, and both barrier loss and PKCα-dependent NHE3 inhibition were required for TNF-induced acute diarrhea, emphasizing the interplay between transcellular and paracellular transport. Finally, studies using immune-mediated inflammatory bowel disease models showed that mice lacking epithelial MLCK were initially protected, but became ill as epithelial damage progressed and provided a tight junction-independent means of barrier loss. None of these advances would have been possible without the insights provided by Ussing and others using Ussing's ingenious, and still useful, chambers.


Synthesis of full interpenetrating hemicellulose hydrogel networks.
Two methods with different cross-linking mechanisms for designing hemicellulose-based full interpenetrating polymer networks (IPNs) were developed through the sequential synthesis of full IPNs from O-acetyl-galactoglucomannan (AcGGM) utilizing free-radical polymerization and a thiol-ene click reaction. A faster swelling rate was observed for all IPN formulations compared with the single-network gels. The highly porous structure of the IPNs with small interconnected pores was verified using scanning electron microscopy. A rheological analysis revealed that the AcGGM IPNs fabricated by the free-radical polymerization of acrylamide and N-N'-methylenebisacrylamide (cross-linker) had shear storage modulus (G') values approximately 5 and 2.5 times higher than that of the corresponding precursor single networks of AcGGM. IPNs achieved through thiol-ene reactions between thiolated AcGGM and polyethylene glycol diacrylate had G' values 35-40 times higher than the single-network reference hydrogels.


Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia.
Evidence from experimental pain research has revealed that metabotropic glutamate receptors (mGluRs) play a pivotal role in nociceptive processing, inflammatory pain and hyperalgesia. The aim of this study was to characterise expression of group I and II mGluRs in spinal cord in a model of naturally occurring persistent inflammation (sheep with unilateral lameness due to inflammation of the digital tissues of the feet, estimated to have been affected by the condition for >2 weeks) and an experimental model of acute inflammation (injection of intradermal carrageenan into lower forelimb in sheep). Animals with unilateral clinical inflammation displayed significant mechanical hyperalgesia on the affected limb. Carrageenan treatment produced significant bilateral limb mechanical hyperalgesia 3 h post-injection. Up-regulation of mGluR(3) and mGluR(5) mRNA was observed in ipsilateral spinal cord recovered from clinically lame animals, restricted to laminae II-V and I-II, respectively. Western blot analyses of protein extracts revealed a bilateral increase in mGluR(2/3) and mGluR(5). No change was detected in spinal cord mGluR(1) or mGluR(2) mRNA. There was no change in mGluR(1,2,3,5) subtype mRNA or proteins in spinal cord recovered from animals 3 h post-carrageenan. These results demonstrate for the first time that mGluR subtypes are differentially expressed in spinal cord dorsal horn in response to persistent inflammation, and suggest that mGluR activity may be involved in mediating altered behaviours associated with clinical inflammatory pain.


IEEE802.15.6 -based multi-accelerometer WBAN system for monitoring Parkinson's disease.
In this paper we present a detailed example of a wireless body area network (WBAN) scenario utilizing the recent IEEE802.15.6 standard as applied to a multi-accelerometer system for monitoring Parkinson's disease and fall detection. Ultra wideband physical layer and standard security protocols are applied to meet application requirements for data rate and security.


Regional pest suppression associated with widespread Bt maize adoption benefits vegetable growers.
Transgenic crops containing the bacterium Bacillus thuringiensis (Bt) genes reduce pests and insecticide usage, promote biocontrol services, and economically benefit growers. Area-wide Bt adoption suppresses pests regionally, with declines expanding beyond the planted Bt crops into other non-Bt crop fields. However, the offsite benefits to growers of other crops from such regional suppression remain uncertain. With data spanning 1976-2016, we demonstrate that vegetable growers benefit via decreased crop damage and insecticide applications in relation to pest suppression in the Mid-Atlantic United States. We provide evidence for the regional suppression of Ostrinia nubilalis (Hübner), European corn borer, and Helicoverpa zea (Boddie), corn earworm, populations in association with widespread Bt maize adoption (1996-2016) and decreased economic levels for injury in vegetable crops [peppers (Capsicum annuum L.), green beans (Phaseolus vulgaris L.), and sweet corn (Zea mays L., convar. saccharata)] compared with the pre-Bt period (1976-1995). Moth populations of both species significantly declined in association with widespread Bt maize (field corn) adoption, even as increased temperatures buffered the population reduction. We show marked decreases in the number of recommended insecticidal applications, insecticides applied, and O. nubilalis damage in vegetable crops in association with widespread Bt maize adoption. These offsite benefits to vegetable growers in the agricultural landscape have not been previously documented, and the positive impacts identified here expand on the reported ecological effects of Bt adoption. Our results also underscore the need to account for offsite economic benefits of pest suppression, in addition to the direct economic benefits of Bt crops.


Keratoconus in Costello syndrome.
Keratoconus is a corneal dystrophy with progressive corneal thinning resulting in abnormal corneal shape and astigmatism. Corneal hydrops and rupture can occur and corneal transplant may become necessary. While keratoconus is rare in the general population occurring in about 1/2,000 individuals, it is more common in individuals with intellectual disability and syndromic conditions. Connective tissue abnormalities, most typically brittle cornea syndrome, have frequently been reported in association with keratoconus. Here, we report on bilateral keratoconus with acute hydrops in the left eye of a 24-year-old male with Costello syndrome. The patient was treated medically. After resolution of the hydrops, he had significant visual impairment from the resulting irregular astigmatism and scarring. This is the second report of keratoconus in Costello syndrome, suggesting an increased risk for this corneal dystrophy in individuals with Costello syndrome. Ongoing ophthalmological surveillance may be necessary for adult individuals with Costello syndrome, and apparent vision changes should be evaluated expediently.


A targeted home- and center-based exercise program for people after total hip replacement: a randomized clinical trial.
To examine the physical function, gait, and quality of life of patients after total hip replacement (THR) randomly assigned to either a targeted home- or center-based exercise program. Randomized controlled trial. Rehabilitation research center in Australia. Twenty-three patients with unilateral THR were randomly assigned to a supervised center-based exercise group (n=11) or an unsupervised home-based exercise group (n=12). The center-based group completed an 8-week targeted exercise program while under the direct supervision of a physiotherapist. After initial instruction, the home-based group completed the 8-week targeted exercise program at home without further supervision. Quality of life, physical function, and spatiotemporal measures of gait. No significant interaction (group by time) or main effects of grouping were found. Within each group, quality of life, and stair climbing improved significantly (P<.05) as did Timed Up & Go test and 6-minute walk test performances (P<.05). Walking speed increased by 16 cm/s (P<.01), cadence by 8 steps/min (P<.05), step length by 4.7 cm (P<.05), and double-support time reduced by a factor of 16%. Step length symmetry showed significant improvement (P<.05) over time. Step length differential between the affected and unaffected limbs reduced from 4.0 to 2.7 cm. The targeted strengthening program was effective for both the home- and center-based groups. No group differences were found in the majority of the outcome measures. This finding is important because it shows that THR patients can achieve significant improvements through a targeted strengthening program delivered at a center or at home.


"I attend at Vanguard and I attend here as well": barriers to accessing healthcare services among older South Africans with HIV and non-communicable diseases.
HIV and non-communicable disease (NCD) are syndemic within sub-Saharan Africa especially among older persons. The two epidemics interact with one another within a context of poverty, inequality and inequitable access to healthcare resulting in an increase in those aged 50 and older living with HIV and experiencing an NCD co-morbidity. We explore the challenges of navigating healthcare for older persons living with HIV and NCD co-morbidity. In-depth semi-structured interviews were conducted with a small sample of older persons living with HIV (OPLWH). The perspectives of key informants were also sought to triangulate the evidence of OPLWH. The research took place in two communities on the outskirts of Cape Town, South Africa. All interviews were conducted by a trained interviewer and transcribed and translated for analysis. Thematic content analysis guided data analysis. OPLWH experienced an HIV-NCD syndemic. Our respondents sought care and accessed treatment for both HIV and other chronic (and acute) conditions, though these services were provided at different health facilities or by different health providers. Through the syndemic theory, it is possible to observe that OPLWH and NCDs face a number of physical and structural barriers to accessing the healthcare system. These barriers are compounded by separate appointments and spaces for each condition. These difficulties can exacerbate the impact of their ill-health and perpetuate structural vulnerabilities. Despite policy changes towards integrated care, this is not the experience of OPLWH in these communities. The population living with HIV is aging increasing the likelihood that those living with HIV will also be living with other chronic conditions including NCDs. Thus, it is essential that health policy address this basic need to integrate HIV and NCD care.


Statin use and clinical outcomes in patients with COVID-19: An updated systematic review and meta-analysis.
Observations studies have shown that prior use of statins is associated with a reduced risk of adverse clinical outcomes in patients with COVID-19. However, the available data are limited, inconsistent and conflicting. Besides, no randomised controlled trial exists in this regard. Hence, the present meta-analysis was conducted to provide an updated summary and collate the effect of statin use on clinical outcomes in COVID-19 using unadjusted and adjusted risk estimates. PubMed, Scopus and Web of Science databases were systematically searched using appropriate keywords till December 18 2020, to identify observational studies reporting clinical outcomes in COVID-19 patients using statins versus those not using statins. Prior and in-hospital use of statins were considered. Study quality was assessed using the Newcastle-Ottawa Scale. Unadjusted and adjusted pooled odds ratio (OR) with 95% CIs were calculated. We included 14 observational studies pooling data retrieved from 19 988 patients with COVID-19. All the studies were of high/moderate quality. Pooled analysis of unadjusted data showed that statin use was not associated with improved clinical outcomes (OR 1.02; 95% CI 0.69 to 1.50, p=0.94, I2=94%, random-effects model). However, on pooling adjusted risk estimates, the use of statin was found to significantly reduce the risk of adverse outcomes (OR 0.51; 95% CI 0.41 to 0.63, p<0.0005, I2=0%, fixed-effects model). Statin use is associated with improved clinical outcomes in patients with COVID-19. Individuals with multiple comorbidities on statin therapy should be encouraged to continue the drug amid the ongoing pandemic.


[Gonococci change more quickly than prescribing practices; resistance to frequently prescribed antibiotics].
Gonococcal resistance to antibiotics is increasing worldwide. In patients tested in Dutch STI clinics in 2009, gonococcal resistance to ciprofloxacin was over 50%. Ceftriaxone, a third-generation cephalosporin, has been the first-choice medication since 2004. General practitioners treated 25% of their gonorrhoea patients with ciprofloxacin in 2010. There is a need for up-to-the-minute, dynamic guidelines for treating gonorrhoea as well as the more systematic use of an up-to-date digital prescription system.


Immunization with crude antigens plus aluminium hydroxide protects cattle from Fasciola hepatica infection.
The ability of total homogenate (TH) of Fasciola hepatica conjugated with aluminium hydroxide (alum) or Freund's complete adjuvant (FCA) to protect cattle against experimental fasciolosis was evaluated. Compared with the infected group, the immunized animals with alum-TH and FCA-TH presented a significant reduction in fluke burden (85.9% and 96.8%, respectively), a higher percentage of short-sized worms, a marked reduction in the released eggs in faeces (89% and 57%, respectively), as well as an increased production of specific antibodies before infection. The alum-TH immunized group also showed a significant increase in the antigen-specific proliferation of peripheral blood mononuclear cells (PBMC) as early as 4 weeks before infection. Although both immunized groups (alum-TH and FCA-TH) were able to develop an efficient protective immune response to metacercarial challenge, an earlier PBMC response, lower hepatic damage and less effect on weight gain were found in alum-immunized animals. Therefore, alum is a good candidate for future immunization against bovine fasciolosis.


Cognitive flexibility in preschoolers: the role of representation activation and maintenance.
Preschoolers' lack of cognitive flexibility has often been attributed to perseverative processing. This study investigates alternative potential sources of difficulty such as deficits in activating previously ignored information and in maintaining currently relevant information. In Experiment 1, a new task tapping attentional switching was designed to isolate the difficulty of overriding an initial representation, that is, perseverative processing ('Perseveration' version), and the difficulty of activating a previously ignored representation, that is, activation deficit ('Activation-deficit' version). Three-year-olds' performance suggested that inflexibility may primarily stem from an activation deficit. Control experiments confirmed that the difficulty of the 'Activation-deficit' version could not be attributed to the effect of attraction to novelty. In Experiment 2, 'distraction' errors, alleged to reflect a failure to maintain a relevant representation, and 'perseverative' errors were distinguished. The results highlighted the important role of representation maintenance in flexibility. The present study indicates that preschoolers' lack of cognitive flexibility is multi-determined and prompts us to reconsider the role of perseveration.


Unlocking NuriPep 1653 From Common Pea Protein: A Potent Antimicrobial Peptide to Tackle a Pan-Drug Resistant Acinetobacter baumannii.
While the antibiotic era has come and gone, antimicrobial peptides (AMPs) hold promise as novel therapies to treat multidrug resistant (MDR) pathogens in an age where the threat of multidrug resistance escalates worldwide. Here, we report the bactericidal properties of NuriPep 1653, a novel 22 mer and non-modified peptide. NuriPep 1653 was identified within the sequence of the non-antimicrobial P54 protein, which is involved in nutrient reservoir activity in Pisum sativum. Total bacterial clearance of Acinetobacter baumannii cells (1 × 108 cells/mL) was observed using only 4 × MIC (48 μg/mL) of NuriPep 1653 after just 20 min of treatment. We uncovered a synergistic interaction between NuriPep 1653 and another antimicrobial peptide, colistin. The MIC of NuriPep 1653 and colistin dropped from 12 and 8 μg/mL to 2 and 1 μg/mL, respectively, when they were combined. NuriPep 1653 exhibits no cytotoxicity in different human cell lines and has a low propensity to induce bacterial resistance in a colistin resistant clinical isolate of A. baumannii. The existence of these peptides embedded in proteins unearths potentially new classes of antimicrobials with activity against clinically relevant pathogens. Our findings push the boundaries of traditional peptide discovery and represent a leading edge for natural bioactive compounds which may have a common existence in nature but remain unexposed.


Clinimetric Testing of the Lumbar Spine Instability Questionnaire.
The Lumbar Spine Instability Questionnaire (LSIQ) is a self-report measure of 15 items. Previous studies have used the LSIQ as a measure of clinical instability; however, a comprehensive evaluation of its clinimetric properties has not been conducted. The aim of this study was to evaluate the clinimetric properties of the LSIQ in patients with chronic nonspecific low back pain (LBP). In this clinical measurement study, the authors included patients with nonspecific LBP presenting to primary care clinicians in Australia. Rasch analysis was conducted to assess item hierarchy, targeting, unidimensionality, person fit, internal consistency, and differential item functioning. The researchers assessed test-retest reliability of total scores and individual item scores, as well as convergent and divergent validity. A total of 107 participants with LBP (60 men and 47 women) were recruited. The results were variable. The LSIQ appeared to constitute a unidimensional measure, targeted the sample well, and showed adequate test-retest reliability. However, the scale had poor internal consistency, did not appear to function as an interval-level measure, and had unclear construct validity. Although no items appeared to be redundant, several items were biased by factors other than the proposed construct of the measure. The LSIQ does not seem to be ready to be implemented in clinical practice and may require theoretical reconsideration. Although the LSIQ provided satisfactory estimates for some clinimetric features, the authors do not consider the instrument to be useful as an interval-level measure but rather as an index. Future studies are needed to investigate whether the LSIQ could measure clinical instability or some other construct. J Orthop Sports Phys Ther 2018;48(12):915-922. Epub 22 Jun 2018. doi:10.2519/jospt.2018.7866.


Diversity of the T-cell receptor BV repertoire in HIV-1-infected patients reflects the biphasic CD4+ T-cell repopulation kinetics during highly active antiretroviral therapy.
Highly active antiretroviral therapy (HAART) induces a decline in viral load and a biphasic increase in peripheral blood CD4+ T-cell counts in HIV-infected patients. To evaluate the effect of HAART on T-cell receptor (TCR) diversity of repopulating naive and memory CD4+ T cells, complementarity determining region 3 (CDR3) spectratyping was performed. For four patients treated with HAART, CD45RO+ (memory) and CD45RA+ (naive) CD4+ T cells were isolated from peripheral blood leukocyte samples obtained 1 week before, 1-2 months after, and 9-11 months after start of treatment. CDR3 regions were amplified by TCR-BV-specific nested PCR from CD4+ T-cell subsets. CDR3 size distributions and single-strand conformation polymorphism profiles were compared as an indication for TCR diversity. Increasing blood CD4+ T-cell counts during the first 2 months of treatment coincided with increased perturbation of CDR3 patterns in CD4+ T-cell subsets, suggesting an early oligoclonal repopulation. At later timepoints, CDR3 size diversity increased when T-cell counts did not substantially decrease. Memory and naive CD4+ T cells generally showed comparable levels of perturbation. Diversity of the TCR repertoire reflected biphasic T-cell repopulation during HAART, compatible with initial redistribution and later CD4+ T-cell production. Sustained elevation of T-cell counts will in principle result in restoration of TCR diversity.


Computerized tomography-based anatomic description of the porcine liver.
The knowledge of the anatomic features is imperative for successful modeling of the different surgical situations. This study aims to describe the anatomic features of the porcine using computerized tomography (CT) scan. Thirty large, white, female pigs were included in this study. The CT image acquisition was performed in four-phase contrast study. Subsequently, analysis of the images was performed using syngo.via software (Siemens) to subtract mainly the hepatic artery and its branches. Analysis of the portal and hepatic veins division pattern was performed using the Myrian XP-Liver 1.14.1 software (Intrasense). The mean total liver volume was 915 ± 159 mL. The largest sector in the liver was the right medial one representing around 28 ± 5.7% of the total liver volume. Next in order is the right lateral sector constituting around 24 ± 5%. Its volume is very close to the volume of the left medial sector, which represents around 22 ± 4.7% of the total liver volume. The caudate lobe represents around 8 ± 2% of the total liver volume.The portal vein did not show distinct right and left divisions rather than consecutive branches that come off the main trunk. The hepatic artery frequently trifurcates into left trunk that gives off the right gastric artery and the artery to the left lateral sector, the middle hepatic artery that supplies both the right and the left medial sectors and the right hepatic artery trunk that divides to give anterior branch to the right lateral lobe, branch to the right medial lobe, and at least a branch to the caudate lobe. Frequently, there is a posterior branch that crosses behind the portal vein to the right lateral lobe. The suprahepatic veins join the inferior vena cava in three distinct openings. There are communications between the suprahepatic veins that drain the adjacent sectors. The vein from the right lateral and the right medial sectors drains into a common trunk. The vein from the left lateral and from the left medial sectors drains into a common trunk. A separate opening is usually encountered draining the right medial sector. The caudate lobe drains separately into inferior vena cava caudal to the other veins. Knowledge of the anatomic features of the porcine liver is crucial to the performance of a successful surgical procedure. We herein describe the CT-depicted anatomic features of the porcine liver.


Bile Microbiome Signatures Associated with Pancreatic Ductal Adenocarcinoma Compared to Benign Disease: A UK Pilot Study.
Pancreatic ductal adenocarcinoma (PDAC) has a very poor survival. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance and, therefore, patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures that can effectively distinguish malignant from benign tumours in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease. Prospective bile samples were obtained from 31 patients who underwent either Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiogram (PTC). Variable regions (V3-V4) of the 16S rRNA genes of microorganisms present in the samples were amplified by Polymerase Chain Reaction (PCR) and sequenced. The cohort consisted of 12 PDAC, 10 choledocholithiasis, seven gallstone pancreatitis and two primary sclerosing cholangitis patients. Using the 16S rRNA method, we identified a total of 135 genera from 29 individuals (12 PDAC and 17 benign). The bile microbial beta diversity significantly differed between patients with PDAC vs. benign disease (Permanova p = 0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering of Aitchison distance. We found three genera to be of significantly lower abundance among PDAC samples vs. benign, adjusting for false discovery rate (FDR). These were Escherichia (FDR = 0.002) and two unclassified genera, one from Proteobacteria (FDR = 0.002) and one from Enterobacteriaceae (FDR = 0.011). In the same samples, the genus Streptococcus (FDR = 0.033) was found to be of increased abundance in the PDAC group. We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation.


Neck posture and muscle activity are different when upside down: a human volunteer study.
Rollover crashes are dynamic and complex events in which head impacts with the roof can cause catastrophic neck injuries. Ex vivo and computational models are valuable in understanding, and ultimately preventing, these injuries. Although neck posture and muscle activity influence the resulting injury, there is currently no in vivo data describing these parameters immediately prior to a head-first impact. The specific objectives of this study were to determine the in vivo neck vertebral alignment and muscle activation levels when upside down, a condition that occurs during a rollover. Eleven human subjects (6F, 5M) were tested while seated upright and inverted in a custom-built apparatus. Vertebral alignment was measured using fluoroscopy and muscle activity was recorded using surface and indwelling electrodes in eight superficial and deep neck muscles. In vivo vertebral alignment and muscle activation levels differed between the upright and inverted conditions. When inverted and relaxed, the neck was more lordotic, C1 was aligned posterior to C7, the Frankfort plane was extended, and the activity of six muscles increased compared to upright and relaxed. When inverted subjects were asked to look forward to eliminate head extension, flexor muscle activity increased, C7 was more flexed, and C1 was aligned anterior to C7 versus upright and relaxed. Combined with the large inter-subject variability observed, these findings indicate that cadaveric or computational models designed to study injuries and prevention devices while inverted need to consider a variety of postures and muscle conditions to be relevant to the in vivo situation.


Acetylcholine-mediated axon-glia signaling in the developing insect olfactory system.
In the olfactory system of the sphinx moth Manduca sexta, migration of neuropil glial cells is triggered by olfactory receptor axons and depends on intraglial Ca(2+) signaling. It is not known, however, how receptor axons and glial cells communicate and whether Ca(2+) signaling is a consequence of this communication. We studied Ca(2+) increases in glial cells in vivo and in situ, evoked by electrical stimulation of olfactory receptor axons in pupae and by odor stimulation of receptor neurons in adult moths. Axonal activity leads to Ca(2+) increases in neuropil glial cells that are blocked by nicotinic acetylcholine receptor antagonists and can be mimicked by acetylcholine and carbachol application. In addition, Ca(2+) transients were abolished by removal of external Ca(2+) and blockage of voltage-gated Ca(2+) channels. During development, acetylcholine-mediated Ca(2+) signaling could first be elicited at stage 6, the time when neuropil glial cells start to migrate. Glial migration was reduced after injection of nicotinic antagonists into pupae. The results show that Ca(2+) signaling can be induced by acetylcholine release from olfactory receptor axons, which activates nicotinic acetylcholine receptors and leads to voltage-gated Ca(2+) influx. The results further suggest that cholinergic signaling in the olfactory system is required for glial cell migration in Manduca.


The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea.
To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.


The effect of angiotensin-converting enzyme inhibitors and statins on the progression of aortic sclerosis and mortality.
Although aortic sclerosis has been associated with an increase in adverse cardiovascular outcomes, no proven therapy has been shown to slow its progression to overt aortic stenosis (AS). Thus, the hypothesis was assessed that treatment with angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs) or statins may be associated with an improvement in the clinical outcome of these patients. A total of 4,105 patients with evidence of aortic sclerosis seen on transthoracic echocardiography (defined as thickening or calcification with a mean valve gradient < or = 15 mmHg) was identified. Patients with a sclerotic valve who were treated with ACE-Is/ARBs or statins were followed for a mean period of 1,078 +/- 615 days. After adjustment for the propensity to receive ACE-Is/ARBs or statins, mortality, hemodynamic progression to AS, hospitalization for ischemic heart disease (IHD), and congestive heart failure (CHF) were assessed and related to the medical treatment. At baseline, patients with aortic sclerosis who were treated with an ACE-I/ARB or a statin suffered significantly more from comorbidities such as IHD, CHF, hypertension, diabetes, and peripheral arterial disease, when compared to subjects with sclerotic valves not treated with these drugs. After adjustment for confounding factors, treatment with statins was associated with a significant reduction in mortality (odds ratio [OR] 0.73, 95% CI 0.56-0.98, p = 0.001), admission for IHD (OR 0.81, 95% CI 0.66-0.99, p = 0.03), admission for CHF (OR 0.68, 95% CI 0.55-0.85, p = 0.01) and progression to AS (OR 0.64, 95% CI 0.42-0.97, p = 0.03). While ACE-I treatment resulted in a significant reduction in admission for IHD (OR 0.80, 95% CI 0.65-0.98, p = 0.03) and CHF (OR 0.76, 95% CI 0.62-0.94, p = 0.01), the beneficial trend towards reduced mortality and delayed progression to AS was not significant. Treatment of this patient population with statins led to a significant reduction in mortality and also slowed the progression to AS--an effect that was not statistically significant with ACE-I treatment.


Gender Differences in Civil Commitment Hearing Experience for Persons Who Use Opioids.
Civil commitment has increasingly served as a court-based legal intervention for severe opioid use, but little research has examined the civil commitment (CC) hearing process from the perspective of the person who is committed. Despite documented gender differences in opioid use and experiences within the legal system, past research has also not investigated gender differences in perceptions of the CC process for persons who use opioids. Participants were 121 persons (43% female) with opioid use who were interviewed upon arrival at the CC facility about their experience of the CC hearing process in Massachusetts. Two thirds of participants were taken to the commitment hearing by police, and 59.5% shared a cell with others while waiting. Overall, the commitment intake process at the courthouse took over 5 hours. Participants spent, on average, less than 15 minutes with their lawyer before the hearing, and a majority of CC hearings lasted less than 15 minutes. Once transferred to a CC facility, opioid withdrawal management began within 4 hours. Compared with women, men reported longer wait times between the hearing and transfer, as well as longer wait times for withdrawal management at the facility ( P < 0.05). Women perceived worse interactions with the judge and greater dissatisfaction with the commitment process compared with men ( P < 0.05). There were few gender differences in the experience of CC. However, overall, participants reported a lengthy court process and low levels of perceived procedural justice.


Comparative phytochemical analysis of five Egyptian strawberry cultivars (Fragaria × ananassa Duch.) and antidiabetic potential of Festival and Red Merlin cultivars.
This work aims to explore the differences in phytochemical composition and biological properties of five strawberry hybrids (Fragaria × ananassa Duch.), and highlights the non-edible part (byproduct) as a source of self-remedy natural herb along with fruits. HPLC/DAD/HRESIMS technique was used in the dereplication of ten ethanolic extracts of five strawberry cultivars leaves and fruits (Festival, Red Merlin, Suzana, Tamar and Winter Dawn). Total phenolic and total flavonoid contents were established using Folin-Ciocalteu and aluminum chloride colorimetric assays, respectively. Ethanolic extracts of leaves and fruits from Festival and Red Merlin cultivars were selected to investigate their anti-hyperglycemic activity using streptozotocin-induced diabetic rats. Oxidative stress markers, lipid profile and kidney and liver function tests were assessed. The results revealed different chemical profiles of ten samples with the identification of 37 metabolites, represented mainly as flavonoids and phenolic acid derivatives. Phytochemical investigation resulted in the isolation of seven known phenolic compounds; quercetin, kaempferol, p-coumaric acid, p-tyrosol, methyl gallate, trans-tiliroside and eutigoside A. Suzana cultivar was the richest cultivar with flavonoids and total phenolics except for the total flavonoid content in leaves referred to Festival cultivar. Ethanolic extract of leaves, especially Festival cultivar was the most bioactive one. The results established the role of strawberry leaves along with fruits as an antioxidant and hypoglycemic natural remedy.


Temporal profiles of the levels of endogenous antioxidants after four-vessel occlusion in rats.
Although it is known that development of lipid peroxidation after ischemia occurs predominantly in vulnerable regions, temporal profiles of antioxidants after ischemia have not been regionally elucidated. After reperfusion periods of 0, 3, 24, and 72 hours following 20 minutes of four-vessel occlusion (n = 6 in each group), the concentration of total glutathione (GSH) and the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) were assayed in the hippocampus, parietal cortex, striatum, thalamus, and brain stem. The levels of all antioxidants were unchanged in all regions without reperfusion; however, the concentration of total GSH significantly decreased in the hippocampus at 3 hours after the onset of reperfusion, and showed a maximum decrease in the hippocampus (68% of the sham-control level), parietal cortex (78% of the sham-control level), and striatum (76% of the sham-control level) after 24 hours of reperfusion. After 72 hours of reperfusion, these regions and the thalamus showed restoration and an increase in the total GSH concentration, respectively. The activities of SOD, GSH-Px, and catalase were stable during the reperfusion period, but the hippocampus showed significant increases in these enzyme activities and the parietal cortex and striatum showed significant increases in SOD activities at 72 hours after the onset of reperfusion. These results indicate that endogenous antioxidants take 72 hours for restoration in vulnerable regions after 20 minutes of four-vessel occlusion in rats.


Success factors and barriers in interprofessional collaboration between dental hygienists and dietitians in community-dwelling older people: Focus group interviews.
Poor nutritional status can impair oral health while poor oral health can influence the individual's dietary intake, which may result in malnutrition. This interaction between nutritional status and oral health in older age requires attention, coordination and collaboration between healthcare professionals. This qualitative study explores dental hygienists' and dietitians' opinions about current collaboration with the aim of identifying success factors and barriers to this interprofessional collaboration. Three focus group interviews were held with Dutch dental hygienists and dietitians about nutritional and oral healthcare in community-dwelling older people. In total, 9 dietitians and 11 dental hygienists participated in three online focus group interviews. Dental hygienists and dietitians seldom collaborated or consulted with each other. They struggled with the professional boundaries of their field of expertise and experienced limited knowledge about the scope of practice of the other profession, resulting in conflicting information to patients about nutrition and oral health. Interprofessional education was scarce during their professional training. Organizational and network obstacles to collaborate were recognized, such as limitations in time, reimbursement and their professional network that often does not include a dietitian or dental hygienist. Dental hygienists and dietitians do not collaborate or consult each other about (mal)nutrition or oral health in community-dwelling older people. To establish interprofessional collaboration, they need to gain knowledge and skills about nutrition and oral health to effectively recognize problems in nutritional status and oral health. Interprofessional education for healthcare professionals is needed to stimulate interprofessional collaboration to improve care for older people.


Super-resolution reconstruction of speckle phase in depth-resolved wavelength scanning interference using the total least-squares analysis.
Depth-resolved wavelength scanning interferometry (DRWSI) is a tomographic imaging tool that employs phase measurement to visualize micro-displacement inside a sample. It is well known that the depth resolution of DRWSI is restricted by a wavelength scanning range. Recently, a nonlinear least-squares analysis (NLS) algorithm was proposed to overcome the limitation of the wavelength scanning range to achieve super-resolution; however, the NLS failed to measure speckle surfaces owing to the sensibility of initial values. To the best of our knowledge, the improvement of depth resolution on measuring a speckle surface remains an open issue for DRWSI. For this study, we redesigned the signal processing algorithm for DRWSI to refine the depth resolution when considering the case of speckle phase measurement. It is mathematically shown that the DRWSI's signal is derived as a model of total least-squares analysis (TLSA). Subsequently, a super-resolution of the speckle phase map was obtained using a singular value decomposition. Further, a numerical simulation to measure the micro-displacements for speckle surfaces was performed to validate the TLSA, and the results show that it can precisely reconstruct the displacements of layers whose depth distance is 5 μm. This study thus provides an opportunity to improve the DRWSI's depth resolution.


Solitary Metastasis to the Facial/Vestibulocochlear Nerve Complex: Case Report and Review of the Literature.
Distant metastasis of mucinous adenocarcinoma from the gastrointestinal tract, ovaries, pancreas, lungs, breast, or urogenital system is a well-described entity. Mucinous adenocarcinomas from different primary sites are histologically identical with gland cells producing a copious amount of mucin. This report describes a very rare solitary metastasis of a mucinous adenocarcinoma of unknown origin to the facial/vestibulocochlear nerve complex in the cerebellopontine angle. A 71-year-old woman presented with several month history of progressive neurological decline and a negative extensive workup performed elsewhere. She presented to our institution with complete left facial weakness, left-sided deafness, gait unsteadiness, headache and anorexia. A repeat magnetic resonance imaging scan of the head revealed a cystic, enhancing abnormality involving the left cerebellopontine angle and internal auditory canal. A left retrosigmoid craniotomy was performed and the lesion was completely resected. The final pathology was a mucinous adenocarcinoma of indeterminate origin. Postoperatively, the patient continued with her preoperative deficits and subsequently died of her systemic disease 6 weeks after discharge. The facial/vestibulocochlear nerve complex is an unusual location for metastatic disease in the central nervous system. Clinicians should consider metastatic tumor as the possible etiology of an unusual appearing mass in this location causing profound neurological deficits. The prognosis after metastatic mucinous adenocarcinoma to the cranial nerves in the cerebellopontine angle may be poor.


Achieving superior performance through process improvement.
The regular and continuous use of process improvement practices leads to superior performance, according to an international study of management practices. Process improvements enable hospitals to translate total quality management (TQM) and continuous quality improvement (CQI) initiatives into action. This article presents a step-by-step approach to process improvement in the hospital environment.


Fulvimonas yonginensis sp. nov., isolated from greenhouse soil, and emended description of the genus Fulvimonas.
A novel strain, designated 5GHs31-2(T), was isolated from a greenhouse soil sample collected from Yongin city, South Korea. Cells of strain 5GHs31-2(T) were Gram-stain-negative, rod-shaped, polar flagellated and yellow-pigmented. The isolate was aerobic, catalase-negative and oxidase-positive and grew optimally at 28-30 °C and pH 7.0. Strain 5GHs31-2(T) revealed the highest 16S rRNA gene sequence similarities with Fulvimonas soli LMG 19981(T) (97.6%), Dyella thiooxydans ATSB10(T) (97.5%) and Frateuria terrea VA24(T) (97.4%). Furthermore, the neighbour-joining tree showed that strain 5GHs31-2(T) was a representative of a member of the genus Fulvimonas. Strain 5GHs31-2(T) contained iso-C(16 : 0), summed feature 9 (iso-C(17 : 1)ω9c and/or C(16 : 0) 10-methyl), iso-C(15 : 0) and iso-C(17 : 0) as the major fatty acids, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and an aminolipid as the main polar lipids and Q-8 as the predominant quinone. The genomic DNA G+C content of 5GHs31-2(T) was 73.0 mol%. According to DNA-DNA hybridization experiments, DNA-DNA relatedness values between strain 5GHs31-2(T) and its closest phylogenetic neighbours were below 70%. Based on the taxonomic data, strain 5GHs31-2(T) represents a novel species of the genus Fulvimonas, for which the name Fulvimonas yonginensis sp. nov. is proposed. The type strain is 5GHs31-2(T) ( = KACC 16952(T) = DSM 28344(T)).


How does drug coverage vary by insurance type? Analysis of drug formularies in the United States.
To quantify how access to on-patent drugs by tier placement varies by insurance type and therapeutic area. Retrospective analysis of insurance plan drug coverage data. Drug coverage information was collected from the Fingertip Formulary database in May 2011 for 3 drug classes (statins, angiotensin II receptor blockers, and protein-tyrosine kinase inhibitors) across 3 therapeutic areas with varying levels of generic drug availability. A generalized linear model was used to estimate the percentage of available on-patent drugs covered in the formulary tiers with lowest copay requirements (tiers 1 and 2) in different types of healthcare insurance plans in the United States. There were substantial differences between insurance types in the number of on-patent drugs reimbursed in tiers 1 and 2 (ie, with a low copay). Compared with commercial plans, there were more on-patent drugs reimbursed with a low copay in employer plans, union plans, and with pharmacy benefit management companies, and substantially fewer on-patent drugs with a low copay in Medicare plans (Medicare Advantage, special needs, prescription drug plans) and discount prescription programs. These results were expected, as union plans are known for their generosity and Medicare plans rely heavily on cost containment (eg, cost sharing). For commercial Medicaid and municipal plans, the findings were dependent on the therapeutic class, or were inconclusive. The number of competitors a plan faces did not consistently affect the coverage of on-patent drugs. The degree of coverage of on-patent drugs in the lowest copay tiers varies dramatically between insurance types, especially for expensive protein-tyrosine kinase inhibitors.


Identification of peptides that antagonize formyl peptide receptor-like 1-mediated signaling.
Formyl peptide receptor-like 1 (FPRL1) is an important classical chemoattractant receptor that is expressed in phagocytic cells in the peripheral blood and brain. Recently, various novel agonists have been identified from several origins, such as host-derived molecules. Activation of FPRL1 is closely related to inflammatory responses in the host defense mechanism and neurodegenerative disorders. In the present study we identified several novel peptides by screening hexapeptide libraries that inhibit the binding of one of FPRL1's agonists (Trp-Lys-Tyr-Met-Val-D-Met-CONH(2) (WKYMVm)) to its specific receptor, FPRL1, in RBL-2H3 cells. Among the novel peptides, Trp-Arg-Trp-Trp-Trp-Trp-CONH(2) (WRWWWW (WRW(4))) showed the most potent activity in terms of inhibiting WKYMVm binding to FPRL1. We also found that WRW(4) inhibited the activation of FPRL1 by WKYMVm, resulting in the complete inhibition of the intracellular calcium increase, extracellular signal-regulated kinase activation, and chemotactic migration of cells toward WKYMVm. For the receptor specificity of WRW(4) to the FPR family, we observed that WRW(4) specifically inhibit the increase in intracellular calcium by the FPRL1 agonists MMK-1, amyloid beta42 (Abeta42) peptide, and F peptide, but not by the FPR agonist, fMLF. To investigate the effect of WRW(4) on endogenous FPRL1 ligand-induced cellular responses, we examined its effect on Abeta42 peptide in human neutrophils. Abeta42 peptide-induced superoxide generation and chemotactic migration of neutrophils were inhibited by WRW(4), which also completely inhibited the internalization of Abeta42 peptide in human macrophages. WRW(4) is the first specific FPRL1 antagonist and is expected to be useful in the study of FPRL1 signaling and in the development of drugs against FPRL1-related diseases.


Hematopoietic cell transplant nurse coordinators' perceptions of related donor care: a European survey from the EBMT Nurses Group.
Allogeneic haematopoietic cell transplantation (HCT) is a curative procedure for patients with haematological malignancies and immune deficiencies. A human leukocyte antigen (HLA) identical sibling is only available for 25-35% of patients in need. The improvement in haplo-identical transplantation has led to a marked increase in cell donation from relatives. Despite international recommendations, discrepancies in related-donors (RD) care exist between centres, particularly regarding medical suitability criteria, consenting procedures and donor follow-up. This European survey aimed to explore hematopoietic cell transplantation coordinators nurses' (HCT-CNs) perceptions of RD care, in particular the association with the presence or not of an independent unit (IU). Ninety-three HCT-CNs from seventy-six EBMT centres responded, representing 19 countries (response rate: 27%). Our results did not show a significant association between IU and HCT-CNs perceptions of related-donors care. The practices for RD care vary among centres regarding presence or not of an IU (48%), person caring for RD (haematologist in 54%, HCT physician in 17%, HCT-CNs in 20%), person to whom the results of HLA typing are communicated, use of a booklet for RD, follow-up or not and periodicity of follow-up. Qualitative data highlight the related-donation ethical issues and the need for improvement in RD care. HCT-CNs' main concerns were: the necessary confidentiality to insure the voluntary status of RD, the perceived conflict of interest felt by professionals when managing both patients and RD, plus the psychosocial aspects of related-donation. Even if there is a variety of a practice among centres, the presence of an IU is not significantly associated with an improvement in RD care.


Surface characteristics, equipment height, and the occurrence and severity of playground injuries.
To evaluate whether surface characteristics (absorption level (g-max), material) and the height of play equipment are related to the occurrence and severity of injuries from falls. During the summers of 1991 and 1995, conformity of play equipment to Canadian standards was assessed in a random sample (n = 102) of Montreal public playgrounds. Surface absorption (g-max) was tested using a Max Hic instrument and the height of equipment was measured. Concurrently, all injuries presenting at the emergency department of Montreal's two children's hospitals were recorded and parents were interviewed. Inspected equipment was implicated in 185 injuries. The g-max measurements (1995 only) were available for 110 of these playground accidents. One third of falls (35 %) occurred on a surface exceeding 200 g and the risk of injury was three times greater than for g level lower than 150 (95% confidence interval (CI) 1.45 to 6.35). On surfaces having absorption levels between 150 g and 200 g, injuries were 1.8 times more likely (95% CI 0.91 to 3.57). Injuries were 2.56 times more likely to occur on equipment higher than 2 m compared with equipment lower than 1.5 m. Analysis of risk factors by severity of injury failed to show any positive relationships between the g-max or height and severity, whereas surface material was a good predictor of severity. This study confirms the relationships between risk of injury, surface resilience, and height of equipment, as well as between type of material and severity of injury. Our data suggest that acceptable limits for surface resilience be set at less than 200 g, and perhaps even less than 150 g, and not exceed 2 m for equipment height. These findings reinforce the importance of installing recommended materials, such as sand, beneath play equipment.


A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction.
We provide a detailed description of the cis-trans isomerization of 4-hydroxytamoxifen/endoxifen catalyzed by several isoforms from the cytochrome P450 (CYP) superfamily, including CYP1B1, CYP2B6, and CYP2C19. We show that the reactions mainly involve redox processes catalyzed by CYP. DFT calculation results strongly suggest that the isomerization occurs via a cationic intermediate. The cationic cis-isomer is more than 3 kcal/mol more stable than the trans form, resulting in an easier conversion from trans-to-cis than cis-to-trans. The cis-trans isomerization is a rarely reported CYP reaction and is ascribed to the lack of a second abstractable proton on the ethenyl group of the triarylvinyl class of substrates. The cationic intermediates thus formed instead of the stable dehydrogenation products allow for isomerization to occur. As a comparison, the reactions for the tamoxifen derivatives are compared to those of other substrates, 4-hydroxyacetanilide and raloxifene, for which the stable dehydrogenation products are formed.


Unanticipated Respiratory Compromise and Unplanned Intubations on General Medical and Surgical Floors.
Unanticipated respiratory compromise that lead to unplanned intubations is a known phenomenon in hospitalized patients. Most events occur in patients at high risk in well-monitored units; less is known about the incidence, risk factors, and trajectory of patients thought at low risk on lightly monitored general care wards. The aims of our study were to quantify demographic and clinical characteristics associated with unplanned intubations on general care floors and to analyze the medications administered, monitoring strategies, and vital-sign trajectories before the event. We performed a multicenter retrospective cohort study of hospitalized subjects on the general floor who had unanticipated, unplanned intubations on general care floors from August 2014 to February 2018. We identified 448 unplanned intubations. The incidence rate was 0.420 per 1,000 bed-days (95% CI 0.374-0.470) in the academic hospital and was 0.430 (95% CI 0.352-0.520) and 0.394 per 1,000 bed-days (95% CI 0.301-0.506) at our community hospitals. Extrapolating these rates to total hospital admissions in the United States, we estimate 64,000 events annually. The mortality rate was 49.1%. Within 12 h preceding the event, 35.3% of the subjects received opiates. All received vital-sign assessments. Most were monitored with pulse oximetry. In contrast, 2.5% were on cardiac telemetry, and only 4 subjects used capnography; 53.7% showed significant vital-sign changes in the 24 h before the event. However, 46.3% had no significant change in any vital signs. Our study showed unanticipated respiratory compromise that required an unplanned intubation of subjects on the general care floor, although not common, carried a high mortality. Besides pulse oximetry and routine vital-sign assessments, very little monitoring was in use. A significant portion of the subjects had no vital-sign abnormalities leading up to the event. Further research is needed to determine the phenotype of the different etiologies of unexpected acute respiratory failure to identify better risk stratification and monitoring strategies.


Parkinson's disease: is the initial treatment established?
Recent studies have suggested that initial dopamine agonist therapy with pramipexole or ropinirole may slow the progression of Parkinson's disease (PD) and also reduce the subsequent risk of levodopa motor complications. This presumed effect on PD progression, however, could be artifactual, resulting from the influence of chronic drug treatment on regulation of dopamine system proteins. With respect to levodopa motor complications, there is no dispute that pramipexole and ropinirole are effective in reducing levodopa dyskinesias and motor fluctuations; however, it is not clear that they must be started early, as opposed to initiation only after the levodopa complications develop. Levodopa therapy has numerous advantages that include greater efficacy, much lesser expense, simpler administration, and a lower frequency of hallucinosis and somnolence. Carbidopa/levodopa, pramipexole, and ropinirole are all appropriate first choices in the treatment of PD.


Food intake alters muscle protein gain with little effect on Na(+)-K(+)-ATPase and myosin isoforms in suckled rats.
Biochemical maturation accompanies the rapid accretion of skeletal muscle in early life. We wished to determine whether changes in muscle protein accretion, induced by variations in food intake, altered the biochemical maturation of the soleus and the extensor digitorum longus (EDL) muscles. Rat pups were suckled in litters of 4, 10, or 16 to induce differences in food intake. At 21 days of age, muscle protein and DNA were quantitated and biochemical maturation was assessed from measurement of [3H]ouabain-binding site abundance and myosin isoform composition. Differences in food intake produced a twofold range in body and muscle weights and protein and DNA contents. Protein accretion was more sensitive to nutrient intake in the soleus than in the EDL. Serum 3-5,3'-triiodothyronine (T3) and insulin concentrations decreased with a reduction in food intake. Total ouabain-binding sites were not altered in either muscle and were independent of muscle size. Differences in myosin isoform composition were more pronounced for the soleus than the EDL, but were relatively small in magnitude. These results demonstrate that, whereas postnatal muscle protein accretion and circulating hormone concentrations are sensitive to food intake, the biochemical maturation is resilient. The immature muscle does not exhibit the fiber type-specific responses to malnutrition typical of mature muscle.


Legumes and soybeans: overview of their nutritional profiles and health effects.
Legumes play an important role in the traditional diets of many regions throughout the world. In contrast in Western countries beans tend to play only a minor dietary role despite the fact that they are low in fat and are excellent sources of protein, dietary fiber, and a variety of micronutrients and phytochemicals. Soybeans are unique among the legumes because they are a concentrated source of isoflavones. Isoflavones have weak estrogenic properties and the isoflavone genistein influences signal transduction. Soyfoods and isoflavones have received considerable attention for their potential role in preventing and treating cancer and osteoporosis. The low breast cancer mortality rates in Asian countries and the putative antiestrogenic effects of isoflavones have fueled speculation that soyfood intake reduces breast cancer risk. The available epidemiologic data are limited and only weakly supportive of this hypothesis, however, particularly for postmenopausal breast cancer. The data suggesting that soy or isoflavones may reduce the risk of prostate cancer are more encouraging. The weak estrogenic effects of isoflavones and the similarity in chemical structure between soybean isoflavones and the synthetic isoflavone ipriflavone, which was shown to increase bone mineral density in postmenopausal women, suggest that soy or isoflavones may reduce the risk of osteoporosis. Rodent studies tend to support this hypothesis, as do the limited preliminary data from humans. Given the nutrient profile and phytochemical contribution of beans, nutritionists should make a concerted effort to encourage the public to consume more beans in general and more soyfoods in particular.


Transfer RNA and human disease.
Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.


HPV-vaccination against cervical carcinoma: will it really work?
Prophylactic HPV vaccination provides an opportunity to profoundly affect cervical cancer incidence worldwide. The quadrivalent HPV VLP 6, 11, 16, 18 vaccine (Gardasil) and the bivalent HPV VLP 16, 18 vaccine (Cervarix) are effective for prevention of HPV infection and cervical precancerous lesions. The quadrivalent vaccine is also effective for prevention of vulvar and vaginal lesions and genital warts. With the introduction of the vaccines general issues have to be raised such as optimal age for vaccination, duration of protection after vaccination, impact on cervical cancer screening, vaccination of males and feasibility of application to developing countries. The prospects of a vaccine which will protect against the most common viral sexually transmitted infection and thereby, protect against the complications of HPV infection such as cervical cancer is extremely appealing. The success of HPV vaccination as a major public health prevention opportunity, however, will entirely depend on efficient infrastructures to deliver the vaccines and on the acceptance by individuals, parents and health care providers.


Controversies in the management of open fractures.
Open fractures are a common problem encountered by orthopaedic surgeons and comprise a broad spectrum of trauma. Management is guided by principle-based steps aimed at reducing the risk of gas gangrene or suppurative infections, whilst maintaining viability in a favourable soft tissue environment to reduce the risk of delayed or non-union of bone. Aspects of these principles, however, create discussion around several areas of controversy. The specific antimicrobial regimen and its duration are questions that have been evaluated for decades. Like the ever-evolving nature of the bacterial pathogens, the answer to this is dynamic and changing. The "six-hour rule" is a hotly debated topic with fervent perseverance of this dogma despite a gross lack of support from the literature. The most appropriate soft tissue management approach for open fractures - immediate definitive soft tissue closure versus leaving wounds open for delayed closure or definitive management - is also an area of debate. Exploration of these controversies and consideration for the historical context of the supporting literature furthers our understanding of the critical elements.


[Genetic characteristics of Chinese hamster cell resistance to colchicine, actinomycin D and ethidium bromide].
We have tried to study genetics of Chinese hamster cellular drug resistance to colchicine, actinomycin D and ethidium bromide. Resistant variants arising at a frequency 10(-5) to 10(-7) were selected from a sensitive population. Pretreatment with MNNG increased this frequency 106, 9-15, 12-26 times for colchicine, actinomycin D and ethidium bromide, respectively. Fluctuation test analysis allows to suppose that phenotypic expression of drug resistance is genetically determined and resulted from random genetical events. Significant values of particular correlation coefficients for selecting resistant variants in a set of independently originated subpopulations suggest the genetical identity of the majority of variants selected by colchicine and actinomycin D. At the same time, the significant portion of colchicine-resistant cells may be selected using ethidium bromide. It is not unlikely that under above experimental conditions, each selective agent reveals genetically different resistant variants. The possible genetic mechanisms of resistance to the drugs used are discussed.


Increased gamma- and decreased delta-oscillations in a mouse deficient for a potassium channel expressed in fast-spiking interneurons.
Kv3.1 is a voltage-gated, fast activating/deactivating potassium (K(+)) channel with a high-threshold of activation and a large unit conductance. Kv3.1 K(+) channels are expressed in fast-spiking, parvalbumin-containing interneurons in cortex, hippocampus, striatum, the thalamic reticular nucleus (TRN), and in several nuclei of the brain stem. A high density of Kv3.1 channels contributes to short-duration action potentials, fast afterhyperpolarizations, and brief refractory periods enhancing the capability in these neurons for high-frequency firing. Kv3.1 K(+) channel expression in the TRN and cortex also suggests a role in thalamocortical and cortical function. Here we show that fast gamma and slow delta oscillations recorded from the somatomotor cortex are altered in the freely behaving Kv3.1 mutant mouse. Electroencephalographic (EEG) recordings from homozygous Kv3.1(-/-) mice show a three- to fourfold increase in both absolute and relative spectral power in the gamma frequency range (20-60 Hz). In contrast, Kv3.1-deficient mice have a 20-50% reduction of power in the slow delta range (2-3 Hz). The increase in gamma power is most prominent during waking in the 40- to 55-Hz range, whereas the decrease in delta power occurs equally across all states of arousal. Our findings suggest that Kv3. 1-expressing neurons are involved in the generation and maintenance of cortical fast gamma and slow delta oscillations. Hence the Kv3. 1-mutant mouse could serve as a model to study the generation and maintenance of fast gamma and slow delta rhythms and their involvement in behavior and cognition.


S6K1 phosphorylates Cdk1 and MSH6 to regulate DNA repair.
The mTORC1 substrate, S6 Kinase 1 (S6K1), is involved in the regulation of cell growth, ribosome biogenesis, glucose homeostasis, and adipogenesis. Accumulating evidence has suggested a role for mTORC1 signaling in the DNA damage response. This is mostly based on the findings that mTORC1 inhibitors sensitized cells to DNA damage. However, a direct role of the mTORC1-S6K1 signaling pathway in DNA repair and the mechanism by which this signaling pathway regulates DNA repair is unknown. In this study, we discovered a novel role for S6K1 in regulating DNA repair through the coordinated regulation of the cell cycle, homologous recombination (HR) DNA repair (HRR) and mismatch DNA repair (MMR) mechanisms. Here, we show that S6K1 orchestrates DNA repair by phosphorylation of Cdk1 at serine 39, causing G2/M cell cycle arrest enabling homologous recombination and by phosphorylation of MSH6 at serine 309, enhancing MMR. Moreover, breast cancer cells harboring RPS6KB1 gene amplification show increased resistance to several DNA damaging agents and S6K1 expression is associated with poor survival of breast cancer patients treated with chemotherapy. Our findings reveal an unexpected function of S6K1 in the DNA repair pathway, serving as a tumorigenic barrier by safeguarding genomic stability.


The bootstrap procedure in individual bioequivalence.
A bootstrap-type hypothesis test procedure for assessing individual (or population) bioequivalence between two drug formulations is suggested in a draft guidance from the United States Food and Drug Administration (FDA). The purpose of this article is to study the unknown properties of this test procedure and propose some improved test procedures. We find that: the FDA's bootstrap computation is not correct; the power of the FDA's test can be very low; the use of the REML method suggested in the draft guidance does not have any advantage over the use of simpler methods such as the moment method; and the method of sample size determination in the draft guidance is inappropriate. We study the size and power of different bootstrap test procedures and suggest a method for sample size determination. It is our hope that this article will draw some attention to further research in this area, and eventually a satisfactory statistical method can be implemented for assessing individual (or population) bioequivalence.


Channels formation in cellulose materials by accelerated transport of gas molecules and glycerin.
In this study, a microporous separator was produced using cellulose acetate (CA), which demonstrates heightened thermal stability in comparison to existing materials like polypropylene (PP) or polyethylene (PE). Furthermore, a pliable component was integrated into the CA membrane using glycerin as the plasticizing agent. Subsequently, gas pressure was exerted onto these areas to induce the formation of nano-sized pores. Examination through Scanning Electron Microscopy (SEM) unveiled the presence of abundant pores in the glycerin-plasticized areas. This substantiates that the pores generated under gas pressure were not only more uniform but also smaller than those created under water pressure. The interaction between CA and glycerin was validated using Fourier-Transform Infrared Spectroscopy (FT-IR), offering confirmation that a portion of the glycerin was extracted following the application of gas pressure. Additionally, the application of Thermogravimetric Analysis (TGA) allowed for an assessment of the thermal stability of the CA membrane, along with a verification of glycerin's removal post gas pressure treatment. The findings indicated that the incorporation of glycerin diminished the thermal stability of the CA membrane due to the plasticization effect. Furthermore, it was observed that a minor quantity of glycerin still persisted after the gas pressure treatment. Following the analysis of gas permeation, the porosity of the CA membrane was quantified at 78.8 %, exhibiting an average pore size measuring 224 nm.


Insights into agar and secondary metabolite pathways from the genome of the red alga Gracilaria domingensis (Rhodophyta, Gracilariales).
Gracilariales is a clade of florideophycean red macroalgae known for being the main source of agar. We present a de novo genome assembly and annotation of Gracilaria domingensis, an agarophyte alga with flattened thallus widely distributed along Central and South American Atlantic intertidal zones. In addition to structural analysis, an organizational comparison was done with other Rhodophyta genomes. The nuclear genome has 78 Mbp, with 11,437 predicted coding genes, 4,075 of which did not have hits in sequence databases. We also predicted 1,567 noncoding RNAs, distributed in 14 classes. The plastid and mitochondrion genome structures were also obtained. Genes related to agar synthesis were identified. Genes for type II galactose sulfurylases could not be found. Genes related to ascorbate synthesis were found. These results suggest an intricate connection of cell wall polysaccharide synthesis and the redox systems through the use of L-galactose in Rhodophyta. The genome of G. domingensis should be valuable to phycological and aquacultural research, as it is the first tropical and Western Atlantic red macroalgal genome to be sequenced.


In vitro organogenesis and transgenosis aspects in globe artichoke (Cynara scolymus L.).
The genetic transformation of globe artichoke (Cynara scolymus L.) cells is possible. However, the percentage of transformed cells is still low and the regeneration process appeared to be the critical step towards the obtention of transgenic plants. The present work reports the organogenesis potentialities from new vegetal materials: cotyledons and leaves from in vitro artichoke plants. The results showed that cotyledons gave better rates of neoformation than leaves and this was reached in a shorter time. Regarding the transfer of genetic resistance to globe artichoke, a model system was developed using Nicotiana benthamiana as systemic host for artichoke viral diseases. Mutagenized sequences of the replicase gene of artichoke motteled crinckle virus (AMCV) as transferable genetic material for resistance induction were performed. Transgenic lines of Nicotiana benthamiana were obtained and some of them presented a considerable attenuation of symptoms when challenged with AMCV.


CB1 receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents.
Activation of cannabinoid receptors (CB(1), CB(2) and GPR(55)) produces analgesic effects in several experimental pain models, including visceral pain arising from the gastrointestinal tract. We assessed the role of CB(1), CB(2), and GPR(55) receptors and the endogenous cannabinoid system on basal pain responses and acute mechanical hyperalgesia during colorectal distension (CRD) in rodents. The effects of cannabinoid receptor agonists and antagonists on pain-related responses to CRD were assessed in rats and in wild-type and CB(1) receptor knock-out mice. The dual CB(1/2) agonist, WIN55,212-2, and the peripherally acting CB(1)-selective agonist, SAB-378, inhibited pain-related responses to repetitive noxious CRD (80 mmHg) in a dose-related manner in rats. The analgesic effects of WIN55,212-2 and SAB-378 were blocked by the selective CB(1) antagonist SR141716, but were not affected by the selective CB(2) antagonist SR144528. SR141716, per se, increased the responses to repetitive noxious CRD, indicative of hyperalgesia, and induced pain-related responses during non-noxious CRD (20 mmHg), indicative of allodynia. The cannabinoid receptor agonists anandamide, virodhamine and O-1602 had no effect. At analgesic doses, WIN55,212-2 did not affect colonic compliance. In accordance to the rat data, WIN55,212-2 produced analgesia, whereas SR141716 induced hyperalgesia, during noxious CRD (55 mmHg) in wild-type but not in CB(1)-knock-out mice. These data indicate that peripheral CB(1) receptors mediate the analgesic effects of cannabinoids on visceral pain from the gastrointestinal tract. The allodynic and hyperalgesic responses induced by SR141716 suggest the existence of an endogenous cannabinoid tone and the activation of CB(1) receptors during noxious CRD.


Effect of chemically modified Vulcan XC-72R on the performance of air-breathing cathode in a single-chamber microbial fuel cell.
The catalytic activity of modified carbon powder (Vulcan XC-72R) for oxygen reduction reaction (ORR) in an air-breathing cathode of a microbial fuel cell (MFC) has been investigated. Chemical modification was carried out by using various chemicals, namely 5% nitric acid, 0.2N phosphoric acid, 0.2N potassium hydroxide and 10% hydrogen peroxide. Electrochemical study was performed for ORR of these modified carbon materials in the buffer solution pH range of 6-7.5 in the anodic compartment. Although, these treatments influenced the surface properties of the carbon material, as evident from the SEM-EDX analysis, treatment with H(2)PO(4), KOH, and H(2)O(2) did not show significant activity during the electrochemical test. The HNO(3) treated Vulcan demonstrated significant ORR activity and when used in the single-chamber MFC cathode, current densities (1115mA/m(2), at 5.6mV) greater than those for a Pt-supported un-treated carbon cathode were achieved. However, the power density for the latter was higher. Such chemically modified carbon material can be a cheaper alternative for expensive platinum catalyst used in MFC cathode construction.