High-frequency EEG covaries with spike burst patterns detected in cortical neurons.
Invasive microelectrode recordings measure neuronal spikes, which are commonly considered inaccessible through standard surface electroencephalogram (EEG). Yet high-frequency EEG potentials (hf-EEG, f > 400 Hz) found in somatosensory evoked potentials of primates may reflect the mean population spike responses of coactivated cortical neurons. Since cortical responses to electrical nerve stimulation vary strongly from trial to trial, we investigated whether the hf-EEG signal can also echo single-trial variability observed at the single-unit level. We recorded extracellular single-unit activity in the primary somatosensory cortex of behaving macaque monkeys and identified variable spike burst responses following peripheral stimulation. Each of these responses was classified according to the timing of its spike constituents, conforming to one of a discrete set of spike patterns. We here show that these spike patterns are accompanied by variations in the concomitant epidural hf-EEG. These variations cannot be explained by fluctuating stimulus efficacy, suggesting that they were generated within the thalamocortical network. As high-frequency EEG signals can also be reliably recorded from the scalp of human subjects, they may provide a noninvasive window on fluctuating cortical spike activity in humans.


Mechanism for electrosilent Ca2+ transport to cause calcification of spicules in sea urchin embryos.
Embryos of the sea urchin, Hemicentrotus pulcherrimus, kept in sea water containing the calcium antagonists, diltiazem and verapamil, or an anion transport inhibitor, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS), during a developmental period between the mesenchyme blastula and the pluteus corresponding stage, became abnormal plutei with poorly developed arms and quite small spicules. Treatment with ethacrynic acid and furosemide, inhibitors of chloride transport, during the same period of development yielded quasi-normal plutei with poor spicules and somewhat developed arms. In late gastrulae, the inhibitory effects of these calcium antagonists and DIDS on the uptake of 45Ca2+ in whole embryos were as strong as those on 45Ca deposition in spicules, whereas the effects of chloride transport inhibitors on calcium deposition in the spicules were markedly stronger than on its uptake in whole embryos. Electrosilent uptake of Ca2+ seems to be established mainly by coupled influx of chloride in the cells which mediate spicule calcification, and by concomitant influx of anions in the other cells. In swimming blastulae, 45Ca2+ uptake was inhibited by calcium antagonists and DIDS, but not by chloride transport inhibitors. Ca2+ uptake probably becomes coupled with chloride influx only in embryos in which spicule calcification occurs.


Service user and staff acceptance of fetal ultrasound telemedicine.
We present qualitative findings from interviews with frontline clinicians and service users of a fetal telemedicine service. Semi-structured interviews with clinical stakeholders and service users were conducted, undertaken as part of a service evaluation. Data collection was undertaken by different teams, using interview schedules aligned to independent evaluation aims. Data were subjected to thematic analysis. Sonographers reported four main challenges: delivering a shared consultation; the requirement to resist scanning intuitively; communications during the scan; and restricted room space. Notwithstanding, all clinicians reported that participating women were accepting of the technology. Service users reported few concerns. The main benefits of fetal telemedicine were identified as upskilled staff, increased access to specialist support and improved management of complex pregnancies. Convenience was identified as the main benefit by service users, including savings in time and money from not having to travel, take time off work, and arrange childcare. Service users and clinical stakeholders were accepting of the service. Service users reported satisfaction with communications during the consultation and awareness that telemedicine had facilitated local access to clinical expertise. Whilst clinical stakeholders reported challenges, the iterative nature of the evaluation meant that concerns were discussed, responded to, and overcome as the pilot developed. Clinical stakeholders' perception of benefits for service users encouraged their acceptance. Moreover, the evaluation established that fetal ultrasound telemedicine is a viable method to access expertise safely and remotely. It provided demonstrable evidence of a potential solution to some of the healthcare challenges facing rural hospitals.


First surveillance of pesticides in soils of the perimeter of Tadla, a Moroccan sugar beet intensive area.
With the long-term application of pesticides on sugar beet farms in the irrigated perimeter of Tadla in Morocco for over 50 years, pesticide monitoring is necessary to assess soil health. The objective of our study was to monitor multiple pesticide residues in topsoil samples collected from post-harvest sugar beet fields and verify their migration to deep soil layers. Topsoil and deep soil samples were collected from arbitrarily selected sugar beet fields in the IPT. In this study, a target-screening method was applied. All target pesticides were detected in soil samples, with tefluthrin being the most frequently detected pesticide. The residue with the highest concentration in soil samples was DDE. All the soil samples contained a mixture of pesticide residues, with a maximum of 13 residues per sample. The total pesticide content decreased toward more profound layers of soil, except in one field where it reached a concentration of 348 µg/kg at the deeper soil layer. For pesticides detected at the three soil depths, only tefluthrin concentration increased in the deep soil layer. The results provide comprehensive and precise information on the pesticide residue status in sugar beet soils warning against the multiple risks that this contamination can cause. This study indicates the need of regular monitoring of pesticides over a large area of the perimeter to enable decision-makers to pronounce the impacts of the extension and intensification of sugar beet cultivation at the irrigated perimeter of Tadla.


Comparison of Cytokine Responses in Ecuadorian Children Infected with Giardia, Ascaris, or Both Parasites.
AbstractMore than 2 billion people are infected with parasites globally, and the majority have coinfections. Intestinal protozoa and helminths induce polarizing CD4+ T-helper cell 1 (Th1) mediated cytokine responses within the host. Such immune polarization may inhibit the ability of the host to mount an adequate immune response for pathogen clearance to concurrent pathogens. The current study evaluated the plasma cytokine profile in Ascaris and Giardia coinfected children compared with Giardia- and Ascaris-only infected children. Fecal samples and blood samples were collected from asymptomatic 3-year-old children living in the district of Quininde, Ecuador. Stool samples that tested positive for Giardia lamblia-only, Ascaris lumbricoides-only, or G. lamblia and A. lumbricoides coinfections were confirmed by quantitative real-time polymerase chain reaction. Plasma samples from the study subjects were used to quantitate cytokines. A total of 39 patients were evaluated. Children with coinfection had a significant decrease in Th1 cytokine production, interleukin 2 (IL-2) (P < 0.05), IL-12 (P < 0.05), and tumor necrosis factor alpha (P < 0.05) compared with Giardia-only infected children. Coinfected children had an increase in IL-10/interferon gamma (IFN-γ) ratio compared with uninfected (P < 0.05) and Ascaris alone (P < 0.05). The increased IL-10/IFN-γ ratio in the setting of decreased Th1 cytokine response indicates Th2 polarization in the coinfected group. Reduced Th1 cytokines in children coinfected with Ascaris and Giardia may impair the host's ability to eradicate Giardia infection leading to chronic giardiasis.


Production and physiological responses of dairy cows to varying dietary potassium during heat stress.
Objectives were to study influences of heat stress and dietary potassium content on production and physiological responses of 8 Jersey and 10 Holstein cows blocked by breed and assigned randomly to no shade or shade environments. Each cow received a different dietary potassium treatment (.66, 1.08, and 1.64% of dry matter) in each of three 30-day periods. Rates of potassium loss from skin were almost five times greater for no shade as for shade cows during the hottest part of the day (1300 to 1500 h). Overall, cows with no shade ate 56% less during the daytime (0800 to 1600 h), 19% more during nighttime (1600 to 0800 h), and 13% less total feed than cows with shade. Interactions of environment and breed with dietary potassium treatment suggest differences in feed intake and milk yield responses to increasing dietary potassium content. Total daily feed intake and milk yield of cows with no shade responded in curvilinear fashion to increasing dietary potassium, whereas responses in shade were small. Largest responses in no shade were as dietary potassium increased from .66 to 1.08%. Milk yield of Holsteins increased with increasing dietary potassium, but yield of Jerseys did not. Combined effects of elevated potassium loss from skin and reduced potassium and dry matter intake during heat stress suggested that lactating dairy cows may benefit from supplemental potassium.


Trends in incidence of head and neck cancer in the northern territory, Australia, between 2007 and 2010.
Incidence trends of head and neck cancer (HNC) have implications for screening strategies, disease management, guiding health policy making, and are needed to further oral cancer research. This paper aims to describe trends in age-adjusted HNC incidence rates focusing on changes across calendar period between 2007 and 2010 in Australian Northern Territory. Age-adjusted incidence rates of HNC were calculated for 2007- 2010 using Northern Territory population based data assembled by Department of Health, Northern Territory Government of Australia. Changes in the HNC rate ratio (RR) and Estimated Annual Percentage Change (EAPC) between 2007-2008, 2008-2009 and 2009-2010 were calculated. A total of 171 HNC patients were recorded by the Northern Territory Department of Health during the time period between 2007 and 2010, out of which, 135 were males (78.9% of male HNC patients) and 36 were females (21.1% of female HNC patients). In conclusion, HNC incidence rate has decreased in the Northern Territory Australian males but remains unchanged in Australian females. High incidences of HNC may be associated with the high smoking rate and high alcohol consumption in the Northern Territory. Continued monitoring of trends in HNC incidence rates is crucial to inform Northern Territory based cancer prevention strategies.


Inheritance characteristics of F1 and F2 offsprings obtained from full diallele crosses of five cowpea cultivars (Vigna unguiculata L. Walp) against pseudocercospora leaf spot disease.
The experiment was carried out at the Experimental Farm, Department of Agricultural Technology, Mahasarakham University, Mahasarakham Province in the 2005 (February to April) for F1 offsprings and also at the Experimental Farm, Khon Kaen University, Khon Kaen Province, Northeast Thailand for F2 offsprings (July to October), i.e., four experiments were carried out, each location had two experiments. The research aimed to investigate inheritance characteristics of F1 and F2 offsprings derived from full diallele crosses of five cowpea cultivars (20 pairs of crosses) against a pathogenic disease of Pseudocercospora cruenta (Sacc,) Deighton. The first two experiments were carried out under field and glasshouse conditions at Mahasarakham University for F1 offsprings and the other two experiments were carried out at Khon Kaen University for F2 offsprings. A Chi square test method was used to justify dominant genes on the infection of the disease. The results showed that the cowpea plants of F1 and F2 offsprings gave only one pair of dominant gene that had its complete dominant effect over recessive gene of the cowpea offsprings.


Students' attitudes towards the introduction of a Personal and Professional Development portfolio: potential barriers and facilitators.
Portfolios, widely used in undergraduate and postgraduate medicine, have variable purposes, formats and success. A recent systematic review summarised factors necessary for successful portfolio introduction but there are no studies investigating the views of students inexperienced in portfolio use towards portfolio learning. This study's aim was to survey student views about a prospective Professional and Personal Development (PPD) portfolio. This was a qualitative, focus group study. All focus groups were taped and transcribed verbatim, and anonymised. The transcripts were analysed inductively, using framework analysis. Four focus groups were carried out with 32 undergraduate medical students naïve in portfolio use. Three themes relevant to portfolio introduction emerged. The first theme was the need for clear information and support for portfolio introduction, and anxieties about how this could be supported effectively. The second was that students had negative views about reflective learning and whether this could be taught and assessed, believing formal assessment could foster socially acceptable content. The third was that participants revealed little understanding of reflective learning and its potential benefits. Rather portfolios were seen as useful for concrete purposes (e.g., job applications) not intrinsic benefits. Undergraduate medical students without experience of portfolios are anxious about portfolio introduction. They require support in developing reflective learning skills. Care must be taken to ensure students do not see portfolios as merely yet another assessment hurdle.


Brownfield redevelopment evaluation based on structure-process-outcome theory and continuous ordered weighted averaging operator-topology method.
As an important part of urban renewal, brownfield restoration and renovation are of great significance to the sustainable development of cities. The structure-process-outcome theory was introduced into this study to improve the rationality and scientific vigor of the redevelopment assessment process and to evaluate whether brownfield sites meet the conditions for redevelopment. Based on this theory, the relationship among structures, processes and outcomes can be well elucidated. Specifically, a good structure should contribute to an effective process, which will increase the possibility of a favorable outcome. The basic conditions, practice principles, and result orientation in the whole procedure of brownfield redevelopment were comprehensively analyzed. In addition, a more complete and reasonable three-level evaluation index system for brownfield redevelopment was established. In order to reduce the subjectivity in the evaluation process, an unbiased scientific brownfield redevelopment evaluation model was constructed using the continuous ordered weighted averaging operator-topology method. The evaluation decision system was applied to the renovation of a tract project in Chengdu, China. The results proved that the model could effectively and accurately evaluate the quality level of the brownfield redevelopment project, and the proposed recommendations can provide a basis for decision-making.


Effects of murine recombinant interleukin 1 alpha on the host response to bacterial infection.
The effects of exogenously administered rIL-1 alpha on elimination of viable listeriae from the liver and spleen during the course of a primary Listeria monocytogenes infection was studied. Similar numbers of L. monocytogenes were recovered from rIL-1 alpha-treated and control mice at up to 24 h after infection; however, by 48 h after infection more than 1 log10 fewer viable L. monocytogenes were recovered from the spleens of rIL-1 alpha-treated mice than from Listeria-infected controls. The difference in bacterial burden between IL-1 alpha-treated and control mice increased with time; by 7 days after infection viable L. monocytogenes had been eliminated from most rIL-1 alpha-treated mice, whereas control mice still harbored 10(4) to 10(5) L. monocytogenes per spleen and liver. Histopathologic examination confirmed that rIL-1 alpha-treated mice suffered considerably less damage to the spleen, liver, lung, and brain than did control mice. To determine whether rIL-1 alpha-mediated protection indirectly by augmenting the release of other cytokines, we determined serum levels of colony-stimulating activity and IFN activity in rIL-1 alpha-treated and control Listeria-infected mice. Treatment with rIL-alpha elicited an early burst of serum colony-stimulating activity as compared with sera from Listeria-infected control mice. These data suggest that exogenous administration of rIL-1 initiates release of colony-stimulating activity, and perhaps other cytokines, that accelerate the protective response of the infected host. Prophylactic augmentation of antimicrobial resistance by administration of rIL-1 alpha may be worthy of further evaluation.


[Correlation between kynurenine metabolites and postpartum depression].
To explore the correlation between kynurenine (KYN) metabolites and postpartum depression (PPD), and to provide new possible explanation for the pathogenesis of postpartum depression (PPD). Methods: A total of 726 Chinese women, who received cesarean section, were enrolled in this study. PPD was diagnosed with an Edinburgh Postnatal Depression Scale (EPDS) score ≥13. Twenty-four women with PPD and 48 matched women without PPD were randomly selected. The perinatal serum concentrations of KYN, quinolinic acid (QUIN) and kynurenic acid (KYNA) were measured. Subsequently, the puerperants were compared for the differences in the serum concentrations of KYN, QUIN and KYNA at the end of term, day 1 and day 3 after cesarean section, respectively. Results: The incidence of PPD was 7.99%. Of clinical characteristics, pressure during pregnancy was significantly different between subjects with or without PPD (P<0.01). Patients with PPD showed significantly increased serum KYN concentration (P<0.05) at the end of term, increased serum QUIN concentration (P<0.05) and decreased KYNA concentration (P<0.05) on the third day after cesarean section as compared with the control women. Furthermore, the KYNA/QUIN ratio was significantly higher in patients with PPD as compared to the control women on the third day after cesarean section (P<0.01). Conclusion: The contribution of alterations in plasma levels of KYN, QUIN and KYNA is closely related with the incidence of PPD, and correction of KYNA/QUIN ratio could be a new strategy for the prevention and treatment of postpartum depressive symptoms.


Immunosenescence and cancer: a review.
The human neoplastic pathologies are age-dependent. The increased occurrence of tumors observed with advancing age may be determined by the accumulation of certain phenomena promoting different phases of neoplastic processes. In these events, important roles can be attributed to mutations of the genome that accumulate during aging and to the immunosenescence. It may be hypothesized that certain tumors controlled by the immune system may become more frequent in the elderly as a consequence of the decreased functionality of this important defense system of the organism. Nevertheless, the problems of the interrelationships between the immunosenescence and tumors are seriously contradictory. Therefore, on the one hand, one has to establish how much the immunodeficit of the elderly patient may be responsible for the neoplastic pathology, while on the other hand, one cannot neglect important environmental and pathophysiological factors in these cases.


Biological, Psychological, and Social Determinants of Depression: A Review of Recent Literature.
Depression is one of the leading causes of disability, and, if left unmanaged, it can increase the risk for suicide. The evidence base on the determinants of depression is fragmented, which makes the interpretation of the results across studies difficult. The objective of this study is to conduct a thorough synthesis of the literature assessing the biological, psychological, and social determinants of depression in order to piece together the puzzle of the key factors that are related to this condition. Titles and abstracts published between 2017 and 2020 were identified in PubMed, as well as Medline, Scopus, and PsycInfo. Key words relating to biological, social, and psychological determinants as well as depression were applied to the databases, and the screening and data charting of the documents took place. We included 470 documents in this literature review. The findings showed that there are a plethora of risk and protective factors (relating to biological, psychological, and social determinants) that are related to depression; these determinants are interlinked and influence depression outcomes through a web of causation. In this paper, we describe and present the vast, fragmented, and complex literature related to this topic. This review may be used to guide practice, public health efforts, policy, and research related to mental health and, specifically, depression.


[The use of sirdalud in cerebral palsy in children].
30 diplegic children (mean age 11.3 +/- 2.8 years old) with severe form of cerebral palsy received sirdalud monotherapy during 2-6 weeks (1 mg for children under 10 years old and 2 mg for older children, 3 times daily). Positive effects were determined in motor, autonomic and mental (emotional) spheres. Sirdalud was also very effective in patients after orthopedic-surgical treatment. Electroneuromyographic analysis showed the decrease of the synergic tonic activity, as well as the improvement of the supraspinal influences and the segmental interaction. Thus, the small doses of sirdalud are effective without side effects in children with cerebral palsy.


Graphic illustration of impairment: science fiction, Transmetropolitan and the social model of disability.
The following paper examines the cyberpunk transhumanist graphic novel Transmetropolitan through the theoretical lens of disability studies to demonstrate how science fiction, and in particular this series, illustrate and can influence how we think about disability, impairment and difference. While Transmetropolitan is most often read as a scathing political and social satire about abuse of power and the danger of political apathy, the comic series also provides readers with representations of impairment and the source of disability as understood by the Social Model of Disability (SMD). Focusing on the setting and fictional world in which Transmetropolitan takes place, as well as key events and illustration styling, this paper demonstrates that the narrative in this work encompasses many of the same theoretical underpinnings and criticisms of society's ignorance of the cause of disability as the SMD does. This paper aims, by demonstrating how Transmetropolitan can be read as an allegory for the disabling potential of society as experienced by individuals with impairments, to prompt readers into thinking more creatively about how narratives, seemingly unconcerned with disability, are informed and can be understood via disability theory.


Genetic mapping of lymphocytic choriomeningitis virus pathogenicity: virulence in guinea pigs is associated with the L RNA segment.
The Armstrong CA 1371 (ARM) and WE strains of lymphocytic choriomeningitis virus (LCMV) differ in the ability to produce disease in adult guinea pigs. Infection with the ARM strain is not lethal, even at high virus doses (greater than 10,000 PFU), whereas the WE strain causes 100% mortality even at low doses (less than 10 PFU). To determine the genetic basis of this virulence, intertypic reassortants were made between the ARM and WE strains of LCMV. The two reassortants with the genotypes WE/ARM (L segment of WE and S segment of ARM) and ARM/WE (L segment of ARM and S segment of WE) were tested for their pathogenicity in guinea pigs. The ARM/WE reassortant was avirulent like the ARM/ARM parental strain. Minimal viral replication was observed in organs of guinea pigs inoculated with 10(2) or 10(5) PFU of ARM/ARM or ARM/WE, and all animals survived. In contrast, the WE/ARM reassortant was highly virulent like the WE/WE parental strain and killed all of the infected animals. High levels of viral replication were observed in guinea pigs infected with the latter two strains. In contrast to these in vivo observations, both the parental strains and the ARM/WE or WE/ARM reassortants had similar growth potential in cultured guinea pig fibroblasts. Thus, the L RNA segment of LCMV WE is important for viral replication in vivo and is associated with fatal acute disease after infection of adult guinea pigs.


An SL3-3 murine leukemia virus enhancer variant more pathogenic than the wild type obtained by assisted molecular evolution in vivo.
SL3-3 is a highly T-lymphomagenic murine retrovirus in which the transcriptional enhancer is a major oncogenic determinant. Here, we describe an SL3-3 enhancer variant that induced T-cell lymphomas in all inoculated mice with a shorter latency period than wild-type SL3-3. The enhancer repeat region of this variant contains two deletions encompassing the nuclear factor 1 binding sites in addition to an additional intact enhancer repeat element. Tumors induced by this variant were T-cell lymphomas, as indicated by T-cell receptor rearrangements, and contained the input provirus enhancer regions. The variant was the result of mutation of specific transcription factor binding sites in the viral enhancer, isolation of rare second-site enhancer variants from the resulting induced tumors, and subsequent restoration of the original first-site mutations of one such variant. We have termed this process assisted molecular evolution.


Utilizing Smartphones for Approachable IoT Education in K-12.
Distributed computing, computer networking, and the Internet of Things (IoT) are all around us, yet only computer science and engineering majors learn the technologies that enable our modern lives. This paper introduces PhoneIoT, a mobile app that makes it possible to teach some of the basic concepts of distributed computation and networked sensing to novices. PhoneIoT turns mobile phones and tablets into IoT devices and makes it possible to create highly engaging projects through NetsBlox, an open-source block-based programming environment focused on teaching distributed computing at the high school level. PhoneIoT lets NetsBlox programs-running in the browser on the student's computer-access available sensors. Since phones have touchscreens, PhoneIoT also allows building a Graphical User Interface (GUI) remotely from NetsBlox, which can be set to trigger custom code written by the student via NetsBlox's message system. This approach enables students to create quite advanced distributed projects, such as turning their phone into a game controller or tracking their exercise on top of an interactive Google Maps background with just a few blocks of code.


Bioethical issues in genome editing by CRISPR-Cas9 technology.
Genome editing technologies have led to fundamental changes in genetic science. Among them, CRISPR-Cas9 technology particularly stands out due to its advantages such as easy handling, high accuracy, and low cost. It has made a quick introduction in fields related to humans, animals, and the environment, while raising difficult questions, applications, concerns, and bioethical issues to be discussed. Most concerns stem from the use of CRISPR-Cas9 to genetically alter human germline cells and embryos (called germline genome editing). Germline genome editing leads to serial bioethical issues, such as the occurrence of undesirable changes in the genome, from whom and how informed consent is obtained, and the breeding of the human species (eugenics). However, the bioethical issues that CRISPR-Cas9 technology could cause in the environment, agriculture and livestock should also not be forgotten. In order for CRISPR-Cas9 to be used safely in all areas and to solve potential issues, worldwide legislation should be prepared, taking into account the opinions of both life and social scientists, policy makers, and all other stakeholders of the sectors, and CRISPR-Cas9 applications should be implemented according to such legislations. However, these controls should not restrict scientific freedom. Here, various applications of CRISPR-Cas9 technology, especially in medicine and agriculture, are described and ethical issues related to genome editing using CRISPR-Cas9 technology are discussed. The social and bioethical concerns in relation to human beings, other organisms, and the environment are addressed.


Binding preference of carbon nanotube over proline-rich motif ligand on SH3-domain: a comparison with different force fields.
With the widespread applications of nanomaterials such as carbon nanotubes, there is a growing concern on the biosafety of these engineered nanoparticles, in particular their interactions with proteins. In molecular simulations of nanoparticle-protein interactions, the choice of empirical parameters (force fields) plays a decisive role, and thus is of great importance and should be examined carefully before wider applications. Here we compare three commonly used force fields, CHARMM, OPLSAA, and AMBER in study of the competitive binding of a single wall carbon nanotube (SWCNT) with a native proline-rich motif (PRM) ligand on its target protein SH3 domain, a ubiquitous protein-protein interaction mediator involved in signaling and regulatory pathways. We find that the SWCNT displays a general preference over the PRM in binding with SH3 domain in all the three force fields examined, although the degree of preference can be somewhat different, with the AMBER force field showing the highest preference. The SWCNT prevents the ligand from reaching its native binding pocket by (i) occupying the binding pocket directly, and (ii) binding with the ligand itself and then being trapped together onto some off-sites. The π-π stacking interactions between the SWCNT and aromatic residues are found to play a significant role in its binding to the SH3 domain in all the three force fields. Further analyses show that even the SWCNT-ligand binding can also be relatively more stable than the native ligand-protein binding, indicating a serious potential disruption to the protein SH3 function.


Enhancing the Localization of Uterine Leiomyomas Through Cutaneous Softness Rendering for Robot-Assisted Surgical Palpation Applications.
Integrating tactile feedback for lump localization in Robot-assisted Minimally Invasive Surgery (RMIS) represents an open research issue, which is still far to be solved. Main reasons for this are related e.g. to the need for a transparent connection with the teleoperating console, and an intuitive decoding of the delivered information. In this article, we focus on the specific case of RMIS treatment of uterine leiomyomas or fibroids, where little has been done in haptics to improve the outcomes of robotics-enabled palpation tasks. In this article, we propose the usage of a wearable haptic interface for softness rendering as a lump display. The device was integrated in a teleoperation architecture that simulates a robot-assisted surgical palpation task of leiomyomas. This article moved from an ex-vivo sample characterization of uterine tissues to show the effectiveness of our interface in conveying meaningful softness information. We extensively tested our system with gynecologic surgeons in palpation tasks with silicone specimens, which replicated the characteristics of uterine tissues with embedded leyomiomas. Results show that our system enables a softness-based discrimination of the embedded fibroids comparable to the one that physicians would achieve using directly their fingers in palpation tasks. Furthermore, the feedback provided by the haptic interface was perceived as comfortable, intuitive, and highly useful for fibroid localization.


Modulation of phosducin-like protein 3 (PhLP3) levels promotes cytoskeletal remodelling in a MAPK and RhoA-dependent manner.
Phosducin-like protein 3 (PhLP3) forms a ternary complex with the ATP-dependent molecular chaperone CCT and its folding client tubulin. In vitro studies suggest PhLP3 plays an inhibitory role in β-tubulin folding while conversely in vivo genetic studies suggest PhLP3 is required for the correct folding of β-tubulin. We have a particular interest in the cytoskeleton, its chaperones and their role in determining cellular phenotypes associated with high level recombinant protein expression from mammalian cell expression systems. As studies into PhLP3 function have been largely carried out in non mammalian systems, we examined the effect of human PhLP3 over-expression and siRNA silencing using a single murine siRNA on both tubulin and actin systems in mammalian Chinese hamster ovary (CHO) cell lines. We show that over-expression of PhLP3 promotes an imbalance of α and β tubulin subunits, microtubule disassembly and cell death. In contrast, β-actin levels are not obviously perturbed. On-the-other-hand, RNA silencing of PhLP3 increases RhoA-dependent actin filament formation and focal adhesion formation and promotes a dramatic elongated fibroblast-like change in morphology. This was accompanied by an increase in phosphorylated MAPK which has been associated with promoting focal adhesion assembly and maturation. Transient overexpression of PhLP3 in knockdown experiments rescues cells from the morphological change observed during PhLP3 silencing but mitosis is perturbed, probably reflecting a tipping back of the balance of PhLP3 levels towards the overexpression state. Our results support the hypothesis that PhLP3 is important for the maintenance of β-tubulin levels in mammalian cells but also that its modulation can promote actin-based cytoskeletal remodelling by a mechanism linked with MAPK phosphorylation and RhoA-dependent changes. PhLP3 levels in mammalian cells are thus finely poised and represents a novel target for engineering industrially relevant cell lines to evolve lines more suited to suspension or adherent cell growth.


Aluminum taken up by transferrin-independent iron uptake affects the iron metabolism in rat cortical cells.
We previously demonstrated that cultured human fibroblasts internalize iron via transferrin-independent iron uptake (Tf-IU), redox, and receptor-mediated endocytosis uptake systems [Oshiro, S., Nakajima, H., Markello, T., Krasnewich, D., Bernardini, I., and Gahl, W.A. (1993) J. Biol. Chem. 268, 21586 21591]. Of these iron transport systems, the Tf-IU system is involved in the accumulation of transition metals in various mammalian cells. It is also known that in experimental animals fed aluminum (Al), Al at micromolar level selectively accumulates in the brain. In the present study, we examined the effects of Al accumulated in the brain cells on iron transport by the Tf-IU system and iron metabolism, using primary cultures from fetal rat cerebral cortex. Pretreatment of cells with 200 microM Al-nitrilotriacetate upregulated the Tf-IU system for iron. Moreover, of various metals tested, Al markedly upregulated the Tf-IU activity. To examine the influence of Al on iron metabolism, the interaction between Al accumulated in the cells and iron-responsive element binding protein (IRE-BP), a cellular iron regulator, was examined by Northern blot analysis, and activity assay: Al decreased the Tf receptor mRNA level and increased the aconitase activity of IRE-BP. The increase of aconitase activity by Al was also observed in vitro. These results suggest that Al accumulated in cortical cells affects iron metabolism.


Fuzzy tree automata and syntactic pattern recognition.
An approach of representing patterns by trees and processing these trees by fuzzy tree automata is described. Fuzzy tree automata are defined and investigated. The results include that the class of fuzzy root-to-frontier recognizable ¿-trees is closed under intersection, union, and complementation. Thus, the class of fuzzy root-to-frontier recognizable ¿-trees forms a Boolean algebra. Fuzzy tree automata are applied to processing fuzzy tree representation of patterns based on syntactic pattern recognition. The grade of acceptance is defined and investigated. Quantitative measures of ``approximate isosceles triangle,'' ``approximate elongated isosceles triangle,'' ``approximate rectangle,'' and ``approximate cross'' are defined and used in the illustrative examples of this approach. By using these quantitative measures, a house, a house with high roof, and a church are also presented as illustrative examples. In addition, three fuzzy tree automata are constructed which have the capability of processing the fuzzy tree representations of ``fuzzy houses,'' ``houses with high roofs,'' and ``fuzzy churches,'' respectively. The results may have useful applications in pattern recognition, image processing, artificial intelligence, pattern database design and processing, image science, and pictorial information systems.


Examining the Effectiveness of a Web-Based Intervention for Depressive Symptoms in Female Adolescents: Applying Social Cognitive Theory.
Depression is a serious mental health illness among adolescents especially girls. Web-based treatment can possibly become a solution for reducing mental health problems in adolescents. This study is one of the first trials aimed to evaluate the efficiency of web-based depression improvement program among female adolescents based on the Social Cognitive Theory (SCT). Randomized Controlled Trial. A six-month randomized controlled trial based on the SCT was implemented in female schools in Hamadan City, west of Iran in 2018 on 128 female students with mild to moderate depressive symptoms (CES-D =10-45). They were randomly assigned to either intervention or control group (n= 64 in each group). Depression improvement program was implemented through the website via short videos, animations and Power-Point slides. Depression was evaluated using Center for Epidemiologic Depression Scale. A researcher-made questionnaire based on the sheerer and Perceived-Social-Support-Scale-Revised (PSSS-R) questionnaires were used to evaluate the SCT constructs. The data were analyzed using SPSS software. The intervention program resulted in the improvement of depression in 12 wk based on Intent-to-treat analyses. Nevertheless, these achievements seem to have decreased by 24 wk in intervention group. The intervention increased the mean scores of the constructs of social support and self-regulation from baseline to 12 wk in the intervention group (P<0.05). The intervention had no effect on outcome expectations and self-efficacy. There were no statistically significant associated between theory constructs changes and changes in depression (P>0.05). The web-based intervention improved depression in female students. Future training using strategies for the sustainable improvement of depression in female students are needed.


BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase.
BK polyomavirus (PyV) is a major source of kidney failure in transplant recipients. The standard treatment for patients with lytic BKPyV infection is to reduce immunosuppressive therapy, which increases the risk of graft rejection. PyVs are DNA viruses that rely upon host replication proteins for viral genome replication. A hallmark of PyV infection is activation of the DNA damage response (DDR) to prevent severe host and viral DNA damage that impairs viral production by an unknown mechanism. Therefore, we sought to better understand why BKPyV activates the DDR through the ATR and ATM pathways and how this prevents DNA damage and leads to increased viral production. When ATR was inhibited in BKPyV-infected primary kidney cells, severe DNA damage occurred due to premature Cdk1 activation, which resulted in mitosis of cells that were actively replicating host DNA in S phase. Conversely, ATM was required for efficient entry into S phase and to prevent normal mitotic entry after G2 phase. The synergistic activation of these DDR kinases promoted and maintained BKPyV-mediated S phase to enhance viral production. In contrast to BKPyV infection, DDR inhibition did not disrupt cell cycle control in uninfected cells. This suggests that DDR inhibitors may be used to specifically target BKPyV-infected cells.IMPORTANCE BK polyomavirus (BKPyV) is an emerging pathogen that reactivates in immunosuppressed organ transplant patients. We wanted to understand why BKPyV-induced activation of the DNA damage response (DDR) enhances viral titers and prevents host DNA damage. Here, we show that the virus activates the DNA damage response in order to keep the infected cells in S phase to replicate the viral DNA. The source of DNA damage was due to actively replicating cells with uncondensed chromosomes entering directly into mitosis when the DDR was inhibited in BKPyV-infected cells. This study clarifies the previously enigmatic role of the DDR during BKPyV infection by demonstrating that the virus activates the DDR to maintain the cells in S phase in order to promote viral replication and that disruption of this cell cycle arrest can lead to catastrophic DNA damage for the host.


Inhaled corticosteroids in COPD and the risk of lung cancer.
Inhaled corticosteroids (ICS) might reduce the risk of lung cancer by controlling airway inflammation in patients with chronic obstructive pulmonary disease (COPD) because both are associated with chronic inflammation. The objective was to assess the impact of ICS on lung cancer risk reduction in COPD patients. We performed a nested case-control study based on the database of the National Health Insurance Service-National Sample Cohort, a nationally representative cohort of 1,125,691 participants in Korea followed over 11 years. The eligible population was patients aged 30-89 years who were newly diagnosed with COPD and initiated inhaled medications after diagnosis. Cases were defined as individuals diagnosed with lung cancer after the initiation of inhaled medications and were matched with controls by propensity score at a 1:4 ratio. We identified 265 individuals with lung cancer, matched with 1,060 controls. Use of ICS was associated with reduced risk of lung cancer (adjusted hazard ratio [aHR] 0.74, 95% CI 0.57-0.96). The high cumulative ICS dose group, defined as those above the third quartile of ICS dose distribution, had a lower risk of lung cancer than the low cumulative dose group (aHR 0.51, 95% CI 0.34-0.75). The effect of ICS on lung cancer risk reduction was more remarkable in former smokers than current smokers. Additionally, the result was consistent in men regardless of the classification according to ICS use, while it was not significant in women. ICS, particularly at high cumulative dose, might be associated with decreased risk of lung cancer in patients with COPD. Severe COPD frequently warrants treatment with inhaled corticosteroids, which exert immunomodulatory and antiproliferative effects. Despite an association between COPD and increased lung cancer risk, patients on ICS appear to have a reduced likelihood of developing lung cancer. Here, analyzing data from the National Health Insurance Service-National Sample Cohort in Korea, the authors show that ICS use is associated with decreased lung cancer risk in COPD patients. An inverse dose-response relationship was detected, whereby increasing cumulative ICS dose was associated with decreasing lung cancer risk. The effect was most pronounced in men and former smokers.


Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice.
Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of melanoma and have developed a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of tumor-bearing mice, activated, and labeled with chromium-51 to facilitate the quantification. Labeled T cells were injected in the tumor-bearing mice, and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration and accumulate in the tissues to various extents. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid tumors was found to be very low, hovering below 1%ID/g (percent of injected dose per gram of tissue) during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T-cell-based therapies may be more successful in treating cancers of the lymphatic system and bone marrow metastases compared to solid tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes such as extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into the spleen, liver, and kidney compartment to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provide unprecedented insight into the biodistribution of exogenously administered T cells.


Screening biochars for heavy metal retention in soil: role of oxygen functional groups.
Oxygen-containing carboxyl, hydroxyl, and phenolic surface functional groups of soil organic and mineral components play central roles in binding metal ions, and biochar amendment can provide means of increasing these surface ligands in soil. In this study, positive matrix factorization (PMF) was first employed to fingerprint the principal components responsible for the stabilization of heavy metals (Cu, Ni, Cd, Pb) and the release of selected elements (Na, Ca, K, Mg, S, Al, P, Zn) and the pH change in biochar amended soils. The PMF analysis indicated that effective heavy metal stabilization occurred concurrently with the release of Na, Ca, S, K, and Mg originating from soil and biochar, resulting in as much as an order or magnitude greater equilibrium concentrations relative to the soil-only control. In weathered acidic soil, the heavy metal (especially Pb and Cu) stabilization ability of biochar directly correlated with the amount of oxygen functional groups revealed by the O/C ratio, pH(pzc), total acidity, and by the (1)H NMR analysis. Equilibrium speciation calculation showed minor influence of hydrolysis on the total soluble metal concentration, further suggesting the importance of binding by surface ligands of biochar that is likely to be promoted by biochar-induced pH increase.


Edge detection based on single-pixel imaging.
In the paper, we propose a new edge detection schemes, based on a single-pixel imaging in the frequency domain. In SCHEME-I, special sinusoidal patterns for the x-direction edge and also y-direction edge of the unknown object are first designed. The frequency spectrum for the edge is then obtained using the a four-step phase-shifting technique with the designed sinusoidal patterns in a single-pixel imaging system. In SCHEME-II, the frequency spectrum of the unknown object is first obtained, then the frequency spectrum for the edge is obtained by calculations. The resulting edges are finally obtained by the inverse Fourier transform on their frequency spectrum. We have also verified the proposed schemes by experiments and numerical simulations. The results show that the proposed schemes can produce higher quality edges of character and also image objects. Comparing with SCHEME-II, the application of SCHEME-I to high frequency components has greatly improved signal-to-noise ratio of the received data in the bucket detector, resulting in better experimental results. Comparing with the edge detection scheme by speckle-shifting in ghost imaging systems, the proposed SCHEME-I shows an improvement in the signal-to-noise ratio. Since a single-pixel imaging system is used, the proposed schemes are capable of reconstructing edges from indirect measurements. The number of measurements required can be effectively reduced due to the sparsity of natural images in the Fourier domain and the conjugate symmetry of real-valued signals' Fourier spectrum.


Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons.
Potassium channels contribute to basic neuronal excitability and modulation. Here, we examined expression patterns of the voltage-gated potassium channel Kv1.4, the nociceptive transduction channels TRPV1 and TRPV2 as well as the putative anti-nociceptive cannabinoid receptor CB1 by immunofluorescence double-labelings in sections of rat dorsal root ganglia (DRGs). Kv1.4, TRPV1 and CB1 were each detected in about one third of neurons (35.7+/-0.5%, 29.4+/-1.1% and 36.4+/-0.5%, respectively, mean diameter 19.1+/-0.3 microm). TRPV2 was present in 4.4+/-0.4% of all neurons that were significantly larger in diameter (27.4+/-0.7 microm; P < 0.001). Antibody double-labeling revealed that the majority of Kv1.4-positive neurons co-expressed TRPV1 (73.9+/-1.5%) whereas none expressed TRPV2. The largest overlap was found with CB1 (93.1+/-0.1%). CB1 expression resembled that seen for Kv1.4 since the majority of neurons expressing CB1-protein also expressed TRPV1 (69.4+/-6.5%) but not TRPV2 (0.6+/-0.3%). When CB1-mRNA was detected using in situ hybridizations an additional subset of larger neurons was labeled including 82.4+/-17.7% of the TRPV2 expressing neurons. However, co-localization of Kv1.4 with CB1-mRNA (92%, mean diameter: 18.5 microm) was essentially the same as with CB1-protein. The almost complete overlap of CB1 and Kv1.4 in nociceptive DRG neurons suggests a functional synergistic action between Kv1.4 and CB1. The potassium channel may have two important roles in nociception. As the molecular basis of A-type current it could be involved in the control of repetitive discharges at peripheral terminals and as a downstream signal transduction site of CB1 in the control of presynaptic transmitter release at central terminals.


Tricuspid annular plane systolic excursion is preserved in young patients with pulmonary hypertension except when associated with repaired congenital heart disease.
Tricuspid annular plane systolic excursion (TAPSE) is a measure of right ventricular (RV) longitudinal function that correlates with functional status and mortality in adults with pulmonary hypertension (PH). The diagnostic and predictive value of TAPSE in children with PH has not been fully examined. We aimed to define TAPSE across aetiologies of paediatric PH and assess the correlation between TAPSE and measures of disease severity. TAPSE measurements were obtained in 84 children and young adults undergoing treatment for PH and 315 healthy children to establish z-scores at moderate altitude for comparison. The relationships between TAPSE and echocardiographic, biomarker, and functional measures of disease severity between aetiologies were assessed. TAPSE z-scores in PH patients with congenital heart disease (CHD) repaired with open cardiac surgery (n = 20, mean -2.73) were significantly decreased compared with normal children and patients with other aetiologies of PH (P < 0.001) but did not reflect poorer clinical status. TAPSE z-scores in children with idiopathic PH (n = 29, -0.41), unrepaired CHD (n = 11, -0.1), and PH related to systemic disease (n = 14, -0.39) were not different from normal. TAPSE correlated modestly with brain natriuretic peptide, echocardiographic function parameters, and functional class except in patients with repaired CHD. Children with PH maintain normal TAPSE values early except when associated with repaired CHD. Superior RV adaptation to high afterload in children compared with adults may account for this finding. Reduced TAPSE after repair of CHD does not correlate with functional status and may reflect post-operative changes rather than poor function primarily due to PH.


[Study of species specificity of the amelogenin system for genetic sex determination].
The properties of amelogenin amplification system and, in particular, of its species specificity, were studied. DNA preparations extracted from cattle (cow/bull), pig, ram and from poultry (hen), as well as from dog and cat, were used as a matrix for polymerase chain reaction (PCR) involving a standard scheme of enzymatic amplification of the amelogenin gene. It was demonstrated that, unlike for the human DNA, the amelogenin test couldn't be used for the DNA of examined animals as a sex-specific marker. However, there is a danger of a false determination of the male sex in the female origin samples during a forensic-experts' typing of the amelogenin gene, if there is an admixture of an animal DNA to a human DNA preparation. As for the biological samples of the animal origin, there is a possibility of a false-female sex determination. It can be attributed to an incorrectly selected standard of the molecular weight or to its remote location on the gel as well as to the use of an inaccurately calculated algorithm designed for determining the sizes of analyzed fragments.


Effect of gemfibrozil and rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects.
Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8. The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects. Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (Cmax ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the Cmax of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0-∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0-∞ by half (90% CI 0.45, 0.59). Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged.


Novel surgical management of cyclodialysis cleft via anterior chamber perfusion: Case report.
Cyclodialysis cleft is a relatively rare but severe condition with persistent ocular hypotony, which can cause morphologic changes and visual loss. Here we report a case of a traumatic cyclodialysis cleft that was successfully managed with direct cyclopexy via anterior chamber perfusion. During the operation, if there is aqueous humor flowing out of the deep scleral incision, the cleft is not closed, and surgery should continue until there is no aqueous outflow. A 66-year-old man was treated for severe blunt ocular trauma of the left eye and a resultant cyclodialysis cleft, lens subluxation, choroidal detachment and a cataract. His intraocular pressure was 6 mm Hg, he presented with a shallow anterior chamber, phacodonesis, iridodonesis, 360° ciliary body detachment, and a suspicious cyclodialysis cleft in the 5 to 8 o'clock position. DIAGNOSES:: ocular blunt trauma (left eye), cyclodialysis cleft (left eye), lens subluxation (left eye), choroidal detachment (left eye), cataract (both eyes). The cataract was extracted by phacoemulsification and a posterior chamber intraocular lens was implanted with 2 capsular tension rings, one in the lens bag and the other in the ciliary sulcus. Throughout the following month, intraocular pressure fluctuated between 4 and 6 mm Hg and the ciliary body failed to reattach. A cyclopexy via anterior chamber perfusion was thus deemed necessary and performed. After cyclopexy, intraocular pressure increased to 27 mm Hg and decreased to 16 mm Hg after brinzolamide eye drops treatment twice daily for 4 days. Subsequently intraocular pressure stabilized between 10 to 21mm Hg. Complete closure of the cyclodialysis cleft was confirmed with ultrasound biomicroscopy. Cyclopexy via anterior chamber perfusion for patients with cyclodialysis cleft is a simple, safe, and efficient technique that ensures a successful surgery.


The hierarchy of the 3D genome.
Mammalian genomes encode genetic information in their linear sequence, but appropriate expression of their genes requires chromosomes to fold into complex three-dimensional structures. Transcriptional control involves the establishment of physical connections among genes and regulatory elements, both along and between chromosomes. Recent technological innovations in probing the folding of chromosomes are providing new insights into the spatial organization of genomes and its role in gene regulation. It is emerging that folding of large complex chromosomes involves a hierarchy of structures, from chromatin loops that connect genes and enhancers to larger chromosomal domains and nuclear compartments. The larger these structures are along this hierarchy, the more stable they are within cells, while becoming more stochastic between cells. Here, we review the experimental and theoretical data on this hierarchy of structures and propose a key role for the recently discovered topologically associating domains.


Regulation of MAPK phosphatase 1 (AtMKP1) by calmodulin in Arabidopsis.
The mitogen-activated protein kinases (MAPKs) are key signal transduction molecules, which respond to various external stimuli. The MAPK phosphatases (MKPs) are known to be negative regulators of MAPKs in eukaryotes. We screened an Arabidopsis cDNA library using horseradish peroxidase-conjugated calmodulin (CaM), and isolated AtMKP1 as a CaM-binding protein. Recently, tobacco NtMKP1 and rice OsMKP1, two orthologs of Arabidopsis AtMKP1, were reported to bind CaM via a single putative CaM binding domain (CaMBD). However, little is known about the regulation of phosphatase activity of plant MKP1s by CaM binding. In this study, we identified two Ca(2+)-dependent CaMBDs within AtMKP1. Specific binding of CaM to two different CaMBDs was verified using a gel mobility shift assay, a competition assay with a Ca(2+)/CaM-dependent enzyme, and a split-ubiquitin assay. The peptides for two CaMBDs, CaMBDI and CaMBDII, bound CaM in a Ca(2+)-dependent manner, and the binding affinity of CaMBDII was found to be higher than that of CaMBDI. CaM overlay assays using mutated CaMBDs showed that four amino acids, Trp(453) and Leu(456) in CaMBDI and Trp(678) and Ile(684) in CaMBDII, play a pivotal role in CaM binding. Moreover, the phosphatase activity of AtMKP1 was increased by CaM in a Ca(2+)-dependent manner. Our results suggest that two important signaling pathways, Ca(2+) signaling and the MAPK signaling cascade, are connected in plants via the regulation of AtMKP1 activity. To our knowledge, this is the first report to show that the biochemical activity of MKP1 in plants is regulated by CaM.


Macrolide and tetracycline resistance and emm type distribution of Streptococcus pyogenes isolates recovered from Turkish patients.
The aims of this study were to determine the susceptibilities to macrolide and tetracycline antibiotics and emm type distribution of Streptococcus pyogenes strains isolated in the Kocaeli University Hospital, Turkey. A total of 127 S. pyogenes clinical isolates were tested. Eleven (9%) isolates were resistant to erythromycin, and 23 (18%) isolates were resistant to tetracycline. Ten of the erythromycin-resistant isolates were also resistant to tetracycline. By the triple-disk test, all erythromycin-resistant isolates showed the inducible macrolide-lincosamide-streptogramin-C phenotype and harbored erm(TR) gene. tet(O) was the most common tetracycline resistance gene. Among erythromycin-tetracycline coresistant isolates, seven harbored the tet(O) gene. emm 4, emm 1, emm 2,114, and emm 89 were the most common emm types. These isolates were more susceptible to erythromycin. There was considerable emm type heterogeneity in macrolide or tetracycline resistant isolates. According to our knowledge, this is the first study in which emm type distribution is investigated in Turkey. More comprehensive studies are needed to obtain true information about the epidemiology of macrolide and tetracycline resistance and emm type distribution in Turkey.


Flaking Stone with Wooden Implements: Flaked stone artifacts from Palliaike, Chile, suggest that wooden flaking tools were used in the New World.
Two of the seven Palliaike points show better quality workmanship than the other five. The better workmanship seems to result from use of a material superior to basalt rather than from greater skill. All seven examples show surface smoothing to a varying degree. The bifacial smoothing could be either intentional abrading by the worker or unintentional smoothing by function. Without the aid of considerable magnification and further experiment, it is difficult to pass final judgment. If these points were hafted, it would seem that the bifacial basal smoothing could not be the result of function. Hafting could be accomplished by using resins and adhesives to affix the base of the point to a wooden shaft, as was done by the Kimberley aborigines. Many Clovis points from western North America are smoothed to an even greater degree-for example, those found at the Simon Site in Idaho. Some points show the detachment of short flakes terminating in step fractures. But this may be a result of the Palliaike points being made of basalt, a very difficult material to work, of the worker being less skilled, or of the wooden flaker being inadequate to overcome the coarse-grained material. All the Palliaike points are thick in relation to their width, which makes them resistant to breakage. However, since only one point in the collection (Fig. 1a) shows an attempt at basal thinning, the worker may have been unable to control the coarse-grained basalt, which is difficult to thin with a wooden flaker, or he may simply have wanted the point thick for a particular function.


A novel mean-centering method for normalizing microRNA expression from high-throughput RT-qPCR data.
Normalization is critical for accurate gene expression analysis. A significant challenge in the quantitation of gene expression from biofluids samples is the inability to quantify RNA concentration prior to analysis, underscoring the need for robust normalization tools for this sample type. In this investigation, we evaluated various methods of normalization to determine the optimal approach for quantifying microRNA (miRNA) expression from biofluids and tissue samples when using the TaqMan® Megaplex™ high-throughput RT-qPCR platform with low RNA inputs. We compared seven normalization methods in the analysis of variation of miRNA expression from biofluid and tissue samples. We developed a novel variant of the common mean-centering normalization strategy, herein referred to as mean-centering restricted (MCR) normalization, which is adapted to the TaqMan Megaplex RT-qPCR platform, but is likely applicable to other high-throughput RT-qPCR-based platforms. Our results indicate that MCR normalization performs comparable to or better than both standard mean-centering and other normalization methods. We also propose an extension of this method to be used when migrating biomarker signatures from Megaplex to singleplex RT-qPCR platforms, based on the identification of a small number of normalizer miRNAs that closely track the mean of expressed miRNAs. We developed the MCR method for normalizing miRNA expression from biofluids samples when using the TaqMan Megaplex RT-qPCR platform. Our results suggest that normalization based on the mean of all fully observed (fully detected) miRNAs minimizes technical variance in normalized expression values, and that a small number of normalizer miRNAs can be selected when migrating from Megaplex to singleplex assays. In our study, we find that normalization methods that focus on a restricted set of miRNAs tend to perform better than methods that focus on all miRNAs, including those with non-determined (missing) values. This methodology will likely be most relevant for studies in which a significant number of miRNAs are not detected.


Mean platelet volume and its relation with arterial stiffness in patients with normotensive polycystic kidney disease.
Autosomal-dominant polycystic kidney disease (ADPKD) demonstrates cardiovascular manifestations, such as hypertension, myocardial infarction, and increased carotid intimae-media thickness. These complications are the main cause of morbidity and mortality in patients with ADPKD. Platelet activation and arterial stiffness are important manifestations that independently predict cardiovascular events. In the present study, we aimed to investigate the relation between arterial stiffness, mean platelet volume (MPV), and highly sensitive C-reactive protein (hs-CRP) in patients with normotensive polycystic kidney disease. We included 30 normotensive subjects with ADPKD with an estimated glomerular filtration rate (eGFR) of 60 mL or more per minute per 1.73 m, 30 normotensive subjects with ADPKD with eGFR from 30 to 60 mL/min per 1.73 m, and 30 healthy controls in our study. Pulse wave velocity (PWV), eGFR, spot urine protein-creatinine ratio, MPV, and hs-CRP levels were measured in all participants. In addition, transthoracic echocardiography and ambulatory blood pressure monitoring were performed. Age, sex, biochemical markers, eGFR, hemoglobin level, and platelet count were similar in the ADPKD subjects and the controls. There were significant differences in MPV (9.8 ± 0.7, 8.7 ± 0.8, and 8.0 ± 0.5 femtolitre; P < 0.001) and hs-CRP (6.8 ± 3.0, 5.3 ± 2.7, and 2.6 ± 0.52 mg/L; P < 0.001) in the groups. Additionally, PWV values were increased from healthy subjects to ADPKD patients who have decreased eGFR (5.5 ± 1.1, 8.8 ± 1.6, and 10.8 ± 1.2 m/s; P for trend <0.001). There were significant positive correlations between PWV and MPV (r = 0.401; P = 0.002) and hs-CRP (r = 0.343; P = 0.007) in the patients with ADPKD. Additionally, PWV was independently predicted by MPV (β = 0.286; P = 0.007), proteinuria (β = 0.255; P = 0.001), eGFR (β = -0.479; P < 0.001), and hs-CRP (β = 0.379; P < 0.001) in the patients with ADPKD. In addition, eGFR, as a sign of severity of disease, was independently predicted by MPV (β = -0.325; P = 0.003), PWV (β = -0.471; P < 0.001), and hs-CRP (β = -0.269; P = 0.008). Our findings suggest that MPV and hs-CRP levels are associated with increased arterial stiffness in patients with early-stage ADPKD and those with late-stage ADPKD. Also, MPV and hs-CRP were independently associated with the severity of ADPKD.


The Repertoire of Adenovirus in Human Disease: The Innocuous to the Deadly.
Adenoviridae is a family of double-stranded DNA viruses that are a significant cause of upper respiratory tract infections in children and adults. Less commonly, the adenovirus family can cause a variety of gastrointestinal, ophthalmologic, genitourinary, and neurologic diseases. Most adenovirus infections are self-limited in the immunocompetent host and are treated with supportive measures. Fatal infections can occur in immunocompromised patients and less frequently in the healthy. Adenoviral vectors are being studied for novel biomedical applications including gene therapy and immunization. In this review we will focus on the spectrum of adenoviral infections in humans.


Effect of pyridoxal phosphate on the formation of cytochrome c1-c and cytochrome c-cytochrome oxidase complexes.
The cytochrome c-cytochrome oxidase complex is formed when c reacts with cytochrome oxidase (Kuboyama et al. (1962) Biochem. Biophys. Res. Commun. 9, 534) and the cytochrome c1-cytochrome c complex is formed when c reacts with cytochrome c1 in the presence of the hinge protein (Kim, C.H. and King, T.E. (1981) Biochem. Biophys. Res. Commun. 101, 607). Both complexes are considered to be possible intermediates in electron transfer reaction between these cytochromes. Triply substituted modified cytochrome c by pyridoxal phosphate at lysine residues (Lys-79, 86 and one to be identified) abolishes both complex formations and electron transfer activity with succinate cytochrome c reductase or cytochrome oxidase.


Increased activities of mitochondrial enzymes in white adipose tissue in trained rats.
During earlier fat cell studies we noticed that homogenates of white fat cells became more brown with training, a fact that might reflect an increased content of mitochondria. This raised the question whether training (as is the case in muscle) increases the oxidative capacity in fat cells. Groups of 8-12 rats were swim trained for 10 wk or served as either sedentary, sham swim-trained, or cold-stressed controls. White adipose tissue was removed, and the activities of the respiratory chain enzyme cytochrome-c oxidase (CCO) and of the enzyme malate dehydrogenase (MDH), which participates in the tricarboxylic acid cycle as well as in the mitochondrial malate-aspartate and acetyl-group shuttles, were determined. The CCO and MDH activities expressed per milligram protein were increased in male rats 4.4- and 2.8-fold, respectively, in the swim-trained compared with the sham swim-trained rats (P less than 0.05). In female rats the CCO activity expressed per milligram protein was increased 4.5-fold in the trained compared with the sedentary control rats (P less than 0.01). Neither cold stress nor sham swim training increased CCO or MDH activities in white adipose tissue (P greater than 0.05). In conclusion, in rats, intensive endurance training induces an increase in mitochondrial enzyme activities in white adipose tissue as is seen in skeletal muscle.


Rehabilitation Guidelines for Use Following a Periacetabular Osteotomy (PAO): A North American Based Delphi Consensus.
Treatment of acetabular dysplasia with a periacetabular osteotomy (PAO) has been shown to improve long term outcomes and is considered the gold standard in the setting of symptomatic hip dysplasia in patients younger than 35 years of age. Post-operative rehabilitation following a PAO plays an important role in helping patients return to their prior level of function and reduce the impact of strength deficits that may persist. Currently, there is a paucity of research supporting post-operative rehabilitation guidelines. The purpose of this study is to present expert-driven rehabilitation guidelines to reduce practice variation following a PAO. A panel of 16 physiotherapists from across the United States and Canada who were identified as experts in PAO rehabilitation by high-volume hip preservation surgeons participated in this Delphi study. Panelists were presented with 11 questions pertaining to rehabilitation guidelines following a PAO. Three iterative survey rounds were presented to the panelists based on responses to these questions. This three-step Delphi method was utilized to establish consensus on post-operative rehabilitation guidelines following a PAO. Total (100%) participation was achieved for all three survey rounds. Consensus (>75%) was reached for 11/11 questions pertaining to the following areas: 1) weight-bearing and range of motion (ROM) precautions, 2) therapeutic exercise prescription including neuromuscular control, cardiovascular exercise, and flexibility, and 3) objective measures for return to straight line running and return to full participation in sports. This Delphi study established expert-driven rehabilitation guidelines for use following a PAO. The standardization of rehabilitative care following PAO is essential for achieving optimal outcomes despite other factors such as geographical location and socioeconomic status. Further research on patient-reported outcomes is necessary to confirm successful rehabilitation following the guidelines outlined in this study.


Incidence of CMV Replication and the Role of Letermovir Primary/Secondary Prophylaxis in the Early Phase After Allogeneic Hematopoietic Stem Cell Transplantation - A Single Centre Study.
Cytomegalovirus (CMV) replication may cause life-threatening complications after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The aim of the study was to characterize CMV events, and the outcome of letermovir (LTV) CMV prophylaxis. In this retrospective analysis of patients treated with an allo-HSCT between 2010 and 2020, we determined plasma CMV events, as well as associated risk factors. We identified 423 patients who had undergone allo-HSCT between 2010 and 2020. CMV DNAemia was found in 130/423 (30.7%) of patients. CMV reactivation rate was significantly higher in patients with acute graft-versus-host disease, HLA mismatch, and CMV IgG seropositivity of donors and recipients. Among 42 patients receiving LTV prophylaxis those, 5 (11.9%) showed CMV DNAemia under LTV versus 87/353 (24.6%) in a control group. Despite the development of better approaches with weekly monitoring and early treatment initiation, CMV reactivations play an important role after allo-HSCT.


HIV testing, care, and treatment experiences among the steady male partners of female sex workers living with HIV in the Dominican Republic.
Male steady partners of female sex workers (FSW) living with human immunodeficiency virus (HIV) represent a key population for treatment as prevention and/or pre-exposure prophylaxis interventions. This study uses data collected from male steady partners who were referred by FSW living with HIV participating in a multi-level HIV prevention and care intervention in Santo Domingo, Dominican Republic. We conducted a socio-behavioral survey and HIV testing with all men (n = 64) and 16 in-depth interviews with a sub-sample to obtain more depth. Thirty-five of the 64 participants were living with HIV; 27 were previously diagnosed and 8 were diagnosed during our study. As a result, 45% of men were members of sero-discordant sexual partnerships. Of men with no previous HIV diagnosis (n = 37), 15 had never been tested for HIV and nine had not been tested in the past two years. Ninety-three percent of men previously diagnosed with HIV reported receiving HIV care in the past 6 months and 78% were taking anti-retrovirals. Low HIV testing was partly due to men not feeling at risk for HIV, despite having an HIV-infected partner. Additionally, a lack of tailored care inhibited engagement in anti-retroviral treatment for those infected. HIV testing was low, highlighting a need for test-and-treat strategies. Men not living with HIV would benefit from regular testing and would be good candidates for pre-exposure prophylaxis. While almost all men who had been diagnosed with HIV were engaged in care and adherent to anti-retroviral therapy, future research should assess whether they are achieving optimal HIV outcomes for their health and prevention of ongoing transmission.


Constitutive activation of STAT5 supersedes the requirement for cytokine and TCR engagement of CD4+ T cells in steady-state homeostasis.
The transcription factor STAT5 is one of several signaling mediators activated via common gamma-chain cytokine receptors. As such, it plays an important role in lymphocyte survival and proliferation during normal homeostasis as well as under lymphopenic conditions. Transgenic mice expressing a constitutively activated form of STAT5b have been shown previously to contain increased numbers of peripheral CD4+CD25- T cells. To define the mechanism(s) for this occurrence, we have used adoptive transfer studies to examine the effects of STAT5 activity on steady-state CD4+ T cell homeostasis. We observed that constitutive STAT5 signaling induced 4- to 7-fold increased levels of basal steady-state proliferation, which was accompanied by a comparable increase in T cell recovery. Most strikingly, steady-state CD4 T cell proliferation occurred independently of both MHC class II and IL-15. These observations demonstrate that the STAT5-driven pathway is important to lymphocyte homeostasis and can supersede the need for both TCR engagement and cytokine stimulation. This suggests that the need for TCR stimulation to induce common gamma-chain cytokine receptor expression, and thus STAT5 activation, is a key factor in maintaining normal CD4+ T cell homeostasis.


Non-suicidal self-injury, suicide ideation, and past suicide attempts: Comparison between transgender and gender diverse veterans and non-veterans.
Transgender and gender diverse (TGD) individuals, especially veterans, experience elevated rates of non-suicidal self-injury (NSSI) and suicide related behaviors compared to gender majority individuals. Research has yet to compare TGD veterans to non-veterans or look at correlates of NSSI and related behaviors to suicide related outcomes. This study examines prevalence and suicide related correlates of NSSI among TGD veterans and TGD non-veterans. Data analyzed in the were part of the Trans Lifeline Mental Health Survey. Both TGD veterans (N = 313) and non-veterans (N = 3,972) completed an online, cross-sectional survey that included self-report measures of NSSI, suicidal ideation (SI), and suicidal attempt (SA) along with lifetime hospitalization and avoidance of care due to NSSI. Results of this paper indicate that prevalence of NSSI, SI, and SA are elevated in both the TGD veterans and non-veteran subpopulations. Further, veterans compared to non-veterans have a lower prevalence of NSSI but higher prevalence of hospitalization when self-harm is inflicted, reflecting more healthcare utilization or increased severity of NSSI episodes. Additionally, veterans were less likely to avoid care due to NSSI. Further, veteran status seemed to be a protective factor against demographic differences that increased rates of NSSI history in non-veteran TGD individuals. The limitations of this study include its cross-sectional study design, one question assessing SA, and few TGD male veterans. NSSI is an important risk factor in future suicide related outcome such as SI and SA. Further, differences in healthcare utilization among TGD veterans and non-veterans are apparent.


B-cell nuclear proteins binding in vitro to the human immunoglobulin kappa enhancer: localization by exonuclease protection.
Proteins capable of interacting with the enhancer of the immunoglobulin kappa gene in vitro have been detected in extracts of nuclei from human B cells and from human, mouse, and rabbit spleens. The experiments, based on an exonuclease protection technique, demonstrate nuclear protein factors binding to a 30- to 35-base-pair domain containing both the simian virus 40 enhancer core element (TTTCCA) and the octamer CAGGTGGC that was previously identified as the consensus sequence for protein-binding sites in the murine immunoglobulin heavy-chain enhancer. This 30- to 35-base-pair domain in the human kappa enhancer is homologous to a site of protein binding detected in the murine kappa enhancer by other investigators using a gel retardation assay. Our results complement in vivo dimethyl sulfate footprinting studies of the human immunoglobulin kappa enhancer which demonstrated B cell-specific changes in guanine reactivity immediately 5' to the consensus octamer. Together, these findings suggest that DNA-binding proteins in B-cell nuclei interact with the 5' portion of the human kappa-gene enhancer. Such proteins could play a role in the B cell-specific transcription of the human immunoglobulin kappa gene.


Predictors of adherence to a multifaceted podiatry intervention for the prevention of falls in older people.
Despite emerging evidence that foot problems and inappropriate footwear increase the risk of falls, there is little evidence as to whether foot-related intervention strategies can be successfully implemented. The aim of this study was to evaluate adherence rates, barriers to adherence, and the predictors of adherence to a multifaceted podiatry intervention for the prevention of falls in older people. The intervention group (n = 153, mean age 74.2 years) of a randomised trial that investigated the effectiveness of a multifaceted podiatry intervention to prevent falls was assessed for adherence to the three components of the intervention: (i) foot orthoses, (ii) footwear advice and footwear cost subsidy, and (iii) a home-based foot and ankle exercise program. Adherence to each component and the barriers to adherence were documented, and separate discriminant function analyses were undertaken to identify factors that were significantly and independently associated with adherence to the three intervention components. Adherence to the three components of the intervention was as follows: foot orthoses (69%), footwear (54%) and home-based exercise (72%). Discriminant function analyses identified that being younger was the best predictor of orthoses use, higher physical health status and lower fear of falling were independent predictors of footwear adherence, and higher physical health status was the best predictor of exercise adherence. The predictive accuracy of these models was only modest, with 62 to 71% of participants correctly classified. Adherence to a multifaceted podiatry intervention in this trial ranged from 54 to 72%. People with better physical health, less fear of falling and a younger age exhibited greater adherence, suggesting that strategies need to be developed to enhance adherence in frailer older people who are most at risk of falling. Australian New Zealand Clinical Trials Registry ACTRN12608000065392.


Critical elements of pediatric testicular germ cell tumors surgery.
Children, adolescents and young adults with testicular germ cell tumors require appropriate surgical care to insure excellent outcomes. This article presents the most critical elements, and their basis in evidence, for surgery in this population. Specifically, the importance of inguinal radical orchiectomy for malignant tumors, partial orchiectomy for prepubertal tumors and normal serum tumor markers, and the appropriate use of post-chemotherapy retroperitoneal lymph node dissection in those with residual retroperitoneal masses.


Immersive virtual reality (VR) training increases the self-efficacy of in-hospital healthcare providers and patient families regarding tracheostomy-related knowledge and care skills: A prospective pre-post study.
Virtual reality (VR)-based simulation in hospital settings facilitates the acquisition of skills without compromising patient safety. Despite regular text-based training, a baseline survey of randomly selected healthcare providers revealed deficiencies in their knowledge, confidence, comfort, and care skills regarding tracheostomy. This prospective pre-post study compared the effectiveness of regular text- and VR-based intervention modules in training healthcare providers' self-efficacy in tracheostomy care skills. Between January 2018 and January 2020, 60 healthcare providers, including physicians, nurses, and respiratory therapists, were enrolled. For the intervention, a newly developed head-mounted display (HMD) and web VR materials were implemented in training and clinical services. Subsequently, in-hospital healthcare providers were trained using either text or head-mounted display virtual reality (HMD-VR) materials in the regular and intervention modules, respectively. For tracheostomy care skills, preceptors directly audited the performance of trainees and provided feedback. At baseline, the degree of trainees' agreement with the self-efficacy-related statements, including the aspects of familiarity, confidence, and anxiety about tracheostomy-related knowledge and care skills, were not different between the control and intervention groups. At follow-up stage, compared with the regular group, a higher percentage of intervention group' trainees reported that they are "strongly agree" or "somewhat agree" that the HMD-VR simulation increases their self-efficacy, including the aspects of familiarity and confidence, and reduced their anxiety about tracheostomy-related knowledge and care skills. After implementation, a higher degree of trainees' average satisfaction with VR-based training and VR materials was observed in the intervention group than in the regular group. Most reported that VR materials enabled accurate messaging and decreased anxiety. The increasing trend of the average written test and hands-on tracheostomy care skills scores among the intervention group trainees was significant compared to those in the regular group. The benefits of HMD-VR simulations and web-VR material-based clinical services for in-hospital healthcare providers and patient families persisted until 3 to 4 weeks later. The current study suggests that VR materials significantly enhance trainees' self-efficacy (increased familiarity, increased confidence, and reduced anxiety) and their satisfaction with the training, while motivating them to use acquired knowledge and skills in clinical practice.


Sex-related differences in crossing over in Caenorhabditis elegans.
In the nematode Caenorhabditis elegans, hermaphrodite recombination has been characterized and is the basis of the genetic map used in this organism. In this study we have examined male recombination on linkage group I and have found it to be approximately one-third less than that observed in the hermaphrodite. This decrease was interval-dependent and nonuniform. We observed less recombination in the male in 5 out of 6 intervals examined, and no observable difference in one interval on the right end of LG I. Hermaphrodite recombination frequencies are the result of recombination in two germlines; oocyte and hermaphrodite spermatocytes. We have measured recombination in the oocyte and have found it to be approximately twofold lower than that calculated for hermaphrodite spermatocytes and not significantly different from the male spermatocyte frequency. Thus, recombination frequencies appear to be a function of gonad physiology rather than the sex of the germline. Evidence from experiments examining the effect of karyotype on recombination in males sexually transformed by the her-1 mutation into XO hermaphrodites (normally XX), suggests the sexual phenotype rather than genotype determines the recombination frequency characteristic of a particular sex. Hermaphrodite recombination is known to be affected by temperature, maternal age, and the rec-1 mutation. We have examined the effect of these parameters on recombination in the male and have found male recombination frequency increased with elevated temperatures and in the presence of Rec-1, and decreased with paternal age.


Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG).
Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders' views on AI for therapy discovery in CDG.


[Effect of nonsteroidal anti-inflammatory drugs on pharmacokinetics of methotrexate: a meta-analysis].
It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) affect the pharmacokinetics of methotrexate, but there are several reports showing negative consequences. In this study, we evaluated drug interactions by performing a meta-analysis on published data examining the effect of NSAIDs on pharmacokinetic parameters of methotrexate. The combined standardized mean difference of the maximum blood concentration after oral administration of methotrexate was calculated to be -0.00 (95% confidence interval, -0.30 to 0.30) based on 6 clinical trials, and there was no significant effect of NSAIDs (p=0.9967). However, it is also represented that the NSAIDs significantly increased the area under the blood concentration-time curve of methotrexate (combined standardized mean difference, 0.73; 95% confidence interval, 0.32 to 1.14; p=0.0004; 11 trials). Furthermore, the combined standardized mean differences in total and renal clearance of methotrexate were estimated to be -0.80 (95% confidence interval, -1.41 to -0.18; p=0.0109; 6 trials) and -0.76 (95% confidence interval, -1.40 to -0.11; p=0.0220; 11 trials), respectively, implying that NSAIDs interfere with urinary excretion of methotrexate. In conclusion, the integration of the published reports by these meta-analyses shows that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate.


Wegener's granulomatosis and the respiratory system.
Wegener's granulomatosis is a disease characterized by necrotizing vasculitis of the upper and lower respiratory tracts, necrotizing glomerulonephritis, and varying degrees of disseminated small vessel vasculitis. Patients can present to an otolaryngologist head and neck surgeon with ear, nose, throat, lung, orbit, salivary gland, or cutaneous lesions. The disease is variable in its presentation and progression. Tissue biopsies may be non-diagnostic even in the presence of active disease. Although the disease was rapidly fatal as recently at 1970, it can now be effectively treated. This paper reviews the diagnosis and management of Wegener's granulomatosis at a major university hospital between 1965 and 1979. during this period there was a significant evolution of treatment methods.


Selected contribution: chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats.
Age and the estrus cycle affect time-dependent respiratory responses to episodic hypoxia in female rats. Respiratory long-term facilitation (LTF) is enhanced in middle-aged vs. young female rats (72). We tested the hypothesis that phrenic and hypoglossal (XII) LTF are diminished in acyclic geriatric rats when fluctuating sex hormone levels no longer establish conditions that enhance LTF. Chronic intermittent hypoxia (CIH) enhances LTF (41); thus we further predicted that CIH would restore LTF in geriatric female rats. LTF was measured in young (3-4 mo) and geriatric (20-22 mo) female Sasco Sprague-Dawley rats and in a group of geriatric rats exposed to 1 wk of nocturnal CIH (11 vs. 21% O2 at 5-min intervals, 12 h/night). In anesthetized, paralyzed, vagotomized, and ventilated rats, time-dependent hypoxic phrenic and XII responses were assessed. The short-term hypoxic response was measured during the first of three 5-min episodes of isocapnic hypoxia (arterial Po2 35-45 Torr). LTF was assessed 15, 30, and 60 min postepisodic hypoxia. Phrenic and XII short-term hypoxic response was not different among groups, regardless of CIH treatment (P > 0.05). LTF in geriatric female rats was smaller than previously reported for middle-aged rats but comparable to that in young female rats. CIH augmented phrenic and XII LTF to levels similar to those of middle-aged female rats without CIH (P < 0.05). The magnitude of phrenic and XII LTF in all groups was inversely related to the ratio of progesterone to estradiol serum levels (P < 0.05). Thus CIH and sex hormones influence the magnitude of LTF in geriatric female rats.


Further studies on the structure of the glycogen-bound form of protein phosphatase-1 from rabbit skeletal muscle.
We have reported previously that the glycogen-bound form of protein phosphatase-1 (termed PP-1G) is a heterodimer, composed of the 37-kDa catalytic (C) subunit complexed to a 103-kDa G-subunit that anchors the enzyme to glycogen [Strålfors, P., Hiraga, A. and Cohen, P. (1985) Eur. J. Biochem. 149, 295-303]. An antibody raised against a synthetic peptide corresponding to the phosphorylation site on the G-subunit was found to immunoprecipitate PP-1G specifically. No precipitation occurred if the antibody was preincubated with the synthetic peptide, or if PP-1G was replaced by either the isolated C-subunit or protein phosphatase-2A. The results confirm by a new and independent method that the G-subunit is complexed to the C-subunit, and that it is not a contaminant. The G-subunit is remarkably sensitive to proteolysis. At the final stage of purification, PP-1G was eluted as a broad peak of activity. The leading fractions contained the 37-kDa C-subunit and 103-kDa G-subunit, while the central and trailing fractions comprised the 37-kDa C-subunit plus a number of bands with molecular masses ranging over 40-80 kDa. The 40-80-kDa bands were phosphorylated by cyclic-AMP-dependent protein kinase and tryptic digestion generated the identical phosphopeptides obtained by trypsinisation of the 103-kDa G-subunit. Furthermore, antibody to the G-subunit immunoprecipitated protein phosphatase activity quantitatively in the leading, central and trailing fractions. The results demonstrate that the 40-80-kDa polypeptides are fragments of the G-subunit, and that fragments as small as 40 kDa retain the sites of phosphorylation as well as the ability to interact with the C-subunit and with glycogen. Khatra [J. Biol. Chem. (1986) 261, 8944-8952] reported that the glycogen-bound form of protein phosphatase-1 did not contain a G-subunit and that it was a dimer composed of two identical C-subunits. The present work has shown that this proposal is incorrect, and that proteolysis of the G-subunit to fragments that stain very poorly with Coomassie blue can explain why this error was made.


The participation of clinical pharmacists in the treatment of patients with central nervous system infection can improve the effectiveness and appropriateness of anti-infective treatments: a retrospective cohort study.
Background: Central nervous system infection (CNSI) treatment in hospital neurosurgery emphasizes the importance of optimizing antimicrobial therapy. Timely and appropriate empiric antibiotic treatment is critical for managing patients with bacterial meningitis. Objectives: To evaluate the activities of clinical pharmacists in the anti-infective treatment of patients with CNSI in neurosurgery. Method: A single-center retrospective cohort study was carried out from January 2021 to March 2023 at a tertiary teaching hospital in China. The study sample included a group that received pharmacy services and a group that did not. In the pharmacy services group, the anti-infective treatment plan was led and developed by pharmacists. Pharmaceutical care, including medication therapy and all CNSI treatment regimens, was administered in daily unit rounds by pharmacists. Baseline demographics, treatment outcomes, and rational use of antibiotics were compared between the two groups, and the impact of a antimicrobial stewardship (AMS) program was evaluated. Results: Of the 306 patients assessed according to the inclusion and exclusion criteria, 151 patients were included, and 155 patients were excluded due to abnormal data and missing information on antibiotic costs or antimicrobial use. Eventually, 73 were included in the pharmacy services group and 78 in the group without pharmacist participation. The antibiotic use density (AUD) of the pharmacy services group decreased from 167.68 to 127.63 compared to the group without pharmacist participation. After the pharmacist services, the AUD for linezolid decreased from 9.15% to 5.23% and that for miscellaneous agents decreased from 17.91% to 6.72%. The pharmacy services group had better improvement (p < 0.05) and a significantly higher score for the rational use of antibiotics (p < 0.05) than the group without pharmacist participation. Conclusion: The clinical pharmacist services evaluation results demonstrated an essential role of clinical pharmacist-led AMS programs in the effective and appropriate use of anti-infective treatments in neurosurgery with patients with CNSI.


Who cares? Moral obligations in formal and informal care provision in the light of ICT-based home care.
An aging population is often taken to require a profound reorganization of the prevailing health care system. In particular, a more cost-effective care system is warranted and ICT-based home care is often considered a promising alternative. Modern health care devices admit a transfer of patients with rather complex care needs from institutions to the home care setting. With care recipients set up with health monitoring technologies at home, spouses and children are likely to become involved in the caring process and informal caregivers may have to assist kin-persons with advanced care needs by means of sophisticated technology. This paper investigates some of the ethical implications of a near-future shift from institutional care to technology-assisted home care and the subsequent impact on the care recipient and formal- and informal care providers.