rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism.
Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates. RESULTS from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations.


Prevalence of equine herpesvirus type 1 in trigeminal ganglia and submandibular lymph nodes of equids examined postmortem.
The objective of this study was to detect and characterise the biovar of equine herpesvirus type 1 (EHV-1) from submandibular lymph nodes (SMLNs) and trigeminal ganglia from 153 equids undergoing routine postmortem examination for various medical and surgical reasons. A combination of nucleic acid precipitation and preamplification steps was used to increase the analytical sensitivity of the analysis. The presence of latent EHV-1 was determined when tissue samples were PCR-positive for the glycoprotein B (gB) gene and the DNA polymerase (ORF 30) gene of EHV-1 in the absence of detectable late structural protein gene (gB gene) mRNA. The SMLNs of five of the study animals (3.3 per cent) were PCR-positive for the gB gene of EHV-1. Two SMLNs carried a latent neurotropic strain of the virus, whereas three SMLNs were PCR-positive for both neurotropic and non-neurotropic EHV-1. A total of 30 trigeminal ganglia collected from 19 horses were PCR-positive for the gB gene of EHV-1. Nine trigeminal ganglia harboured either latent non-neurotropic or neurotropic EHV-1 strains. Twelve trigeminal ganglia contained both latent neurotropic and non-neurotropic EHV-1. The prevalence and distribution of EHV-1 biovars among the study horses appeared to be influenced by their breed and the type of tissue tested.


RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.
Tumours with mutant BRAF are dependent on the RAF-MEK-ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.


Changing Human Behavior to Improve Animal Welfare: A Longitudinal Investigation of Training Laboratory Animal Personnel about Heterospecific Play or "Rat Tickling".
Despite evidence for rat tickling's animal welfare benefits, the technique is rarely implemented in part because of a lack of training. This study's purpose was to determine the efficacy of online-only or online + hands-on training programs on key outcomes for rat tickling in comparison to a waitlist control condition. After completing a baseline survey, laboratory animal personnel currently working with rats in the United States were semi-randomized to receive online-only training (n = 30), online + hands-on training (n = 34), or waitlist control (n = 32). Participants received further surveys directly after training and 2 months later. Data were analyzed using general linear mixed models. At the 2-month follow-up compared to baseline, both training groups reported increased implementation, self-efficacy, knowledge, and familiarity of rat tickling while only the online + hands-on training participants reported increased control beliefs (while the waitlist group stayed the same). At the 2-month follow-up compared to the waitlist, hands-on training participants reported increased self-efficacy and familiarity with rat tickling. Overall, findings show that both online-only and online + hands-on training can improve key outcomes for rat tickling. Although online + hands-on training is slightly more effective, the interactive online-only training has the potential to improve widescale implementation of a welfare-enhancing technique.


Real-Time Detection of Sleep Arousals with a Head-Mounted Accelerometer.
Wearable electroencephalography (EEG) enables real-time interactions with the sleeping brain in real-life settings. An important parameter to monitor during these interactions are sleep arousals, i.e. temporary increases in EEG frequency, that compose sleep dynamics, but are challenging to detect without delay. We describe the development of an EEG- and accelerometer(ACC)-based sensing approach to detect arousals in real-time. We investigated the ability of these sensing modalities to timely and accurately detect arousals. When evaluated on 6 nights of mobile recordings, ACC had a median real-time delay of 2 s and was therefore better suited for an early detection of arousals than EEG (4.7 s). The detection performance was independent of sleep stages, but worked better on longer arousals. Our results demonstrate that a head-mounted ACC might be a cost-effective and easy-to-integrate solution for arousal detection where short delays are important or EEG signals are not available.


Patients' response to tubal division.
Of the 187 women who underwent laparoscopic tubal division at the Massachusetts General Hospital between September 1969 and June 1973, one hundred thirty-nine were interviewed in a follow-up study. The mean age was 33.9 years; the mean gravidity was 5.0 and mean parity 3.8. Most women were married, with religious affiliations reflecting those of the general hospital population, and most underwent tubal division because they felt they had had enough children. The majority (85.6%) were satisfied with their decision and reported similar or improved mental and physical health and sexual activity. Almost all (93.5%) said that they would make the same choice again, and more than half (54.7%) would have liked to have had this operation earlier. Those ambivalent or regretful about their decision could not be readily identified by any preoperative characteristics such as age, parity, and marital status.


[Formation of F'-episomes in Flexner shigellae].
Genetic characteristics of Shigella flexneri virulent donor strain 3s, isolated in the laboratory, are studied. The data obtained showed that Sh. flexneri 3s 6832 is of F'protype it did not transmit even closely located chromosome markers, except pro+. The transition of pro+ marker was reproduced in recA- strain. F'pro plasmid was eliminated with a frequency similar to that of F'lac factor in the control strain of Escherichia coli. The study of virulence by means of keratoconjunktival test revealed its retaining in clones which lost F'pro plasmid. Probably, KCP-A gene retained in the chromosome of F'pro strain. Crossing with proA- and procC- C. coli strains revealed a small length of F'pro episome, enly ProA+ hybrids being obtained. A complex mechanism of F'system formation in interspecies genetic recombination between E. coli K-12 and Sh. flexneri 3s is demonstrated.


Time-dependent effect of kainate-induced seizures on glutamate receptor GluR5, GluR6, and GluR7 mRNA and Protein Expression in rat hippocampus.
Glutamate receptor 6 is strongly implicated in human refractory epilepsy and in kainic acid (KA)-induced status epilepticus (SE). In vitro pharmacologic studies with newer antiepileptic drugs (AEDs) are increasingly indicating the role of glutamate receptor 5 (GluR5) in epilepsy. Glutamate receptor 7 (GluR7) has been the least investigated in the context of epilepsy. We studied the messenger ribonucleic acid (mRNA) and protein expression of GluR5, GluR6, and GluR7 in rat hippocampus 72 h, 90 days, and 180 days after KA-induced SE. SE was induced by injecting KA intraperitoneally (i.p.) into adult rats. The hippocampi were isolated 72 h, 90 days, and 180 days after SE. Reverse transcription-polymerase chain reaction (RT-PCR) was performed for mRNA expression. Western blots determined the protein expression. A significant increase was noted in GluR5 expression in KA-treated animals compared with controls at 72 h and 180 days, with no significant difference at the intervening 90-day point. Protein levels for GluR5 increased at 72 h and remained elevated until 180 days. GluR7 mRNA showed a significant decrease at 90 days after seizures. Neither the mRNA expression nor the protein levels of GluR6 differed from controls at any of the times after SE. KA-induced SE leads to an upregulation of GluR5 mRNA and protein and a downregulation of GluR7 mRNA in rat hippocampus, with no change in GluR6 mRNA or protein expression.


Isosilibinin inhibits advanced human prostate cancer growth in athymic nude mice: comparison with silymarin and silibinin.
Earlier studies have shown the cancer chemopreventive efficacy of silymarin and its semi-purified constituent silibinin against prostate cancer (PCa), but the efficacy of other constituents of silymarin is largely unknown. In the present study, we assessed the in vivo growth inhibitory efficacy of one such constituent isosilibinin (a 50:50 mixture of isosilybin A and isosilybin B) in comparison with silymarin and silibinin in human PCa DU145 xenograft in athymic nude mice. Isosilibinin feeding (200 mg/kg body weight per day) significantly inhibited the growth of xenograft after 53 days of treatment (p < or = 0.005), which was equally or slightly better effective than silymarin and silibinin, respectively. Treatment with isosilibinin, silymarin and silibinin was stopped after 53 days and tumor volume was measured till 77 days. After 24 days of treatments withdrawal, tumor volume remain decreased, however, it was statistically significant only with isosilibinin (p < or = 0.05), suggesting its prolonged effect. Biomarker analysis showed that isosilibinin, silymarin and silibinin treatment for 53 days significantly inhibited the immunoreactivity for proliferating cell nuclear antigen (PCNA), microvessel density (CD31) and vascular endothelial growth factor along with significant increase in apoptotic cell population. The PCNA levels in tumors remained significantly low even after 24 days of treatments withdrawal. Western blot analysis of tumor tissue suggested that these flavonolignan formulations differentially alter the expression of cell cycle regulatory molecules, cyclins and Cdks. Overall, the results of present study suggest that isosilibinin has comparatively better efficacy against PCa and should be further analyzed for its clinical utility.


Increased numbers of both airway basophils and mast cells in sputum after allergen inhalation challenge of atopic asthmatics.
Mast cells and basophils are metachromatic cells that participate in allergic inflammation. Allergen challenge to the airways of atopic asthmatic individuals increases levels of metachromatic cells, which may reflect an increase in mast cells, basophils, or both. We conducted a study to characterize the kinetics of basophil and mast cell recruitment to the airways of atopic asthmatic subjects after allergen inhalation challenge, using monoclonal antibodies specific for each type of cell. Of 19 subjects, 14 developed both early- and late-phase asthmatic responses (dual responders [DRs]), whereas five developed only early asthmatic responses (early responders [ERs]) after allergen inhalation. There was a significant increase in the number of sputum eosinophils (p < 0.002) and basophils (p < 0.002) at 7 h and 24 h after challenge in both ERs and DRs. There was also a significant increase in the number of activated eosinophils (p = 0. 00002) and mast cells (p = 0.009) in sputum at 7 h and 24 h after challenge in DRs, but not in ERs (p > 0.4). DRs had a significantly higher number of allergen-induced sputum basophils than did ERs (p < 0.01), and sputum basophils correlated significantly with airway hyperresponsiveness (AHR) to methacholine at 24 h after challenge (r = 0.66, p = 0.002). DRs tended to have higher allergen-induced basophil levels than did ERs, which may contribute to the observed AHR.


Digital holography of total internal reflection.
We introduce a new microscopy technique termed total internal reflection holographic microscopy (TIRHM). Quantitative phase microscopy by digital holography is used to image the phase profile of light in total internal reflection, which is modulated by the materials present on or near the surface of internal reflection. The imaging characteristics are theoretically modeled and imaging capabilities are experimentally demonstrated.


Construction of group exercise sessions in geriatric inpatient rehabilitation.
There is little knowledge about the ways geriatric physiotherapy is being carried out in practice and about the situational construction of formal policies for promoting physical activity. This article examines how professional physiotherapists and frail community-dwelling older adults as their clients use talk and action to construct a group exercise session in an inpatient rehabilitation setting in Finland. The analysis of 7 group exercise sessions with a total of 52 clients and 9 professional physiotherapists revealed 3 different practitioner approaches, which served different functions in older adults' empowerment and lifestyle activity change. The highly structured approach favored taciturn physical performances completed independently and successfully by frail older adults. The guided exercise approach with individualized guidance encouraged occasional coconstruction of shared understanding of learning the exercises. The circuit training approach facilitated occasional self-regulation by the clients. The results of this study indicate that a combination of different approaches is required to address the multifaceted needs of heterogeneous frail older adults.


Managing professionals: The emerging leadership role of Victorian Maternal and Child Health coordinators.
Drawing on research into cultural and organizational change in the Victorian Maternal and Child Health Service during the 1990s, this paper examines implications for the nursing leadership provided by service coordinators. The project included a quantitative survey of nurses and semistructured interviews with managers and coordinators. Under a strongly neo-liberal state government in Victoria, Australia, services were fundamentally restructured through tendering processes. A competitive, productivist culture was introduced that challenged the professional ethos of nurses and a primary health orientation to the care of mothers and infants. This paper focuses on the pressures that the entrepreneurial environment presented to maternal and child health nurses' identity and collegial relations and to the coordination role. It argues that coordinators emerged as a significant nursing management group at the interface of administrative change and the management of professional practice. Although many nurses skillfully negotiated tensions with peers and management, their leadership role needs further clarification and support.


Fundamental behavioral and neurophysiologic relationships between sensory processing, intolerance of uncertainty, and autistic traits in children: A hybrid approach.
Sensory differences are common and often challenging for autistic children. Furthermore, atypical sensory processing is associated with autistic traits and other autism-related behaviors, such as intolerance of uncertainty (IU). Such traits and their relatedness vary continuously across autistic and non-autistic children alike. However, the underlying neural correlates of these continuous variables, and their associations, are not well understood. Therefore, this study examined relationships between sensory processing, IU, autistic traits, and associated resting state brain connectivity, across a sample of both autistic (n = 30) and non-autistic (n = 26) children. In addition to computing behavioral correlations between these factors, we carried out independent component network functional connectivity analysis to investigate associations between cortical and cerebellar networks and behavioral results between groups and across our entire sample. Across-group correlations between sensory processing, autistic traits, and IU were significant. In addition, data demonstrated overlapping sensory processing and intolerance of uncertainty scores, spanning the groups. Brain (rs-fMRI)-behavioral relationships revealed strong associations between sensory, large-scale resting state, and cerebellar networks and behavioral scores. Overall, our findings suggest that sensory differences are related to IU and autistic traits across the population. Neurophysiologic data pointed to functional connectivity between sensory cortices and supramodal brain networks. These findings provide evidence for the continuous variation of behaviors common to autism throughout the entire population and their neurobiological correlates.


Hospital executives: perceptions of skills and experiences desired in health care graduates.
The modern health care organization is a complex entity with numerous stakeholders having divergent interests. Managing these complex organizations requires individuals with a variety of skills. In this study, an assessment of the academic preparation, skills, and experiential learning desired in health care graduates was made. To determine the perception of executives, a 16-item questionnaire was developed and distributed to over 587 hospital executives. The data showed a significant correlation (.001) between the responses of the executives regarding a preference for individuals with a master's degree with a health specialty and a preference for individuals with some experiential learning activities. The findings showed a strong preference among executives for hiring a health graduate with a master's in health administration. Although there were some limitations to this study, the hospital executives responded positively to questions regarding a preference for individuals with health care management degrees and experiential learning over persons without these experiences.


Metabolomic Alterations of Volatile Organic Compounds and Bile Acids as Biomarkers of Microbial Shifts in a Murine Model of Short Bowel Syndrome.
Pediatric short bowel syndrome (SBS) is a rare condition characterized by a massive loss of the small intestine, leading to the inability to meet nutritional requirements without the use of parenteral or enteral supplementation. SBS causes profound alterations in the intestinal microbiome and metabolome. The aim of this study was a detailed assessment of the intestinal microbiome and metabolome in a murine model of SBS. We performed a 60% proximal small bowel resection versus a sham operation in C57BL/6 mice. Four weeks postoperatively, the microbial communities of different intestinal segments (jejunum, ileum, colon) and stool were assessed by 16S rRNA gene sequencing. Bile acids in serum and stool and volatile organic compounds (VOCs) in the fecal headspace were assessed using LC-MS and GC-MS techniques. The α-diversity of the different intestinal segments did not significantly differ between the two groups. β-diversity significantly differed between sham and SBS mice. While in the jejunum, Faecalibaculum was significantly increased in SBS animals, a significant reduction in Lactobacillus and Sporosarcina was detected in the ileum of SBS mice. In the colon of SBS mice, a significant decrease in Ruminococcaceae and a significant increase in Proteobacteria such as Faecalibaculum and Escherichia-Shigella were found. Serum levels of deoxycholic, taurocholic and taurochenodeoxycholic acids were significantly higher in the SBS group. Of the 29 VOCs tested, hexane, isoflurane and pentane were significantly higher in the SBS group, and pyrrole was significantly lower. We were able to show that SBS causes shifts in the murine intestinal microbiome and metabolome including serum BAs and fecal VOCs.


Aquaculture practices and potential human health risks: current knowledge and future priorities.
Annual global aquaculture production has more than tripled within the past 15 years, and by 2015, aquaculture is predicted to account for 39% of total global seafood production by weight. Given that lack of adequate nutrition is a leading contributor to the global burden of disease, increased food production through aquaculture is a seemingly welcome sign. However, as production surges, aquaculture facilities increasingly rely on the heavy input of formulated feeds, antibiotics, antifungals, and agrochemicals. This review summarizes our current knowledge concerning major chemical, biological and emerging agents that are employed in modern aquaculture facilities and their potential impacts on public health. Findings from this review indicate that current aquaculture practices can lead to elevated levels of antibiotic residues, antibiotic-resistant bacteria, persistent organic pollutants, metals, parasites, and viruses in aquacultured finfish and shellfish. Specific populations at risk of exposure to these contaminants include individuals working in aquaculture facilities, populations living around these facilities, and consumers of aquacultured food products. Additional research is necessary not only to fully understand the human health risks associated with aquacultured fish versus wild-caught fish but also to develop appropriate interventions that could reduce or prevent these risks. In order to adequately understand, address and prevent these impacts at local, national and global scales, researchers, policy makers, governments, and aquaculture industries must collaborate and cooperate in exchanging critical information and developing targeted policies that are practical, effective and enforceable.


The kinship2 R package for pedigree data.
The kinship2 package is restructured from the previous kinship package. Existing features are now enhanced and new features added for handling pedigree objects. Pedigree plotting features have been updated to display features on complex pedigrees while adhering to pedigree plotting standards. Kinship matrices can now be calculated for the X chromosome. Other methods have been added to subset and trim pedigrees while maintaining the pedigree structure. We make the kinship2 package available for R on the Contributed R Archives Network (CRAN), where data management is built-in and other packages can use the pedigree object.


Effect of hydrogen peroxide exposure on normal human erythrocyte deformability, morphology, surface characteristics, and spectrin-hemoglobin cross-linking.
To further define the conditions for forming spectrin-hemoglobin cross-linking in human erythrocyte membranes and to examine its possible effects on membrane function, we incubated normal human erythrocytes for up to 3 h in concentrations of H2O2, varying from 45 to 180 microM, in an azide phosphate buffer, pH 7.4. The chemical changes observed indicated that methemoglobin formation occurred early and at a low concentration (45 microM). Morphologic changes characterized by increased echinocyte formation occurred in a dose-dependent fashion. In addition, decreased cell deformability commensurate with increased membrane rigidity was found. Finally, an increase in cell recognition as determined by monocyte phagocytosis and adherence in vitro, as well as decreased phosphatidylcholine accessibility to bee venom phospholipase A2, was found in H2O2-treated erythrocytes compared with controls. Both of these latter changes were closely correlated with the extent of spectrin-hemoglobin cross-linking. In addition to these protein-mediated interactions, lipid peroxidation also occurred after H2O2 exposure, as shown by generation of fluorescent amino propene derivatives. The addition of the antioxidant, butylated hydroxytoluene, decreased the fluorescent derivatives, but did not prevent the effects on membrane function. This suggests that lipid peroxidation, though present, was not necessary for the membrane changes found. In contrast, spectrin-hemoglobin aggregation and the alterations in membrane function were completely prevented by prior exposure of the erythrocytes to carbon monoxide.


Successful pregnancy in a patient with Takayasus arteritis.
This report describes a case of Takayasus arteritis in a 19-year-old Palestinian female. She conceived after diagnosis. Her pregnancy was complicated by uncontrolled hypertension, which was not associated with other markers of disease activity. Despite aggressive medical treatment, cesarean section had to be carried out at 34 weeks of pregnancy because of uncontrolled hypertension. A live fetus was borne, and her blood pressure was subsequently controlled with a single antihypertensive agent.


Concordant Oral and Vaginal Human Papillomavirus Infection in the United States.
Human papillomavirus (HPV) is a common infection in adults, with tropism for sites in the head and neck and the genital tracts. To date, few studies have addressed concurrent infection in these sites. To understand the prevalence, characteristics, and concordance of HPV infections in the oral and vaginal regions. This study was a retrospective analysis of cross-sectional survey data from the National Health and Nutrition Examination Survey, 2009-2012. The database was reviewed for all women aged 18 to 69 years with available oral and vaginal HPV DNA screening data. The study was performed from August 1, 2014, to November 1, 2014. Data analysis was performed from November 1, 2014, to June 30, 2015. Logistic regression models were constructed to identify factors associated with infection. Covariates for multivariate analysis included age, income to poverty ratio, number of prior sexual partners, number of prior oral sex partners, and having recent oral sex partners. Dual infection was defined as having an infection of any serotype in both the oral and vaginal HPV regions. Concordant infection was defined as an infection of matching serotype in both locations. A total of 3463 women were identified (mean [SD] age, 37.5 [12.1] years). Racial distribution was 1341 white (38.7%), 786 black (22.7%), 554 Mexican American (16.0%), 378 other Hispanic (10.9%), and 404 self-identified as other (11.7%). Vaginal HPV infection was present in 1586 (45.2%) and oral HPV infection in 141 (4.1%). Dual infection was identified in 107 (3.0%) of all patients, and concordant infection was observed in 41 (1.1%). The prevalence of dual infection was 75.9% in those with oral infection and 6.8% in those with vaginal infection. On multivariate analysis, age (30-50 years) and higher income to poverty ratios had negative associations with dual and concordant infections. A new sexual partner within the last year was positively associated with dual infection (odds ratio, 2.28; 95% CI, 1.03-5.02; P = .04). More than 2 oral sex partners in the past year was positively associated with concordant infection (odds ratio, 3.43; 95% CI, 1.06-11.06; P = .04). This analysis reveals the importance of several demographic factors (age and socioeconomic status) and behavioral factors (oral sex practices) in the development of dual and concordant HPV infection in women. Notably, other sexual behaviors, other sexually transmitted infections, sexual orientation, and number of lifetime sexual partners did not demonstrate any significant associations. Women with multiple oral sex partners and oral HPV infection have a high likelihood of having concurrent vaginal HPV infection.


T-2 toxin induces cytotoxicity and disrupts tight junction barrier in SerW3 cells.
T-2 toxin, which is produced in grain and grain products as a secondary metabolite by Fusarium species, is also potentially dangerous for human health. Up to date, no study was reported the cytotoxicity of T-2 toxin on SerW3 cells in the perspective of junctional barriers. This study focused on revealing the cytotoxic effects of T-2 on Sertoli cells associated with cell junctional barriers. In the present study, SerW3 cells were exposed to T-2 toxin at 12, 120 and 1200ng/ml doses for 24 and 48h. Cytotoxicity tests including cell viability (MTT), lactate dehydrogenase (LDH) cytotoxicity test and trypan blue exclusion assay were performed. Occludin, ZO-1, N-cadherin and β-catenin were immunolabelled, expressions of occludin and N-cadherin were determined by western blotting. SerW3 cell barrier integrity was measured by transepithelial electrical resistance (TEER). Cytotoxicity caused by T-2 toxin increased in a dose dependent manner, expressions of proteins and TEER measurement decreased. This study may underlie the early targets of T-2 toxin on SerW3 cells mimicking blood-testis barrier in vitro.


Stem cell-derived small extracellular vesicles embedded into methacrylated hyaluronic acid wound dressings accelerate wound repair in a pressure model of diabetic ulcer.
Over the past years, the development of innovative smart wound dressings is revolutionizing wound care management and research. Specifically, in the treatment of diabetic foot wounds, three-dimensional (3D) bioprinted patches may enable personalized medicine therapies. In the present work, a methacrylated hyaluronic acid (MeHA) bioink is employed to manufacture 3D printed patches to deliver small extracellular vesicles (sEVs) obtained from human mesenchymal stem cells (MSC-sEVs). The production of sEVs is maximized culturing MSCs in bioreactor. A series of in vitro analyses are carried out to demonstrate the influence of MSC-sEVs on functions of dermal fibroblasts and endothelial cells, which are the primary functional cells in skin repair process. Results demonstrate that both cell populations are able to internalize MSC-sEVs and that the exposure to sEVs stimulates proliferation and migration. In vivo experiments in a well-established diabetic mouse model of pressure ulcer confirm the regenerative properties of MSC-sEVs. The MeHA patch enhances the effectiveness of sEVs by enabling controlled release of MSC-sEVs over 7 days, which improve wound epithelialization, angiogenesis and innervation. The overall findings highlight that MSC-sEVs loading in 3D printed biomaterials represents a powerful technique, which can improve the translational potential of parental stem cell in terms of regulatory and economic impact.


Is diagnostic hysteroscopy adhesiogenic?
To determine whether diagnostic hysteroscopy posed any risk of causing the formation of intrauterine adhesions 108 women were studied. Diagnostic hysteroscopy was performed; following tubal surgery, a second-look hysteroscopy was undertaken. Adhesion were noted in 1 of 100 of those patients in whom no prior adhesions had been noted.


High frequency rTMS over the left parietal lobule increases non-word reading accuracy.
Increasing evidence in the literature supports the usefulness of Transcranial Magnetic Stimulation (TMS) in studying reading processes. Two brain regions are primarily involved in phonological decoding: the left superior temporal gyrus (STG), which is associated with the auditory representation of spoken words, and the left inferior parietal lobe (IPL), which operates in phonological computation. This study aimed to clarify the specific contribution of IPL and STG to reading aloud and to evaluate the possibility of modulating healthy participants' task performance using high frequency repetitive TMS (hf-rTMS). The main finding is that hf-rTMS over the left IPL improves non-word reading accuracy (fewer errors), whereas hf-rTMS over the right STG selectively decreases text-reading accuracy (more errors). These results confirm the prevalent role of the left IPL in grapheme-to-phoneme conversion. The non-word reading improvement after Left-IPL stimulation provide a direct link between left IPL activation and advantages in sublexical procedures, mainly involved in non-word reading. Results indicate also the specific involvement of STG in reading morphologically complex words and in processing the representation of the text. The text reading impairment after stimulation of the right STG can be interpreted in light of an inhibitory influence on the homologous area. In sum, data document that hf-rTMS is effective in modulating the reading accuracy of expert readers and that the modulation is task related and site specific. These findings suggest new perspectives for the treatment of reading disorders.


Functional role of protease activated receptors in vascular biology.
Protease activated receptors (PARs) are a small family of G protein-coupled receptors (GPCR) mediating the cellular effects of some proteases of the coagulation system, such as thrombin, or other proteases, such as trypsin or metalloproteinase 1. As the prototype of PARs, PAR1 is a seven transmembrane GPCR that, upon cleavage by thrombin, unmasks a new amino-terminus able to bind intramolecularly to PAR1 itself thus inducing signaling. In the vascular system, thrombin and other proteases of the coagulation-fibrinolysis system, such as plasmin, factor VIIa and factor Xa, activated protein C, are considered physiologically relevant agonists, and PARs appear to largely account for the cellular effects of these enzymes. In the vasculature, PARs are expressed on platelets, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In the vessel wall, under physiological conditions, PARs are mainly expressed in ECs and participate in the regulation of vascular tone, by inducing endothelium-dependent relaxation. PAR activation on ECs promotes conversion of these cells into a proinflammatory phenotype, causes increase of vascular permeability, and the exposure/secretion of proteins and cytokines mediating the local accumulation of platelets and leukocytes. These effects contribute to the vascular consequences of sepsis and of diseases such as acute lung injury and acute respiratory distress syndrome. In normal arteries PARs are to a much lesser amount expressed on VSMCs. However, in conditions associated with endothelial dysfunction, PARs mediate contraction, proliferation, migration, hypertrophy of VSMCs and their production of extracellular matrix, thereby contributing to the pathophysiology of atherosclerosis and hypertension. Inhibition of protease-PAR interaction might thus become a potential therapeutic target in various vascular diseases.


Discovering nature's diverse pathways to vitamin B12: a 35-year odyssey.
The chronology of the discoveries along the pathway of vitamin B(12) biosynthesis is reviewed from a personal perspective, including discussion of the most recent finding that two pathways to B(12) exist-one aerobic and one anaerobic-which differ mainly in the ring contraction mechanisms that convert porphyrin to corrin.


Analysis of expressed sequence tags of flower buds in Lotus japonicus.
In order to study gene expression in a reproductive organ, we constructed a cDNA library of mature flower buds in Lotus japonicus, and characterized expressed sequence tags (ESTs) of 842 clones randomly selected. The EST sequences were clustered into 718 non-redundant groups. From BLAST and FASTA search analyses of both protein and DNA databases, 58.5% of the EST groups showed significant sequence similarities to known genes. Several genes encoding these EST clones were identified as pollen-specific genes, such as pectin methylesterase, ascorbate oxidase, and polygalacturonase, and as homologous genes involved in pollen-pistil interaction. Comparison of these EST sequences with those derived from the whole plant of L. japonicus, revealed that 64.8% of EST sequences from the flower buds were not found in EST sequences of the whole plant. Taken together, the EST data from flower buds generated in this study is useful in dissecting gene expression in floral organ of L. japonicus.


Cellulose and pectin alter intestinal beta-glucuronidase (EC 184.108.40.206) in the rat.
Groups of rats were given a fibre-free diet containing none or one of the three fibre components: pectin, cellulose or galactomannan. After feeding for 16 weeks, total protein level and beta-glucuronidase (EC 220.127.116.11) activity in the contents and mucosa of jejunum and ileum, and in the contents only of the caecum, were determined. The pectin supplement reduced protein concentration in jejunal contents while cellulose reduced protein concentration in the ileal and caecal contents. beta-Glucuronidase activity of caecal contents was significantly reduced in both the pectin- and cellulose-fed groups. Cellulose affected the beta-glucuronidase activity of both the ileal contents while pectin reduced the beta-glucuronidase of the ileal but not the jejunal contents. Dietary fibre components did not significantly affect jejunal or ileal mucosal beta-glucuronidase activity.


Adjuvant chemotherapy combined with immunotherapy in patients with cholangiocarcinoma after radical resection.
The malignancy of cholangiocarcinoma is highly pronounced, and it exhibits a propensity for recurrence and metastasis even in the presence of standard chemotherapy. The efficacy of adjuvant chemotherapy combined with immunotherapy in patients with resected cholangiocarcinoma needs to be substantiated. Data from 101 patients with cholangiocarcinoma treated at the Sun Yat-sen University Cancer Center between 2015 and 2020 were studied. After propensity score matching, there were no significant differences in baseline characteristics between patients in the combined adjuvant chemotherapy and immunotherapy group (AC + IM group) and the adjuvant chemotherapy alone group (AC group) (all p > 0.05). The AC + IM group demonstrated a statistically significant improvement in relapse-free survival (RFS) compared to the AC group (p = 0.032). Likewise, the AC + IM group exhibited a significantly superior overall survival (OS) outcome when compared to the AC group (p = 0.044). Multivariate Cox analysis unveiled perineural invasion (p = 0.041), lymph node metastasis (p = 0.006), and postoperative immunotherapy (p = 0.008) as independent prognostic factors exerting a significant impact on the OS of patients. In the cohort of patients with perineural invasion, the AC + IM group exhibited significantly improved OS compared to the AC group (p = 0.0077). Similarly, within the subset of patients with lymph node metastasis, the AC + IM group exhibited a significantly superior OS outcome when compared to the AC group (p = 0.023). Combining postoperative adjuvant chemotherapy with immunotherapy extends the RFS and OS of patients with cholangiocarcinoma following radical resection.


Role of Polymer Concentration on the Release Rates of Proteins from Single- and Double-Network Hydrogels.
Controlled delivery of proteins has immense potential for the treatment of various human diseases, but effective strategies for their delivery are required before this potential can be fully realized. Recent research has identified hydrogels as a promising option for the controlled delivery of therapeutic proteins, owing to their ability to respond to diverse chemical and biological stimuli, as well as their customizable properties that allow for desired delivery rates. This study utilized alginate and chitosan as model polymers to investigate the effects of hydrogel properties on protein release rates. The results demonstrated that polymer properties, concentration, and crosslinking density, as well as their responses to pH, can be tailored to regulate protein release rates. The study also revealed that hydrogels may be combined to create double-network hydrogels to provide an additional metric to control protein release rates. Furthermore, the hydrogel scaffolds were also found to preserve the long-term function and structure of encapsulated proteins before their release from the hydrogels. In conclusion, this research demonstrates the significance of integrating porosity and response to stimuli as orthogonal control parameters when designing hydrogel-based scaffolds for therapeutic protein release.


The Gos28 SNARE protein mediates intra-Golgi transport of rhodopsin and is required for photoreceptor survival.
SNARE proteins play indispensable roles in membrane fusion events in many cellular processes, including synaptic transmission and protein trafficking. Here, we characterize the Golgi SNARE protein, Gos28, and its role in rhodopsin (Rh1) transport through Drosophila photoreceptors. Mutations in gos28 lead to defective Rh1 trafficking and retinal degeneration. We have pinpointed a role for Gos28 in the intra-Golgi transport of Rh1, downstream from α-mannosidase-II in the medial- Golgi. We have confirmed the necessity of key residues in Gos28's SNARE motif and demonstrate that its transmembrane domain is not required for vesicle fusion, consistent with Gos28 functioning as a t-SNARE for Rh1 transport. Finally, we show that human Gos28 rescues both the Rh1 trafficking defects and retinal degeneration in Drosophila gos28 mutants, demonstrating the functional conservation of these proteins. Our results identify Gos28 as an essential SNARE protein in Drosophila photoreceptors and provide mechanistic insights into the role of SNAREs in neurodegenerative disease.


[Comparison of lipid metabolism in rat liver cells and nuclei during cycloheximide-induced superinduction of nuclear oncogenes].
Using a model of cycloheximide (CHI)-induced expression of nuclear oncogens, a comparative study of metabolism of the major lipid classes in rat liver nuclei and cells was carried out. A short-term activation of sphingomyelinase which preceded on a time scale the maximal accumulation of c-fos and c-myc transcripts was observed both in the cells and in the nuclei. In contrast with the whole cell, the level of phospholipase C activity in the nuclei did not change under conditions of oncogene activation. It was found that the maximal expression of nuclear oncogens coincided in time with cyclic changes in the content of practically all phospholipids and neutral lipids with simultaneous activation of their synthesis both in the cells and in the nuclei. However, in the nuclei the sphingomyelin metabolism activation was predominant. It is concluded that in the nucleus sphingomyelin and its metabolites may influence oncogene expression via nuclear protein kinase C.


Imaginaries of patienthood: Constructions of HIV patients by HIV specialist health professionals.
This paper explores the ways in which HIV specialists based in the United Kingdom (UK) construct, conceptualise and imagine their patient group via the concept of the 'imaginary', a notion encompassing the symbols, concepts and values through which people make sense of their social environment. In discussing their work with men who have sex with men (MSM), practitioners described patients as knowledgeable and highly adherent to treatment, yet apt to pursue hedonistic lives involving sex and recreational drugs. Recent innovations in treatment were formulated in terms of optimism and progress and the ascent of biomedical approaches was cast as an advance over former emphases on psychosocial interventions and attempts to facilitate behaviour change. In contrast to the imaginary of patients who were well-informed and highly compliant with treatment, participants also sought to explain those who were not easily enfolded within modern treatment regimens or who were seen to be overly emotional. These patients, it was said, had some pre-existing psychological problem or perhaps were especially vulnerable to societal pressures. Overall, the imaginary of the public was pervaded by therapeutic optimism, a sense of progress and an invigoration of biomedical themes in overcoming the challenges of delivering services to MSM.


Do pictures of faces, and which ones, capture attention in the inattentional-blindness paradigm?
Faces and self-referential material (eg one's own name) are more likely to capture attention in the inattentional-blindness (IB) paradigm than other stimuli. This effect is presumably due to the meaning of these stimuli rather than to their familiarity [Mack and Rock, 1998 Inattentional Blindness (Cambridge, MA: MIT Press)]. In previous work, IB has been investigated mostly with schematic stimuli. In the present study, the generalisability of this finding was tested with photographic stimuli. In support of the view that faces constitute a special category of stimuli, pictures of faces were found to resist more to IB than pictures of common objects (experiment 1) or than pictures of inverted faces (experiment 2). In a third experiment, the influence of face familiarity and identity (the participant's own face, a friend's face, and an unknown face) on IB rates was evaluated. Unexpectedly, no differential resistence to blindness across these three kinds of faces was found. In conclusion, pictures of faces attracted attention more than pictures of objects or inverted faces in the IB paradigm. However, this effect was not dependent on face familiarity or identity.


Toxic Tetrahydrocannabinol (THC) Dose in Pediatric Cannabis Edible Ingestions.
The study characterizes cannabis toxicity in relation to tetrahydrocannabinol (THC) dose in pediatric edible cannabis ingestions. This is a retrospective review of children aged <6 years presenting with edible cannabis ingestions of known THC dose within a pediatric hospital network (January 1, 2015-October 25, 2022). Cannabis toxicity was characterized as severe if patients exhibited severe cardiovascular (bradycardia, tachycardia/hypotension requiring vasopressors or intravenous fluids, other dysrhythmias), respiratory (respiratory failure, apnea, requiring oxygen supplementation), or neurologic (seizure, myoclonus, unresponsiveness, responsiveness to painful stimulation only, requiring intubation or sedation) effects. Cannabis toxicity was characterized as prolonged if patients required >6 hours to reach baseline. The relationship between THC dose and severe and prolonged toxicity was explored using multivariable logistic regression and receiver operator characteristic curve analyses. Eighty patients met inclusion. The median age was 2.9 years. The median THC ingestion was 2.1 mg/kg. Severe and prolonged toxicity was present in 46% and 74%, respectively. THC dose was a significant predictor of severe (adjusted odds ratio 2.9, 95% confidence interval: 1.8-4.7) and prolonged toxicity (adjusted odds ratio 3.2, 95% confidence interval: 1.6-6.5), whereas age and sex were not. Area under the curve was 92.9% for severe and 87.3% for prolonged toxicity. THC ingestions of ≥1.7 mg/kg can predict severe (sensitivity 97.3%) and prolonged toxicity (sensitivity 75.4%). The THC dose of edible cannabis correlates to the degree of toxicity in children <6 years old. The threshold of 1.7 mg/kg of THC may guide medical management and preventive regulations.


Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA.
Throughout life, new neurons generated in the ventricular-subventricular zone take the long journey to the olfactory bulb. The intracellular mechanisms that precisely control the neurons' migration speed, enabling their well-organized movement, remain unclear. Rho signalling is known to affect the morphology and movement of various cell types, including neurons. Here we identify Gem-interacting protein (Gmip), a RhoA-specific GTPase-activating protein, as a key factor in saltatory neuronal migration. RhoA is activated at the proximal leading process of migrating neurons, where Gmip is also localized and negatively regulates RhoA. Gmip controls the saltatory movement of neurons that regulate their migration speed and 'stop' positions in the olfactory bulb, thereby altering the neural circuitry. This study demonstrates that Gmip serves as a brake for the RhoA-mediated movement of neuronal somata, and highlights the significance of speed control in the well-organized neuronal migration and the maintenance of neuronal circuits in the postnatal brain.


Isospin Properties of Nuclear Pair Correlations from the Level Structure of the Self-Conjugate Nucleus ^{88}Ru.
The low-lying energy spectrum of the extremely neutron-deficient self-conjugate (N=Z) nuclide _{44}^{88}Ru_{44} has been measured using the combination of the Advanced Gamma Tracking Array (AGATA) spectrometer, the NEDA and Neutron Wall neutron detector arrays, and the DIAMANT charged particle detector array. Excited states in ^{88}Ru were populated via the ^{54}Fe(^{36}Ar,2nγ)^{88}Ru^{*} fusion-evaporation reaction at the Grand Accélérateur National d'Ions Lourds (GANIL) accelerator complex. The observed γ-ray cascade is assigned to ^{88}Ru using clean prompt γ-γ-2-neutron coincidences in anticoincidence with the detection of charged particles, confirming and extending the previously assigned sequence of low-lying excited states. It is consistent with a moderately deformed rotating system exhibiting a band crossing at a rotational frequency that is significantly higher than standard theoretical predictions with isovector pairing, as well as observations in neighboring N>Z nuclides. The direct observation of such a "delayed" rotational alignment in a deformed N=Z nucleus is in agreement with theoretical predictions related to the presence of strong isoscalar neutron-proton pair correlations.


Is screening for prostate cancer necessary in men with symptoms of benign prostatic hyperplasia?
In this report, we review the critical issues concerning the early detection of prostate cancer in patients presenting with symptoms of benign prostatic hyperplasia (BPH). Only with the recent introduction of serum prostate-specific antigen (PSA) testing and transrectal ultrasonography (TRUS)-guided biopsy has the question arisen to what extent the treating physician has a responsibility to rule out prostate cancer before recommending treatment-or watchful waiting-for men with clinical BPH. Uneasiness and uncertainty also result from the development of alternative therapies that do not provide tissue for pathological analysis, or alter serum PSA levels in a poorly predictable fashion. Current early detection strategies, in this clinical situation, pose unique problems, largely because of the great degree of overlap in serum PSA among men with localized prostate cancer and BPH. The underlying goal is to distinguish patients with BPH alone from those with clinically significant, but organ-confined and potentially curable prostate cancer. Treatment for prostate cancer may take precedence over BPH management strategies, while at the same time address the symptoms associated with coexistent clinical BPH. The issues discussed in this report should aid the clinician in the evaluation of patients with clinical BPH. Further studies are clearly needed that may ultimately enhance our ability to discriminate patients with clinically significant organ-confined prostate tumors from those with BPH alone.


Structure and receptor binding specificity of hemagglutinin H13 from avian influenza A virus H13N6.
Interspecies transmission (host switching/jumping) of influenza viruses is a key scientific question that must be addressed. In addition to the vigorous research on highly pathogenic avian influenza viruses (HPAIVs), studies of the mechanism of interspecies transmission of low-pathogenic avian influenza viruses (LPAIVs) could also provide insights into host tropism and virulence evolution. Influenza A viruses harboring hemagglutinin (HA) H13 (e.g., H13N6) are LPAIVs. In this study, soluble H13 HA glycoprotein was purified, and its receptor binding activity was characterized. The results revealed that H13 exclusively binds the avian α2-3-linked sialic acid receptor; no binding to the mammalian α2-6-linked sialic acid receptor was detected. Furthermore, the molecular basis of the H13 receptor binding specificity was revealed by comparative analysis of the crystal structures of both receptor-bound H13 and H5 HAs, which might be contributed by the hydrophobic residue V186. Work with an H13N186 mutant confirmed the importance of V186 in the receptor binding specificity of H13 HA, which shows that the mutant protein reduced the binding of an avian receptor analog but increased the binding of a human receptor analog. Detailed structural analysis also demonstrated that the conserved binding sites of the recently well-studied broadly neutralizing human monoclonal antibodies targeting the HA2 domain are found in H13. Our results expand our understanding of virulence evolution, receptor binding preference, and species tropism of the LPAIVs and HPAIVs.


Rescue of protein splicing activity from a Magnetospirillum magnetotacticum intein-like element.
The self-catalytic protein splicing mechanism is mediated by the intein plus the first amino acid following the intein C-terminus (termed the +1 residue). Although polymorphisms of conserved residues elsewhere in inteins have been widely reported, no splicing-competent intein has been observed without a Ser, Thr or Cys in this functionally essential +1 position. This residue is the nucleophile in two steps of the protein splicing pathway: ligation of the extein fragments during transesterification and formation of a peptide bond between the exteins by an acyl rearrangement. An intein-like element in a hypothetical protein (gene Magn8951) from Magnetospirillum magnetotacticum has all intein signature sequences except the +1 residue, where it has a Tyr. Although the Tyr side-chain hydroxyl can potentially mediate the transesterification reaction, an acyl shift has never been observed with this residue. When the activities of this bacterial intein-like element were studied, protein splicing was not observed and N-terminal cleavage predominated. Mutation of Tyr+1 to Phe or Ala indicated that the Tyr side-chain hydroxyl was not necessary for N-terminal cleavage. Protein splicing activity could be rescued by "reversion" of Tyr+1 to Cys.


A tale of two eras: Phytoplankton composition influenced by oceanic paleochemistry.
We report the results of simple experiments which support the hypothesis that changes in ocean chemistry beginning in the Mesozoic Era resulted in an increase in the nutritional quality per mole of C and per cell of planktonic algal biomass compared to earlier phytoplankton. We cultured a cyanobacterium, a diatom, a dinoflagellate, and a green alga in media mimicking aspects of the chemistry of Palaeozoic and Mesozoic-Cenozoic oceans. Substantial differences emerged in the quality of algal biomass between the Palaeozoic and Mesozoic-Cenozoic growth regimes; these differences were strongly affected by interspecific interactions (i.e., the co-existence of different species alters responses to the chemistry of the medium). The change was in the direction of a Mesozoic-Cenozoic biomass enriched in protein per mole C, although cells contained less carbon overall. This would lead to a lower C:N ratio. On the assumption that Mesozoic-Cenozoic grazers' assimilation of total C was similar to that of their earlier counterparts, their diet would be stoichiometrically closer to their C:N requirement. This, along with an increase in mean cell size among continental shelf phytoplankton, could have helped to facilitate observed evolutionary changes in the Mesozoic marine fauna. In turn, increased grazing pressure would have operated as a selective force for the radiation of phytoplankton clades better equipped with antigrazing capabilities (sensu lato), as found widely in phytoplankton with biomineralization. Our results emphasize potential links between changing seawater chemistry, increased predation pressure and the rise to ecological dominance of chlorophyll a+c algae in Mesozoic oceans. The experiments also suggest a potential role for ocean chemistry in changes of marine trophic structure from the Palaeozoic to the later Mesozoic Era.


[On proportionate medical actions and extraordinary methods of treatment].
As a general rule, any medical action should be proportionated. That is, the expected benefit of the treatment provided must be commensurate to the diagnosis and prognosis, the therapeutic efforts the suffering caused to the patient, and the eventual risks. Inversely a disproportionate or excessive medical action that will result in no benefit to the patient is technically incorrect and ethically reprebensible. As opposed to ordinary methods of treatment (basic nursing, feeding, hydration, drugs and regular clinical procedures), we reserve the name of "extraordinary methods of treatment" to those medical actions using complex and invasive highcost procedures and equipment that should be urgently indicated in any critically ill patient with a potentially reversible disease. These do not have any indication in terminally ill patients, except in the case of concomitant potentially reversible acute complications. When a DNR (do not resuscitate) order is adopted it should be reassessed periodically. The use, withholding and withdrawal of these extraordinary measures of treatment are subject to a series of medical and ethical requirements, which receive full discussion in this paper.


The impact of severe stalking experienced by acutely battered women: an examination of violence, psychological symptoms and strategic responding.
Stalking has been relatively understudied compared to other dimensions of intimate partner violence. The purpose of this article was to examine concurrent and subsequent intimate partner abuse, strategic responses and symptomatic consequences of severe stalking experienced by battered women. Thirty-five battered women classified as "relentlessly stalked" and 31 infrequently stalked battered women were compared. Compared to infrequently stalked battered women, relentlessly stalked battered women reported: (a) more severe concurrent physical violence, sexual assault and emotional abuse: (b) increased post-separation assault and stalking; (c) increased rates of depression and PTSD; and (d) more extensive use of strategic responses to abuse. Results underscore the scope and magnitude of stalking faced by battered women and have implications for assessment and intervention strategies.


Functional characterization of rhodopsin monomers and dimers in detergents.
Rhodopsin (Rho) is a G protein-coupled receptor that initiates phototransduction in rod photoreceptors. High expression levels of Rho in the disc membranes of rod outer segments and the propensity of Rho to form higher oligomeric structures are evident from atomic force microscopy, transmission electron microscopy, and chemical cross-linking experiments. To explore the structural and functional properties of Rho in n-dodecyl-beta-maltoside, frequently used to purify heterologously expressed Rho and its mutants, we used gel filtration techniques, blue native gel electrophoresis, and functional assays. Here, we show that in micelles containing n-dodecyl-beta-maltoside at concentrations greater than 3 mM, Rho is present as a single monomer per detergent micelle. In contrast, in 12 mM 3-[(3-cholamidopropyl)dimethyl-ammonio]-1-propanesulfonate (CHAPS), micelles contain mostly dimeric Rho. The cognate G protein transducin (Gt) appears to have a preference for binding to the Rho dimer, and the complexes fall apart in the presence of guanosine 5'-3-O-(thio)triphosphate. Cross-linked Rho dimers release the chromophore at a slower rate than monomers and are much more resistant to heat denaturation. Both Rho(*) monomers and dimers are capable of activating Gt, and both of them are phosphorylated by Rho kinase. Rho expressed in HEK293 cells is also readily cross-linked by a bifunctional reagent. These studies provide an explanation of how detergent influences the oligomer-dimermonomer equilibrium of Rho and describe the functional characterization of Rho monomers and dimers in detergent.


The geographic scale of diversification on islands: genetic and morphological divergence at a very small spatial scale in the Mascarene grey white-eye (Aves: Zosterops borbonicus).
Oceanic islands provide unique scenarios for studying the roles of geography and ecology in driving population divergence and speciation. Assessing the relative importance of selective and neutral factors in driving population divergence is central to understanding how such divergence may lead to speciation in small oceanic islands, where opportunities for gene flow and population mixing are potentially high. Here we report a case of genetic and morphological structure in the Mascarene grey white-eye (Zosterops borbonicus) a species that shows a striking, geographically structured plumage polymorphism on the topographically and ecologically complex island of Réunion, yet is monotypic on the relatively uniform neighbouring island of Mauritius. Analysis of 276 AFLP loci in 197 individuals revealed prolonged independent evolution of Réunion and Mauritius populations, which is congruent with previous mtDNA assessments. Furthermore, populations on Réunion showed significant differentiation into three main genetic groups separating lowland from highland areas despite the small geographic distances involved. Genetic differentiation along the altitudinal gradient is consistent with morphometric analysis of fitness-related traits. Birds in the highlands were larger, yet had relatively smaller beaks than in the lowlands, suggesting the role of selection in shaping morphology and restricting gene flow along the gradient. No genetic differentiation between plumage morphs was detected in neutral markers, suggesting that plumage differences are of recent origin. Our results suggest a dual role of vicariance and natural selection in differentiating populations of a passerine bird in an oceanic island at very small spatial scales. We propose a combination of past microallopatry driven by volcanic activity and selection-constrained dispersal along steep ecological gradients to explain the striking levels of population structure found within the island, although the possibility that genetic differences evolved in situ along the gradient cannot be ruled out at present. The lack of congruence between genetic groups and plumage morphs suggests that the latter are of recent origin and likely due to social or sexual selection acting on few loci. The presence of sharp and stable contact zones between plumage morphs suggests that they could be on independent evolutionary trajectories, yet whether or not they represent incipient species will require further research to directly assess the degree of reproductive isolation among them.


Deposition of copper, iron, manganese and zinc in the empty body of growing lambs of the breed German Merino Landsheep.
A growth experiment with 108 lambs (breed: German Merino Landsheep) was carried out to examine the effect of gender, body weight (BW) and feeding intensity on the deposition of Fe, Zn, Cu and Mn in the empty body (whole animal minus contents of the gastrointestinal tract and bladder). The lambs (50% female and 50% male animals) were fed at three feeding levels ('low', 'medium' and 'high' by varying daily amounts of concentrate and hay) and slaughtered at different final BWs (30, 45 or 55 kg). Six male and six female animals were killed at a BW of 18 kg representing the animals' BW at the beginning of the comparative slaughter experiment. There were significant main effects for the treatments growth rate and final weight on the daily rate of accretion of the trace elements examined. Feeding intensity had a marked influence on the accretion rate for Fe (P < 0.001), Zn (P < 0.001), Cu (P < 0.001) and Mn (P = 0.003). With increasing feeding intensity (low, medium, high) the daily deposition of these trace elements increased (4.4, 5.2, 6.6 mg/day for Fe; 4.9, 5.5, 6.9 mg/day for Zn; 0.20, 0.36, 0.44 mg/day for Cu; 0.14, 0.16, 0.21 mg/day for Mn). Heavier final BW led to increased daily retention of Zn (P < 0.001) and Mn (P = 0.002). Gender had a marked influence only on the accretion rate for Zn (P < 0.001). Ram lambs had a higher daily deposition of this element than female lambs. Related to 1000 g empty body gain, the following concentrations were found for the trace elements examined: Fe 26.1 mg, Zn 30.0 mg, Cu 1.41 mg and Mn 1.04 mg. A feeding influence was given for Zn (P < 0.001) and Cu (P = 0.039). Feeding level low had higher Zn and lower Cu concentrations. Male animals showed less Fe (P < 0.001) and Zn (P = 0.034) per kg empty body gain than females.


Chronic anterior dislocation of the proximal interphalangeal joint.
Anterior dislocation of the proximal interphalangeal joint is a complex injury involving specific pathomechanics. Progression of this injury to a chronic stage is associated with considerable morbidity in the form of pain, instability, and loss of motion in the involved joint. Surgical reconstruction is complicated and results of delayed intervention are compromised. Two cases of anteriorly dislocated interphalangeal joints, unrecognized as such early and allowed to progress to a chronic stage, presented to us as boutonniere deformities. Descriptions of clinical presentation, surgical findings, and treatment results in these cases attest to the disabling potential of this injury. Emphasis is therefore placed on early recognition of the anteriorly dislocated proximal interphalangeal joint so that appropriate treatment can be initiated and progression to a chronic stage prevented.


Testosterone and erectile dysfunction.
Aging is associated with a decline in several important health factors in men, including libido. Serum testosterone concentrations also decrease with age, and many age-related clinical features are closely associated with androgen deficiency, including erectile function (ED). Approximately 70% of ED is of organic origin, with the major risk factors being diabetes mellitus, hypercholesterolemia, smoking and chronic medical illnesses. These are also established risk factors for atherosclerosis, which is the predominant predisposing factor of vasculogenic ED. The introduction of phosphodiasterase-5 (PDE-5) inhibitors for the treatment of ED made a significant impact both in terms of clinical efficacy, and increasing the awareness of the condition. In spite of this, some patients fail to respond to PDE-5 inhibitors alone. Both animal and clinical studies indicate that testosterone therapy improves both erectile function and the response to PDE-5 inhibitors in patients with ED and hypogonadism. Indeed, interventional studies demonstrate that testosterone replacement therapy improves erectile function in hypogonadal men who have previously failed to respond to PDE-5 inhibitors alone. Furthermore, it has been demonstrated that the full therapeutic potential of PDE5 inhibitors will only become manifest in a eugonadal state. Recent studies have demonstrated a close relationship between testosterone and ED and suggest that testosterone therapy may be a valuable option for an increasing number of affected men. European guidelines recommend that all men presenting with ED should have their testosterone concentrations measured.


Actinomycetales from corn.
Mesophilic Actinomycetales were isolated from whole corn, brewers grits, and break flour received from three different mills. In addition, strains were isolated from high-moisture (27 per cent) field corn; high-moisture, silo-stored corn (untreated); and high-moisture corn treated with ammonia, ammonium isobutyrate, or propionic-acetic acid. According to standard techniques, 139 strains were extensively characterized and 207 additional strains were partially characterized. On the basis of these characterizations, the streptomycete strains were identified by both the systems of Pridham et al. and Hütter because these systems are rapid and accurate. In general, only Streptomyces griseus (Krainsky) Waksman and Henrici was isolated from high-moisture whole corn (treated or untreated) except from grain exposed to ammonium isobutyrate. Strains isolated from high-moisture corn subjected to that treatment represented both S. griseus and S. albus (Rossi Doria) Waksman and Henrici. The strains isolated from corn and corn products from the three mills were identified with a number of streptomycete species. Of all Actinomycetales isolated, only three were not streptomycetes--two from brewer's grits and one from break flour.


Are numbers grounded in a general magnitude processing system? A functional neuroimaging meta-analysis.
It is currently debated whether numbers are processed using a number-specific system or a general magnitude processing system, also used for non-numerical magnitudes such as physical size, duration, or luminance. Activation likelihood estimation (ALE) was used to conduct the first quantitative meta-analysis of 93 empirical neuroimaging papers examining neural activation during numerical and non-numerical magnitude processing. Foci were compiled to generate probabilistic maps of activation for non-numerical magnitudes (e.g. physical size), symbolic numerical magnitudes (e.g. Arabic digits), and nonsymbolic numerical magnitudes (e.g. dot arrays). Conjunction analyses revealed overlapping activation for symbolic, nonsymbolic and non-numerical magnitudes in frontal and parietal lobes. Contrast analyses revealed specific activation in the left superior parietal lobule for symbolic numerical magnitudes. In contrast, small regions in the bilateral precuneus were specifically activated for nonsymbolic numerical magnitudes. No regions in the parietal lobes were activated for non-numerical magnitudes that were not also activated for numerical magnitudes. Therefore, numbers are processed using both a generalized magnitude system and format specific number regions.


Design of achromatic and apochromatic plastic micro-objectives.
The possibility and the efficiency of using a single diffractive lens to achromatize and apochromatize micro-objectives with plastic lenses are shown. In addition, recommendations are given on assembling the starting configurations of the objectives and calculating the design parameters required for subsequent optimization. It is also shown that achievable optical performance of achromatic and apochromatic micro-objectives with plastic lenses satisfy the qualifying standards for cell-phone objectives and closed-circuit television (CCTV) cameras.


Yield of Neuroimaging in Infant Physical Abuse Evaluations: Do Infant Age and Injury Type Matter?
Neuroimaging can be an important part of the medical workup for children with suspected physical abuse, but there are not specific guidelines on which children should undergo neuroimaging. We sought to evaluate the yield of neuroimaging in children <12 months of age who are undergoing physical abuse evaluations and to determine how the yield varied by age, injuries, and social risk factors. This was a retrospective observational study of infants who presented to an urban children's hospital between September 2007 and October 2012, were evaluated by the hospital's child abuse team, and who received skeletal surveys and underwent neuroimaging for suspected physical abuse. Infants who were diagnosed with head trauma before the abuse evaluation were excluded. Logistic regression was used to investigate the relationship between neuroimaging yield and patient age, presenting injury, and social features. Head injuries were identified in 14 of 170 infants (8.2%). The yield was similar in children <6 months of age and children ≥6 months of age (7.5% and 9.4%, respectively; p = 0.674). Infants with bruises and cases involving a delay in seeking care or cases with previous Child Protective Services involvement were more likely to have injuries identified on neuroimaging. Infants with current or past neurologic signs/symptoms were also more likely to have head injuries on neuroimaging (5/17, 29%), although most infants with abnormal neuroimaging findings did not have neurologic signs/symptoms (9/14, 64%). We found that while certain features were associated with abnormal findings on neuroimaging, infant age (<6 months vs. 6-12 months) was not.


Breathing pattern and carbon dioxide retention in severe chronic obstructive pulmonary disease.
The factors leading to chronic hypercapnia and rapid shallow breathing in patients with severe chronic obstructive pulmonary disease (COPD) are not completely understood. In this study the interrelations between chronic carbon dioxide retention, breathing pattern, dyspnoea, and the pressure required for breathing relative to inspiratory muscle strength in stable COPD patients with severe airflow obstruction were studied. Thirty patients with COPD in a clinically stable condition with forced expiratory volume in one second (FEV1) of < 1 litre were studied. In each patient the following parameters were assessed: (1) dyspnoea scale rating, (2) inspiratory muscle strength by measuring minimal pleural pressure (PPLmin), and (3) tidal volume (VT), flow, pleural pressure swing (PPLsw), total lung resistance (RL), dynamic lung elastance (ELdyn), and positive end expiratory alveolar pressure (PEEPi) during resting breathing. Arterial carbon dioxide tension (PaCO2) related directly to RL/PPLmin, and ELdyn/PPLmin, and inversely to VT and PPLmin. There was no relationship between PaCO2 and functional residual capacity (FRC), total lung capacity (TLC), or minute ventilation. PEEPi was similar in eucapnic and hypercapnic patients. Expressing PaCO2 as a combined function of VT and PPLmin (stepwise multiple regression analysis) explained 71% of the variance in PaCO2. Tidal volume was directly related to inspiratory time (TI), and TI was inversely related to the pressure required for breathing relative to inspiratory muscle strength (PPLsw, %PPLmin). There was an association between the severity of dyspnoea and both the increase in PPLsw (%PPLmin) and the shortening in TI. The results indicate that, in stable patients with COPD with severe airflow obstruction, hypercapnia is associated with shallow breathing and inspiratory muscle weakness, and rapid and shallow breathing appears to be linked to both a marked increase in the pressure required for breathing relative to inspiratory muscle strength and to the severity of the breathlessness.


Performance of the Global Diet Quality Score (GDQS) App in Predicting Nutrient Adequacy and Metabolic Risk Factors among Thai Adults.
The Global Diet Quality Score (GDQS) was developed for monitoring nutrient adequacy and diet-related noncommunicable disease risk in diverse populations. A software application (GDQS app) was recently developed for the standardized collection of GDQS data. The application involves a simplified 24-h dietary recall (24HR) where foods are matched to GDQS-food groups using an onboard database, portion sizes are estimated at the food group level using cubic models, and the GDQS is computed. The study aimed to estimate associations between GDQS scores collected using the GDQS app and nutrient adequacy and metabolic risks. In this cross-sectional study of 600 Thai males and nonpregnant/nonlactating females (40-60 y), we collected 2 d of GDQS app and paper-based 24HR, food-frequency questionnaires (FFQs), anthropometry, body composition, blood pressure, and biomarkers. Associations between application scores and outcomes were estimated using multiple regression, and application performance was compared with that of metrics scored using 24HR and FFQ data: GDQS, Minimum Dietary Diversity-Women, Alternative Healthy Eating Index-2010, and Global Dietary Recommendations score. In covariate-adjusted models, application scores were significantly (P < 0.05) associated with higher energy-adjusted mean micronutrient adequacy computed using 24HR (range in estimated mean adequacy between score quintiles 1 and 5: 36.3%-44.5%) and FFQ (Q1-Q5: 40.6%-44.2%), and probability of protein adequacy from 24HR (Q1-Q5: 63%-72.5%). Application scores were inversely associated with BMI kg/m2 (Q1-Q5: 26.3-24.9), body fat percentage (Q1-Q5: 31.7%-29.1%), diastolic blood pressure (Q1-Q5: 84-81 mm Hg), and a locally-developed sodium intake score (Q1-Q5: 27.5-24.0 points out of 100); positively associated with high-density lipoprotein cholesterol (Q1-Q5: 49-53 mg/dL) and 24-h urinary potassium (Q1-Q5: 1385-1646 mg); and inversely associated with high midupper arm circumference (Q5/Q1 odds ratio: 0.52) and abdominal obesity (Q5/Q1 odds ratio: 0.51). Significant associations for the application outnumbered those for metrics computed using 24HR or FFQ. The GDQS app effectively assesses nutrient adequacy and metabolic risk in population surveys.


Rapid single-step separation of pluripotent mouse embryonic stem cells from mouse feeder fibroblasts.
Highly enriched, pure populations of pluripotent mouse embryonic stem (mES) cells are a prerequisite to downstream experimental manipulations. However, the existing preplating method does not allow complete removal of co-cultured mouse embryonic fibroblast (MEF) feeder cells. The primary objective of the current investigation was to develop and validate a rapid, single-step separation technique for the complete removal of MEF feeder cells from mES cells. A discontinuous density gradient was prepared using Histopaque 1119 at incremental percentages from the top to bottom of a test tube (20, 40, 60, and 100% in culture medium). A suspension of mES cells and MEF feeder cells was layered on top of the gradient. After centrifugation at 400 x g, ES cells and MEF feeder cells were segregated discretely in separate layers at the 40/20% and 100/60% density interfaces, respectively. The mES cells were enriched to a purity of greater than 99% with a recovery rate of greater than 90%. The separation did not alter the viability or the differentiation potential of mES cells. This study validates a simple technique that enables the preparation of highly enriched mES cells that are essentially free of contaminating MEF feeder cells. The discontinuous density gradient separation method is inexpensive, efficient, rapid, and reproducible. The method can be readily scaled-up to accommodate large batch preparations, enabling a broad range of processing needs. Overall, this simple technique significantly expedites the recovery and enrichment of mES cells from MEFs.


Community-curated and standardised metadata of published ancient metagenomic samples with AncientMetagenomeDir.
Ancient DNA and RNA are valuable data sources for a wide range of disciplines. Within the field of ancient metagenomics, the number of published genetic datasets has risen dramatically in recent years, and tracking this data for reuse is particularly important for large-scale ecological and evolutionary studies of individual taxa and communities of both microbes and eukaryotes. AncientMetagenomeDir (archived at https://doi.org/10.5281/zenodo.3980833 ) is a collection of annotated metagenomic sample lists derived from published studies that provide basic, standardised metadata and accession numbers to allow rapid data retrieval from online repositories. These tables are community-curated and span multiple sub-disciplines to ensure adequate breadth and consensus in metadata definitions, as well as longevity of the database. Internal guidelines and automated checks facilitate compatibility with established sequence-read archives and term-ontologies, and ensure consistency and interoperability for future meta-analyses. This collection will also assist in standardising metadata reporting for future ancient metagenomic studies.


Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis.
To determine whether antibodies against peptidyl arginine deiminase type 4 (PAD-4) are present in the preclinical phase of rheumatoid arthritis (RA) and to compare the timing and extent of their appearance with those of other preclinical autoantibodies. Prediagnosis serum samples from 83 patients with RA were evaluated for the presence of anti-PAD-4 antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, and rheumatoid factor. In addition, a control cohort (n = 83) matched by age, sex, race, number of serum samples, and duration of serum storage was tested for the presence of anti-PAD-4 antibody to determine its sensitivity and specificity for the subsequent development of RA. Fifteen of 83 patients with RA (18.1%) had at least 1 prediagnosis sample positive for anti-PAD-4. One of 83 control subjects (1.2%) had at least 1 positive sample, resulting in a sensitivity and specificity of 18.1% and 98.8%, respectively, of anti-PAD-4 for the future development of RA. The mean duration of anti-PAD-4 positivity prior to clinical diagnosis was 4.67 years. Anti-PAD-4 positivity was associated with anti-CCP positivity (odds ratio 5.13 [95% confidence interval 1.07-24.5]). In subjects with prediagnosis samples that were positive for both antibodies, anti-CCP positivity predated anti-PAD-4 positivity in 9 of 13 cases (69%). Autoantibodies to PAD-4 are present during the preclinical phase of RA in a subset of patients and are associated with anti-CCP positivity. Further exploration is needed regarding the timing of appearance and disease-related effects of PAD-4 autoimmunity.


Comparative study of descendent colon rupture resistance considering traction force of rupture and total energy of rupture in rats.
To compare total energy of rupture and traction force of rupture tests within a rupture resistance study of descendent colon of rats. Twelve descendent colon segments of rats were considered to perform the study. For each one of the specimens, total energy of rupture and traction force of rupture necessary to promote colic wall burst were evaluated through the biomechanical total energy of rupture test using the Biomechanical Data Acquisition and Analysis System, version 2.0. Average, standard deviation, standard error of average and coefficient of variation were considered for analysis of results. Traction force of rupture average, standard deviation, standard error of average and coefficient of variation were 380.05 gf, 98.74, 28.5 e 25.98%, respectively while total energy of rupture presented average of 244.85 gf, standard deviation of 57.76, standard error of average of 16.67 and coefficient of variation of 23.59. Although, total energy of rupture considered a larger number of attributes to its calculation related to non-linear viscoelastic materials, such as colic wall, it presented a smaller coefficient of variation when compared to traction force of rupture, thus demonstrating to constitute a possible parameter to analyze intestinal resistance of rats.


Absence/presence calling in microarray-based CGH experiments with non-model organisms.
Structural variations in genomes are commonly studied by (micro)array-based comparative genomic hybridization. The data analysis methods to infer copy number variation in model organisms (human, mouse) are established. In principle, the procedures are based on signal ratios between test and reference samples and the order of the probe targets in the genome. These procedures are less applicable to experiments with non-model organisms, which frequently comprise non-sequenced genomes with an unknown order of probe targets. We therefore present an additional analysis approach, which does not depend on the structural information of a reference genome, and quantifies the presence or absence of a probe target in an unknown genome. The principle is that intensity values of target probes are compared with the intensities of negative-control probes and positive-control probes from a control hybridization, to determine if a probe target is absent or present. In a test, analyzing the genome content of a known bacterial strain: Staphylococcus aureus MRSA252, this approach proved to be successful, demonstrated by receiver operating characteristic area under the curve values larger than 0.9995. We show its usability in various applications, such as comparing genome content and validating next-generation sequencing reads from eukaryotic non-model organisms.


GazeR: A Package for Processing Gaze Position and Pupil Size Data.
Eye-tracking is widely used throughout the scientific community, from vision science and psycholinguistics to marketing and human-computer interaction. Surprisingly, there is little consistency and transparency in preprocessing steps, making replicability and reproducibility difficult. To increase replicability, reproducibility, and transparency, a package in R (a free and widely used statistical programming environment) called gazeR was created to read and preprocess two types of data: gaze position and pupil size. For gaze position data, gazeR has functions for reading in raw eye-tracking data, formatting it for analysis, converting from gaze coordinates to areas of interest, and binning and aggregating data. For data from pupillometry studies, the gazeR package has functions for reading in and merging multiple raw pupil data files, removing observations with too much missing data, eliminating artifacts, blink identification and interpolation, subtractive baseline correction, and binning and aggregating data. The package is open-source and freely available for download and installation: https://github.com/dmirman/gazer . We provide step-by-step analyses of data from two tasks exemplifying the package's capabilities.


The choreographed dynamics of bacterial chromosomes.
Despite decades of study, the exquisite temporal and spatial organization of bacterial chromosomes has only recently been appreciated. The direct visualization of specific chromosomal loci has revealed that bacteria condense, move and position their chromosomes in a reproducible fashion. The realization that bacterial chromosomes are actively translocated through the cell suggests the existence of specific mechanisms that direct this process. Here, we review bacterial chromosome dynamics and our understanding of the mechanisms that direct and coordinate them.


Daikenchuto increases blood flow in the superior mesenteric artery in humans: A comparison study between four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction magnetic resonance imaging and Doppler ultrasound.
Respiratory-gated four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction (4D PC-VIPR) is magnetic resonance (MR) imaging technique that enables analysis of vascular morphology and hemodynamics in a single examination using cardiac phase resolved 3D phase-contrast magnetic resonance imaging. The present study aimed to assess the usefulness of 4D PC-VIPR for the superior mesenteric artery (SMA) flowmetry before and after flow increase was induced by the herbal medicine Daikenchuto (TJ-100) by comparing it with Doppler ultrasound (DUS) as a current standard. Twenty healthy volunteers were enrolled in this prospective single-arm study. The peak cross-sectionally averaged velocity was measured by 4D PC-VIPR, peak velocity was measured by DUS, and flow volume (FV) of SMA and aorta were measured by 4D PC-VIPR and DUS 25 min before and after the peroral administration of TJ-100. The peak cross-sectionally averaged velocity, peak velocity, and FV of SMA measured by 4D PC-VIPR and DUS significantly increased after administration of TJ-100 (4D PC-VIPR: the peak cross-sectionally averaged velocity; p = 0.004, FV; p = 0.035, DUS: the peak velocity; p = 0.003, FV; p = 0.010). Furthermore, 4D PC-VIPR can analyze multiple blood vessels simultaneously. The ratio of the SMA FV to the aorta, before and after oral administration on the 4D PC-VIPR test also increased (p = 0.015). The rate of change assessed by 4D PC-VIPR and DUS were significantly correlated (the peak cross-sectionally averaged velocity and peak velocity: r = 0.650; p = 0.005, FV: r = 0.659; p = 0.004). Retrospective 4D PC-VIPR was a useful modality for morphological and hemodynamic analysis of SMA.


Experience with pilonidal disease in children.
Controversy exists regarding the optimum treatment for pediatric pilonidal disease. It is a complex disease process with a high rate of recurrence. A spectrum of surgical strategies exists, including drainage, cyst marsupialization, complete cyst and sinus tract excision with primary versus secondary closure, and excision utilizing flap closure. There is little published in the pediatric literature; therefore, we reviewed our experience in an attempt to document how various interventions affect the natural history. A retrospective review was conducted in which all patients who underwent surgical intervention for pilonidal disease at our institution from January 2000 to June 2010 were identified. Data collection included demographics, surgical procedure performed, presence of wound breakdown, presence of infection, recurrence, total procedures performed, number of follow-up visits, and total hospital days. In the study period, 120 patients were identified, and 58% were female. Mean age was 14.9 y old (1-19 y). These patients were then subdivided into closed versus open groups based on the status of their operative wound. In the closed group, 74 patients underwent excision with midline closure and 18 underwent excision with flap closure. There were 28 patients left open after excision. In the closed group, wound breakdown occurred in a total of 41 patients (45%). There was no difference in breakdown between midline and flap closure. Postoperative wound infection occurred in 15% of all patients. The midline closure group had a higher infection rate (20%) compared with those with flap closures (11%), which was not significant (P = 0.30). There was no difference in recurrence rate between patients who were primarily closed and patients who were left open (20.6% versus 25%, P = 0.51). There was also no difference in their hospital length of stay (0.44 ± 2.53 d versus 1.18 ± 2.9 d, P = 0.18). Conversely, the patients who were left open had more follow-up visits (6.48 ± 7.6 versus 4.18 ± 3.3, P = 0.02) and subsequently required more operative procedures (1.71 ± 1.12 versus 1.25 ± 0.49, P = 0.002). Management of pilonidal disease remains a complex problem, and operative intervention is fraught with complications, including wound breakdown, infection, and cyst recurrence. Primary closure appears to have better outcomes compared with healing by secondary intention. There does not appear to be a clear advantage of primary closure utilizing flaps over primary closure based on our early experience with flap closures.


A two-photon ratiometric fluorescent probe for the synergistic detection of the mitochondrial SO2/HClO crosstalk in cells and in vivo.
Known as a new member of the reactive sulphur species (RSS), endogenous sulfur dioxide (SO2) plays potentially reductive roles such as antioxidation, anti-aging, anti-inflammation, and cytoprotection; however, SO2 is also a metabolite of antioxidation. Hypochlorous acid (HClO) has powerful bio-effects on the innate immune system, and its uncontrolled production leads to adverse damage in cells. To illuminate the potential crosstalk between SO2 and HClO in redox homeostasis, we designed a two-photon ratiometric fluorescent probe for dual-response to mitochondrial SO2/HClO crosstalk in cells and in vivo. Our probe can effectively achieve ratio-type fluorescence dual-response to SO2 and HClO with desirable properties such as large two-photon absorption cross sections, rapid response times (SO2 < 50 s, HClO < 20 s), high sensitivities (limit of detection 8.0 nM for SO2 and 15.2 nM for HClO), and favorable selectivity. The probe has been successfully applied to quantitatively detect endogenous SO2 and HClO in HeLa and Raw 264.7 cells. We have verified that there exists a crosstalk between SO2 and HClO during the process of oxidative stress in mitochondria. We have also detected that SO2 can be endogenously produced through oxidation of intracellular sulfur-containing amino acids by HClO in zebrafish in real-time.


Research on diabetes management and the family: a critique.
Research on diabetes management and the family has been traditionally viewed within a linear model, in which parental attitudes toward diabetes are seen as the principal influence on the child's adjustment and metabolic control. Recently the focus of research has shifted to the broader family milieu, with an emphasis on patterns of cooperation and conflict among all family members in implementing the treatment regimen. As investigators have begun to study the entire family, the linear model of parental influences has been overshadowed by a systems model of family interaction, based on the concept of mutual influences among all individuals in the family. Several methodological problems have characterized research in this area, such as inadequate assessments of family functioning, unreliable indices of metabolic control, and insensitivity to differences in age and disease variables. Future studies of diabetes management will have much to gain from consideration of the role of the father and siblings in treatment, attention to the diabetic child's impact on family functioning, and recognition of sources of support and stress outside the family that affect adaptation to diabetes.


Enhancing effects of immunization with rectal extract on rectal carcinogenesis by local X-irradiation caused in male A/HeJ mice.
The influence of preimmunization with a rectal extract on X-irradiation rectal carcinogenesis in the rectum was investigated in male 4-7-week-old A/HeJ mice. They were given 20 Gy per week for a total 40 Gy in the pelvic region with or without 2 prior injections of rectal extract emulsified with complete Freund's adjuvant. Rectal adenocarcinomas were observed in 21 of 34 (62%) immunized animals and in 4 of 22 (18%) non-immunized mice 32 weeks after the last X-irradiation (P<0.01). The total incidences of adenocarcinomas at the 84 week time point were 25/45 (56%) and 12/36 (33%), respectively (P<0.05).