Differential expression of alternatively spliced pX mRNAs in HTLV-I-infected cell lines.
Human T cell leukemia/lymphotropic virus (HTLV) is a complex 9 kb human retrovirus with at least eight alternatively spliced mRNAs expressed from the 3' or pX region of the genome. These mRNAs allow for the expression of novel proteins from the previously recognized pX open reading frames I and II in addition to Tax, Rex and p21rex encoded from orf III and IV. These alternatively spliced messages have been detected using reverse-transcriptase polymerase chain reaction (RT/PCR) amplification in HTLV-I-transformed T cell lines as well as in peripheral blood mononuclear cells (PBMC) from infected patients with and without disease. To gain insight into the role of these alternatively spliced mRNAs in pathogenesis, we developed a semi-quantitative non-PCR-based RNase protection assay to detect and quantitate their presence in HTLV-I-infected cells. Analysis of RNA from HTLV-I-infected cells established from patients with adult T cell leukemia (ATL) as well as tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) and both IL-2-dependent and IL-2-independent HTLV-I-infected cell lines by RNase protection has confirmed the existence of all of the alternatively spliced messages in each cell line analyzed. However, the relative quantity of each message was significantly different among these lines suggesting that splice site utilization is an important viral regulatory pathway.


Fetal-to-maternal transfer of 3,3',5-triiodothyronine sulfate and its metabolite in sheep.
Earlier studies have shown that sulfoconjugation is a major pathway of thyroid hormone metabolism in fetal mammals. To assess the placental transfer of sulfoconjugates in the pregnant sheep model, we measured 3,3',5-triiodothyronine (T(3)) sulfate (T(3)S), 3, 3'-diiodothyronine sulfate (T(2)S), and T(3) concentrations in fetal serum and in maternal serum and urine after T(3)S infusion to the fetus (n = 5) or the ewe (n = 6). Maternal infusion of T(3)S did not increase fetal serum T(2)S, T(3)S, or T(3) concentrations. In contrast, fetal infusion of T(3)S produced significant increases in maternal serum T(2)S and T(3)S but not T(3) concentrations. Fetal T(3)S infusion also increased maternal urine excretion of T(3)S. However, the 4-h cumulative maternal urinary excretion of T(2)S and T(3)S after fetal T(3)S infusion was less than the excretion observed after fetal infusion of equimolar amounts of T(3) in our previous study. It is concluded that fetal serum T(2)S and T(3)S can be transferred to maternal compartments. However, compared with T(3), these sulfoconjugates may be less readily transferred.


Being a Female Veteran: A Grounded Theory of Coping With Transitions.
Female veterans, the fastest growing segment in the military, have unique pre-military histories and military experiences that are associated with post-military physical and mental health service needs. Successful treatment is contingent on a clearer understanding of the processes underlying these experiences. Data from 20 female veterans who served post-Gulf War were analyzed to generate a substantive theory of the process of women who entered, served in, and transitioned out of the military. Coping with transitions emerged as the basic psychosocial process used by female veterans. The Coping with transitions process is comprised of seven categories: Choosing the Military, Adapting to the Military, Being in the Military, Being a Female in the Military, Departing the Military, Experiencing Stressors of Being a Civilian, and Making Meaning of Being a Veteran-Civilian. The results of this study provide a theoretical description of the process female veterans experience when transitioning from a civilian identity, through military life stressors and adaptations, toward gaining a dual identity of being a veteran-civilian.


16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.
Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.


Human Oro-Nasopharyngeal Myiasis by Chrysomya Bezziana (Old-World Screwworm): The First Reported Case in Sri Lanka.
Myiasis is the invasion of mammalian tissues by dipterous larvae. Cutaneous myiasis is the commonest type, and less commonly, internal tissues and organs are affected. Here, we report the first case of oro-nasopharyngeal myiasis caused by the third-instar larvae of Chrysomya bezziana (Old-World screwworm) in Sri Lanka. A retired 71-year-old female tea-plucker presented to the hospital with a 4-day history of nasal bleeding and neck discomfort. Except for well-controlled hypertension, she had no significant medical history. On examination, there was an ulcerated area in the posterior oro-nasopharynx filled with maggots. Hematological analysis showed a high C-reactive protein level (24 mg/dL) and white blood cell count (17.5 × 109/L) with 80% neutrophils. Computed tomography showed severe inflammation of the pharynx with no features of a neoplasm or parapharyngeal abscess. An examination was performed under anesthesia followed by manual removal of larvae, surgical debridement with biopsy, and treatment with antiparasitic medicines and antibiotics. Histopathology excluded neoplasm and only showed inflammatory changes. All extracted larvae were morphologically similar and identified as third-instar larvae of C. bezziana using a trinocular zoom stereomicroscope. The patient recovered and was discharged from the hospital on the 15th day and was well at 2 months follow-up.


Achieving Extreme Light Intensities using Optically Curved Relativistic Plasma Mirrors.
This Letter proposes a realistic implementation of the curved relativistic mirror concept to reach unprecedented light intensities in experiments. The scheme is based on relativistic plasma mirrors that are optically curved by laser radiation pressure. Its validity is supported by cutting-edge three-dimensional particle-in-cell simulations and a theoretical model, which show that intensities above 10^{25} W cm^{-2} could be reached with a 3 PetaWatt (PW) laser. Its very high robustness to laser and plasma imperfections is shown to surpass all previous schemes and should enable its implementation on existing PW laser facilities.


[Randomised trial of acupuncture compared with conventional massage and "sham" laser acupuncture for treatment of chronic neck pain - range of motion analysis].
The aim of this study was to compare the effects of acupuncture on active motion of the cervical spine in patients with chronic neck pain with those of "sham" laser acupuncture and massage. 177 patients with chronic neck pain were included in this prospective, randomized, placebo-controlled study. The patients were allocated by external randomization to five treatments over three weeks with acupuncture, massage and "sham" laser acupuncture. The range of active motion was measured by means of a 3D ultrasound real time motion analyzer. The analysis of cervical motion in three directions showed the largest increase in range of motion 14 days after acupuncture. Compared to massage, a significant improvement in total range of motion was seen in those patients treated by acupuncture immediately (p = 0,03) and one week (p = 0,03) weeks after therapy. There was no significant difference in those patients treated by sham laser acupuncture. The results of the study indicate that acupuncture is superior to conventional massage for improving active range of motion in patients with chronic neck pain. Because of its positive effects, its acceptance among patients and the lack of severe side effects, acupuncture can be recommended for the treatment of chronic neck pain, although there was no significant difference in results between "sham" laser acupuncture and acupuncture.


Slow speech rate effects on stuttering preschoolers with disordered phonology.
To study the effects of clinicians' slow rate on the speech of children who stutter with and without a concomitant phonological disorder, an A-B-A-B single case design was used with six clinician-child dyads, where B = Clinician's slow speech rate model. Two boys and one girl, aged 49-54 months, stuttering with disordered phonology (S + DP), were compared to three boys aged 42-50 months, stuttering with normal phonology (S + NP). Articulation rates were measured in phones per second (pps) in clinician-child adjacent utterance pairs. The S + NP dyads showed improved fluency in the B condition through a larger effect size, higher mean baseline stutter reductions and lower percentages of non-overlapping data than did the S + DP dyads. The S + DP girl showed relatively improved fluency in the B condition. S + DP children showed no articulation rate alignment (Range: 16% decrease to a 1.2% increase), whereas S + NP children averaged a 20% pps rate reduction (Range: 19.6-25.4% decrease), aligning with their clinicians who averaged a 38% pps rate reduction from baseline. The S + DP group spoke significantly (z = -4.63; p < 0.00) slower at baseline (Mdn = 6.9 pps; SE = 0.07 pps) than S + NP children in previously published samples (Mdn = 9.8 pps; SE = 0.22 pps). Results suggest that a slow rate model alone is not effective for facilitating fluency in S + DP boys with time since onset of about 2 years.


Granulocyte-Colony Stimulating Factor Receptor, Tissue Factor, and VEGF-R Bound VEGF in Human Breast Cancer In Loco.
Doxorubicin and docetaxel-based chemotherapy regimens used in breast cancer patients are associated with high risk of febrile neutropenia (FN). Granulocyte colony-stimulating factors (G-CSF) are recommended for both treating and preventing chemotherapy-induced neutropenia. Increased thrombosis incidence in G-CSF treated patients was reported; however, the underlying mechanisms remain unclear. The principal activator of blood coagulation in cancer is tissue factor (TF). It additionally contributes to cancer progression and stimulates angiogenesis. The main proangiogenic factor is vascular endothelial growth factor (VEGF). The aim of the study was to evaluate granulocyte-colony stimulating factor receptor (G-CSFR), tissue factor (TF) expression and vascular endothelial growth factor receptor (VEGF-R) bound VEGF in human breast cancer in loco. G-CSFR, TF and VEGFR bound VEGF (VEGF: VEGFR) were assessed in 28 breast cancer tissue samples. Immunohistochemical (IHC) methodologies according to ABC technique and double staining IHC procedure were employed utilizing antibodies against G-CSFR, TF and VEGF associated with VEGFR (VEGF: VEGFR). Expression of G-CSFR was demonstrated in 20 breast cancer tissue specimens (71%). In 6 cases (21%) the expression was strong (IRS 9-12). Strong expression of TF was observed in all investigated cases (100%). Moreover, expression of VEGF: VEGFR was visualized in cancer cells (IRS 5-8). No presence of G-CSFR, TF or VEGF: VEGFR was detected on healthy breast cells. Double staining IHC studies revealed co-localization of G-CSFR and TF, G-CSFR and VEGF: VEGFR, as well as TF and VEGF: VEGFR on breast cancer cells and ECs. The results of the study indicate that GCSFR, TF and VEGF: VEGFR expression as well as their co-expression might influence breast cancer biology, and may increase thromboembolic adverse events incidence.


Sex: differences in mutation, recombination, selection, gene flow, and genetic drift.
In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear gene- and organism-specific. When there is recombination in only one sex, it is always the homogametic sex. When there is recombination in both sexes, females often have higher recombination but there are many exceptions. There are a number of hypotheses to explain the sex differences in recombination. Sex-specific differences in selection may result in stable polymorphisms or for sex chromosomes, faster evolutionary change. In addition, sex-dependent selection may result in antagonistic pleiotropy or sexually antagonistic genes. There are many examples of sex-specific differences in gene flow (dispersal) and a number of adaptive explanations for these differences. The overall effective population size (genetic drift) is dominated by the lower sex-specific effective population size. The mean of the mutation, recombination, and gene flow rates over the two sexes can be used in a population genetics context unless there are sex-specific differences in selection or genetic drift. Sex-specific differences in these evolutionary factors appear to be unrelated to each other. The evolutionary explanations for sex-specific differences for each factor are multifaceted and, in addition, explanations may include chance, nonadaptive differences, or mechanistic, nonevolutionary factors.


Predictive performance of gentamicin dosing nomograms.
Several nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients. Gentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with "other" infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated. Gentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%-72.3% vs 4.3%-45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients. Gentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.


Patient Perceptions of Video Visits Using Veterans Affairs Telehealth Tablets: Survey Study.
Video-based health care can help address access gaps for patients and is rapidly being offered by health care organizations. However, patients who lack access to technology may be left behind in these initiatives. In 2016, the US Department of Veterans Affairs (VA) began distributing video-enabled tablets to provide video visits to veterans with health care access barriers. This study aimed to evaluate veterans' experiences with VA-issued tablets and identify patient characteristics associated with preferences for video visits vs in-person care. A baseline survey was sent to the tablet recipients, and a follow-up survey was sent to the respondents 3 to 6 months later. Multivariate logistic regression was used to identify patient characteristics associated with preferences for care, and we examined qualitative themes around care preferences using standard content analysis methods for coding the data collected in the open-ended questions. Patient-reported access barriers centered around transportation and health-related challenges, outside commitments, and feeling uncomfortable or uneasy at the VA. Satisfaction with the tablet program was high, and in the follow-up survey, approximately two-thirds of tablet recipients preferred care via a tablet (194/604, 32.1%) or expressed that video-based and in-person care were "about the same" (216/604, 35.7%), whereas one-third (192/604, 31.7%) indicated a preference for in-person care. Patients were significantly more likely to report a preference for video visits (vs a preference for in-person visits or rating them "about the same") if they felt uncomfortable in a VA setting, reported a collaborative communication style with their doctor, had a substance use disorder diagnosis, or lived in a place with better broadband coverage. Patients were less likely to report a preference for video visits if they had more chronic conditions. Qualitative analyses identified four themes related to preferences for video-based care: perceived improvements in access to care, perceived differential quality of care, feasibility of obtaining necessary care, and technology-related challenges. Many recipients of VA-issued tablets report that video care is equivalent to or preferred to in-person care. Results may inform efforts to identify good candidates for virtual care and interventions to support individuals who experience technical challenges.


Role of macrophage phospholipase D in natural and CpG-induced antimycobacterial activity.
The present study addresses the differential ability of macrophages to control intracellular growth of non-pathogenic Mycobacterium smegmatis (Msm) and pathogenic M. tuberculosis (MTB). Results reported herein show that 3 h post infection, intracellular Msm, but not MTB, was significantly killed by macrophages. As the role of human macrophage phospholipase D (PLD) in the activation of antimicrobial mechanisms has been documented, we hypothesised the role of such enzyme in antimycobacterial mechanisms. To this aim, macrophage PLD activity was analysed at different times after exposure with either pathogenic MTB or non-pathogenic Msm. Results showed that, starting from 15 min after mycobacterial exposure, MTB did not induce macrophage PLD activity, whereas the environmental non-pathogenic Msm stably increased it. The direct contribution of PLD in intracellular mycobacterial killing was also analysed by inhibiting enzymatic activity with ethanol or calphostin C. Results show that PLD inhibition significantly increases intracellular Msm replication. In order to see whether the innate PLD-mediated antimicrobial mechanisms against MTB are also induced after CpG ODN stimulation, the role of PLD has been analysed in the course of CpG-mediated intracellular MTB killing. CpG DNA increased PLD activity in both uninfected and MTB-infected macrophages, and the inhibition of PLD activity resulted in a significant reduction of CpG-induced MTB killing. Taken together, our data suggest a relationship between host PLD activation and the macrophage ability to control intracellular mycobacterial growth.


Self-Reported Engagement in a Drug Prevention Program: Individual and Classroom Effects on Proximal and Behavioral Outcomes.
Numerous studies emphasize the role of student engagement in academic learning and performance. Less known is whether engagement plays a role in drug prevention program outcomes. We examined a self-report measure of engagement as part of the All Stars Core drug prevention program evaluation, assessing its impact on target risk mechanisms and behavioral outcomes. Students completed pretests just prior to and posttests just after completing the intervention. Surveys assessed demographics, proximal intervening measures (i.e., commitments to avoid substance use and antisocial behavior, perceived lifestyle incongruence with substance use and antisocial behavior, normative beliefs about substance use and antisocial behavior, and parental attentiveness), and distal outcome measures of alcohol, cigarette use, and antisocial behaviors. A brief 6-item posttest measure including items tapping the students' perspective on the quality of teaching the program material and their level of engagement with the program was internally consistent (α = .79). Multi-level analyses positing engagement effects at both the classroom- and individual-level indicated that classroom average engagement was significantly associated with all the targeted risk mechanisms, and outcomes of antisocial behavior and alcohol use, controlling for pretest measures and classroom size. Individual student engagement relative to classroom peers was significantly associated with all posttest target risk mechanisms and behavioral outcomes. The current findings suggest that students should routinely provide assessments of engagement and perceived quality of teaching, which would improve our understanding of how prevention programs work. Teachers can improve engagement by paying attention to students when they speak in class, making the program enjoyable to participants, encouraging students to share opinions, stimulating attentiveness, being well prepared to deliver the intervention, and helping students think broadly about implications of drug prevention as it affects their lives. This type of support will ultimately engage students in ways that will enhance the likelihood that these programs will have their desired effects.


The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork.
Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.


[Pupilography in early diagnosis of primary open-angle glaucoma].
The pupil reactions in young subjects with emmetropic and myopic refraction, in normal subjects aged over 40, and in patients with primary open-angle glaucoma (POAG) are analyzed in relation to the trophic changes in the iris and functional activity of the ciliary muscle. These processes course in parallel with each other, but in POAG the changes in the pupil reaction are preceded by dystrophy of the iris and ciliary body, which is due to a slower conduction of pulses via the conduction routes. This permits the use of pupilography for early diagnosis of POAG.


Chronic insomnia: clinical and research challenges--an agenda.
Chronic insomnia afflicts up to 10% of the population in Western industrialized countries. It is characterized by delayed sleep onset, problems in maintaining sleep, early morning awakening or the feeling of non-restorative sleep coupled with significant daytime impairments on an emotional, social or professional level. It can occur as a co-morbid condition in any other medical or mental disorder, but also as a primary condition. Within the last decade new diagnostic and differential diagnostic approaches have been suggested that enhance diagnostic precision. Epidemiological data and data relating to the health care and cost situation of chronic insomnia suggest a huge burden for society. Chronic insomnia leads to a clear-cut increased risk for psychopathology (i. e., affective disorders) and probably also for cardiovascular and metabolic dysfunction. The pathophysiology of the condition is still poorly understood and will profit from integrating modern neuroscientific approaches (animal studies, molecular biology, neuroimaging, neurophysiology, etc.). Current treatment strategies are mainly based on cognitive behavioural interventions (CBT-I) and hypnotic treatment with benzodiazepine receptor agonists and sedating antidepressants. Although the effectiveness of these treatments has been clearly demonstrated, a substantial proportion of patients proves to be treatment-resistant or profits only poorly. The question of long-term pharmaceutical treatment of chronic insomnia, at least in Europe, is unresolved and urgently needs answers. Novel rational treatment avenues require clues on causes and mechanisms from integrated neuroscientific approaches. The important issues concerning insomnia treatment in the future especially in Europe will be reviewed and discussed critically.


Identification of protein kinases responsible for phosphorylation of Epstein-Barr virus nuclear antigen leader protein at serine-35, which regulates its coactivator function.
Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is a phosphoprotein suggested to play important roles in EBV-induced immortalization. Earlier studies have shown that the major site of phosphorylation of EBNA-LP by cellular kinase(s) is a serine residue at position 35 (Ser-35) and that the phosphorylation of Ser-35 is critical for regulation of the coactivator function of EBNA-LP (Yokoyama et al., J Virol 75, 5119-5128, 2001). In the present study, we have attempted to identify protein kinase(s) responsible for the phosphorylation of EBNA-LP at Ser-35. A purified chimeric protein consisting of glutathione S-transferase (GST) fused to a domain of EBNA-LP containing Ser-35 was found to be specifically phosphorylated by purified cdc2 in vitro, while GST fused to a mutated domain of EBNA-LP in which Ser-35 was replaced with alanine was not. In addition, overexpression of cdc2 in mammalian cells caused a significant increase in the phosphorylation of EBNA-LP, while this increased phosphorylation was eliminated if Ser-35 of EBNA-LP was replaced with alanine. These results indicate that the cellular protein kinase cdc2 mediates the phosphorylation of EBNA-LP at Ser-35. Recently, we reported that cdc2 and conserved protein kinases encoded by herpesviruses phosphorylate the same amino acid residue of target proteins (Kawaguchi et al., J Virol 77, 2359-2368, 2003). Consistent with this, the EBV-encoded conserved protein kinase BGLF4 specifically mediated the phosphorylation of EBNA-LP at Ser-35. These results indicate that the coactivator function of EBNA-LP can be regulated by the activity of these cellular and viral protein kinases.


Colonial nervous control of lophophore retraction in cheilostome Bryozoa.
Nervous impulses causing lophophore retraction over large areas of Membranipora membranacea and Electra pilosa were recorded with external electrodes. The response propagates at about 100 centimeters per second, presumably through the colonial nerve plexus of Hiller and Lutaud. Impulses are rapid up to 200 per second. A second impulse was recorded from individual zooids, probably generated by the polypide's nervous system. The retractor muscle shortens at more than 20 times its own length per second and is apparently the most rapidly contracting muscle known.


Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.
Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.


Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium).
The results of class prediction and the determination of prognostic markers in diffuse large B-cell lymphoma (DLBCL) have been variably reported. Apart from biological variations, this may be caused by differences in laboratory techniques, scoring definitions and inter- and intra-observer variation. In this study, an international collaboration of clinical lymphoma research groups has concentrated on validation and standardisation of immunohistochemistry of the currently potentially interesting prognostic markers in DLBCL. Sections of a tissue microarray with 36 cases of DLBCL were stained in eight laboratories with antibodies to CD20, CD5, bcl-2, bcl-6, CD10, HLA-DR, MUM-1 and Ki-67 according to local methods. The study was performed in two rounds, firstly focused on the evaluation of laboratory staining variation, and secondly on the scoring variation. Different techniques resulted in highly variable results and poor reproducibility for almost all markers. Reproducibility of the nuclear markers was highly sensitive to technical variations, including immunological enhancement techniques (agreements 34%). With elimination of variation due to staining and uniformly agreed on scoring criteria, significant improvement was seen; however less so for bcl-6 and Ki-67 (agreement 53-58%). Absence of internal controls that preclude scoring, significantly influenced the results for CD10 and bcl-6. Semi-quantitative immunohistochemistry for subclassification of DLBCL is feasible, but with varying rates of concordance for different markers and only using optimised techniques and strict scoring criteria. These findings may explain the wide variation in prognostic impact reported in the literature. Harmonisation of techniques and centralised consensus review appears mandatory when using immunohistochemical biomarkers for treatment stratification.


Retrospective Analysis of Official Data on Anthrax in Europe with a Special Reference to Ukraine.
Anthrax is an acute infectious zoonotic disease caused by Bacillus anthracis that mostly affects grazing livestock and wildlife. Furthermore, B. anthracis is considered one of the most important biological agents of bioterrorism that could also be potentially misused in biological weapons. The distribution of anthrax in domestic animals and wildlife in Europe with a particular focus on Ukraine as a country of war was analyzed. Between 2005 and 2022, 267 anthrax cases were registered at the World Organization of Animal Health (WOAH) in animals in Europe, including 251 cases in domestic animals and 16 in wildlife. The highest numbers of cases were recorded in 2005 and 2016 followed by 2008, and the highest numbers of registered cases were reported from Albania, Russia, and Italy. In Ukraine, anthrax is currently a sporadic infection. Since 2007, 28 notifications were registered, with isolates mainly from soil samples. The highest number of confirmed anthrax cases was registered in 2018, and Odesa, which is close to Moldova, had the highest number of cases, followed by the Cherkasy region. The presence of thousands of biothermal pits and burial grounds of fallen cattle nationwide favors the re-emergence of new foci. Most confirmed cases were in cattle; however, single cases were confirmed in dogs, horses, and pigs. Further investigation of the disease in wildlife and in environmental samples is needed. The genetic analysis of isolates, investigation of susceptibility to antimicrobial compounds, and determination of virulence and pathogenicity factors are required in this volatile region of the world for awareness raising and preparedness.


Identifying a Upper-Limb Phase-Dependent Variable under Perturbations for Powered Prosthesis Arm Control.
This paper investigates upper-limb kinematic reaching responses during a mechanical perturbation to understand interjoint arm coordination used towards powered prosthesis control development. Common prosthesis arm controllers use electromyography sensors with data-driven models to decode muscle activation signals in controlling prosthesis joint movements. However, these control approaches produce non-natural, discrete movements with no guarantee the controller can react to unexpected disturbances during continuous task motion. Determining a continuous phase-dependent variable for measuring a human's progression during reaching can derive a time-invariant kinematic function to control the prosthesis joint in a natural, continuous manner. A perturbation experimental study was conducted across three participants in evaluating the shoulder and elbow joint kinematics to examine the existence of a phase shift during reaching. Experimental results demonstrated the effects of arm proximal-distal interjoint coordination that validated the proposed mechanical phase variable of the shoulder used in parameterizing elbow joint kinematic for reaching. This could allow for a continuous phase-based control strategy that can handle disturbances to achieve arm reaching in prosthesis control.


The Causal Association between Alcohol, Smoking, Coffee Consumption, and the Risk of Arthritis: A Meta-Analysis of Mendelian Randomization Studies.
Objective: To evaluate the genetic causality between alcohol intake, smoking, coffee consumption, and arthritis. Methods: Mendelian randomization (MR) studies with alcohol, smoking, and coffee consumption behaviors as exposures, and osteoarthritis (OA) and rheumatoid arthritis (RA) as outcomes were retrieved from up to July 2023. Two researchers with relevant professional backgrounds independently assessed the quality and extracted data from the included studies. Meanwhile, we applied MR analyses of four lifestyle exposures and five arthritis outcomes (two for OA and three for RA) with gene-wide association study (GWAS) data that were different from the included studies, and the results were also included in the meta-analysis. Statistical analyses were performed using Stata 16.0 and R software version 4.3.1. Results: A total of 84 studies were assessed. Of these, 11 were selected for meta-analysis. As a whole, the included studies were considered to be at a low risk of bias and were of high quality. Results of the meta-analysis showed no significant genetic causality between alcohol intake and arthritis (odds ratio (OR): 1.02 (0.94-1.11)). Smoking and arthritis had a positive genetic causal association (OR: 1.44 (1.27-1.64)) with both OA (1.44 (1.22-1.71)) and RA (1.37 (1.26-1.50)). Coffee consumption and arthritis also had a positive genetic causal association (OR: 1.02 (1.01-1.03)). Results from the subgroup analysis showed a positive genetic causality between coffee consumption and both OA (OR: 1.02 (1.00-1.03)) and RA (OR: 1.56 (1.19-2.05)). Conclusion: There is positive genetic causality between smoking and coffee consumption and arthritis (OA and RA), while there is insufficient evidence for genetic causality between alcohol intake and arthritis.


Ultrasonographic study of initial size and postnatal growth of kidneys in preterm infants.
Preterm birth is known to be associated with risks of impaired nephrogenesis. To determine the normal range of renal sizes at birth in preterm infants as well as their short-term postnatal renal growth, to assess the correlation between initial renal size and growth parameters at birth and to compare the initial and serial renal sizes between appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) preterm infants. Initial ultrasonography (US) was prospectively performed in 125 preterm infants within the first 72 h of life and every 2 weeks thereafter until a postmenstrual age (PMA) of 37 weeks was reached. Correlation between renal size and growth parameters was investigated. Renal lengths of AGA and SGA preterm infants were compared with those of age-matched fetuses described in the literature. The renal sizes at birth in preterm infants are presented. Multiple regression analysis showed the strongest correlation between initial renal size and birth weight (p < 0.0001). Initial renal lengths of AGA infants were not significantly different from those of age-matched fetuses at ≥30 weeks' gestational age (GA), whereas those of SGA infants were significantly smaller at ≥28 weeks' GA. Serial renal lengths of SGA infants were significantly smaller than fetal renal lengths at ≥30 weeks' GA. With US, the normal range of initial renal sizes of AGA preterm infants was defined according to GA. In contrast to AGA infants, SGA infants showed smaller initial renal sizes and no significant catch-up growth until a PMA of 37 weeks.


Modeling the Role of Contour Integration in Visual Inference.
Under difficult viewing conditions, the brain's visual system uses a variety of recurrent modulatory mechanisms to augment feedforward processing. One resulting phenomenon is contour integration, which occurs in the primary visual (V1) cortex and strengthens neural responses to edges if they belong to a larger smooth contour. Computational models have contributed to an understanding of the circuit mechanisms of contour integration, but less is known about its role in visual perception. To address this gap, we embedded a biologically grounded model of contour integration in a task-driven artificial neural network and trained it using a gradient-descent variant. We used this model to explore how brain-like contour integration may be optimized for high-level visual objectives as well as its potential roles in perception. When the model was trained to detect contours in a background of random edges, a task commonly used to examine contour integration in the brain, it closely mirrored the brain in terms of behavior, neural responses, and lateral connection patterns. When trained on natural images, the model enhanced weaker contours and distinguished whether two points lay on the same versus different contours. The model learned robust features that generalized well to out-of-training-distribution stimuli. Surprisingly, and in contrast with the synthetic task, a parameter-matched control network without recurrence performed the same as or better than the model on the natural-image tasks. Thus, a contour integration mechanism is not essential to perform these more naturalistic contour-related tasks. Finally, the best performance in all tasks was achieved by a modified contour integration model that did not distinguish between excitatory and inhibitory neurons.


The psychophysiology of anxiety disorder: fear memory imagery.
Psychophysiological response to fear memory imagery was assessed in specific phobia, social anxiety disorder, panic disorder with agoraphobia, post-traumatic stress disorder (PTSD), and healthy controls. Heart rate, skin conductance, and corrugator muscle were recorded as participants responded to tone cues signaling previously memorized descriptor sentences. Image contents included personal fears, social fears, fears of physical danger, and neutral (low arousal) scenes. Reactions to acoustic startle probes (eyeblink) were assessed during recall imagery and nonsignal periods. Participants were significantly more reactive (in physiology and report of affect) to fear than neutral cues. Panic and PTSD patients were, however, less physiologically responsive than specific phobics and the socially anxious. Panic and PTSD patients also reported the most anxiety and mood symptoms, and were most frequently comorbidly depressed. Overall, physiological reactivity to sentence memory cues was greatest in patients with focal fear of specific objects or events, and reduced in patients characterized by generalized, high negative affect.


Holistic approach to chemical degradation of Nafion membranes in fuel cells: modelling and predictions.
The state of health of polyfluorinated sulfonic-acid ionomer membranes (e.g. Nafion®) in low-temperature proton exchange membrane fuel cells (LT-PEMFCs) is negatively influenced by degradation phenomena occurring during their operation. As a consequence, the performance and durability of the membrane are decreased. In this article, we focus on simulating and predicting chemical membrane degradation phenomena using a holistic zero-dimensional kinetic framework. The knowledge of chemical degradation mechanisms is widely spread. We have collected and evaluated an extensive set of chemical mechanisms to achieve a holistic approach. This yields a set of 23 coupled chemical equations, which provide the whole cause and effect chain of chemical degradation in LT-PEMFCs (based on the Fenton reaction between Fe2+ and H2O2via the attack of hydroxyl radicals on the membrane, loss of ionomer moieties and emission of fluoride). Our kinetic framework allows the reproduction of experimentally accessible data such as fluoride emission rates and concentrations of ionomer moieties (from both in situ and ex situ tests). We present an approach, which allows estimations of the membrane lifetime based on fluoride emission rates. In addition, we outline the demetallation of Fe-N-C catalysts as a source of additional harmful iron species, which accelerate chemical membrane degradation. To demonstrate the expandability and versatility of the kinetic framework, a set of five chemical equations describing the radical scavenging properties of cerium agents is coupled to the main framework and its influence on membrane degradation is analysed. An automated solving routine for the system of coupled chemical equations on the basis of the chemical kinetic simulation tool COPASI has been developed and is freely accessible online ().


Purification and properties of the gp340 component of Epstein-Barr virus membrane antigen in an immunogenic form.
Preparative SDS-polyacrylamide gel electrophoresis has been used in the purification of the gp340 component of Epstein-Barr (EB) virus-determined membrane antigen (MA), in tractable quantities, from the B95-8 marmoset lymphoblastoid cell line. Successful renaturation of the purified molecule was achieved. This procedure gave a 50-fold increase in the recovery of antigen compared to conventional techniques. The data suggest that the antigenic sites recognized by human sera containing antibodies to MA are largely confined to the protein portion of the molecule. An eightfold improvement in the yield of gp340 was obtained when B95-8 cells were cultured in the presence of 12-O-tetradecanoyl-phorbol-13-acetate. Gel filtration studies indicate that the major polypeptide components of MA are not associated in detergent solution. Immunization of rabbits with purified and renatured gp340 resulted in the generation of high-titre antisera which were specific for gp340, demonstrating that antigen prepared by this procedure is suitable for further evaluation as an experimental vaccine against EB virus infection.


Changes of lymphocyte populations in pediatric steroid-sensitive nephrotic syndrome are more pronounced in remission than in relapse.
Although clinical and immunological findings in steroid-sensitive nephrotic syndrome (SSNS) favor an immunopathogenesis, many issues remain unsolved. Comprehensive studies analyzing cellular and humoral immunity in SSNS are scarce, and few studies addressed the effect of steroids on immunological factors. We therefore performed a cross-sectional study of T and B lymphocyte populations in 89 children during the different stages of the disease and related the findings to parameters of humoral immunity and treatment with steroids. In untreated relapse, an increase in the proportion of activated CD3+ lymphocytes with a concomitant reduction of CD19+ B cells was noted compared to healthy controls. Conversely, patients with steroid dependency, relapsing on alternate-day steroids, showed a decline of the absolute numbers as well as proportion of CD4+ lymphocytes but a relative increase in CD19+ B cells, compared to healthy controls. Also untreated remission was characterized by an absolute and relative decrease in CD4+ lymphocytes compared to healthy controls which was accompanied by a significant increase in the proportion of CD8+ and also activated CD3+ lymphocytes. Steroid-induced remission resulted in suppression of absolute and relative CD4+, while absolute and relative B cells were upregulated in this group compared to untreated remission. Alterations of lymphocyte populations in SSNS are not limited to relapse but seem to be more pronounced in remission and show a different profile with steroid treatment. Changes of lymphocyte populations do not only affect T but also B lymphocytes, which may be of relevance in the pathogenesis of this disorder.


Observing Grasping Actions Directed to Emotion-Laden Objects: Effects upon Corticospinal Excitability.
The motor system is recruited whenever one executes an action as well as when one observes the same action being executed by others. Although it is well established that emotion modulates the motor system, the effect of observing other individuals acting in an emotional context is particularly elusive. The main aim of this study was to investigate the effect induced by the observation of grasping directed to emotion-laden objects upon corticospinal excitability (CSE). Participants classified video-clips depicting the right-hand of an actor grasping emotion-laden objects. Twenty video-clips differing in terms of valence but balanced in arousal level were selected. Motor evoked potentials (MEPs) were then recorded from the first dorsal interosseous using transcranial magnetic stimulation (TMS) while the participants observed the selected emotional video-clips. During the video-clip presentation, TMS pulses were randomly applied at one of two different time points of grasping: (1) maximum grip aperture, and (2) object contact time. CSE was higher during the observation of grasping directed to unpleasant objects compared to pleasant ones. These results indicate that when someone observes an action of grasping directed to emotion-laden objects, the effect of the object valence promotes a specific modulation over the motor system.


Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates.
A better understanding of the mechanisms employed by HIV-1 to escape immune responses still represents one of the major tasks required for the development of novel therapeutic approaches targeting a disease still lacking a definitive cure. Host innate immune responses against HIV-1 are key in the early phases of the infection as they could prevent the development and the establishment of two hallmarks of the infection: chronic inflammation and viral reservoirs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to a family of transmembrane proteins able to dampen host immune responses and set appropriate immune activation thresholds upon ligation with their natural ligands, the sialylated carbohydrates. This immune-modulatory function is also targeted by many pathogens that have evolved to express sialic acids on their surface in order to escape host immune responses. HIV-1 envelope glycoprotein 120 (gp120) is extensively covered by carbohydrates playing active roles in life cycle of the virus. Indeed, besides forming a protecting shield from antibody recognition, this coat of N-linked glycans interferes with the folding of viral glycoproteins and enhances virus infectivity. In particular, the sialic acid residues present on gp120 can bind Siglec-7 on natural killer and monocytes/macrophages and Siglec-1 on monocytes/macrophages and dendritic cells. The interactions between these two members of the Siglec family and the sialylated glycans present on HIV-1 envelope either induce or increase HIV-1 entry in conventional and unconventional target cells, thus contributing to viral dissemination and disease progression. In this review, we address the impact of Siglecs in the pathogenesis of HIV-1 infection and discuss how they could be employed as clinic and therapeutic targets.


Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer's disease.
One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid β (Aβ) plaques. While Aβ has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Aβ plaque pathology manifests itself upon aggregation of distinct Aβ peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the Aβ aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Aβ species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix-assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - matrix-assisted laser desorption/ionization imaging mass spectrometry - that allows for delineating Aβ aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long Aβ (Aβ1-42). Plaque maturation was found to be characterized by a relative increase in deposition of Aβ1-40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C-terminally truncated Aβ species (Aβ1-38 and Aβ1-39) exhibited a similar aggregation pattern as Aβ1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Aβ1-42; a process that is followed by plaque maturation upon deposition of Aβ1-40 as well as deposition of other C-terminally modified Aβ species.


Expansion of a Telomeric FLO/ALS-Like Sequence Gene Family in Saccharomycopsis fermentans.
Non-Saccharomyces species have been recognized for their beneficial contribution to fermented food and beverages based on their volatile compound formation and their ability to ferment glucose into ethanol. At the end of fermentation brewer's yeast flocculate which provides an easy means of separation of yeasts from green beer. Flocculation in Saccharomyces cerevisiae requires a set of flocculation genes. These FLO-genes, FLO1, FLO5, FLO9, FLO10, and FLO11, are located at telomeres and transcription of these adhesins is regulated by Flo8 and Mss11. Here, we show that Saccharomycopsis fermentans, an ascomycete yeast distantly related to S. cerevisiae, possesses a very large FLO/ALS-like Sequence (FAS) family encompassing 34 genes. Fas proteins are variable in size and divergent in sequence and show similarity to the Flo1/5/9 family. Fas proteins show the general build with a signal peptide, an N-terminal carbohydrate binding PA14 domain, a central region differing by the number of repeats and a C-terminus with a consensus sequence for GPI-anchor attachment. Like FLO genes in S. cerevisiae, FAS genes are mostly telomeric with several paralogs at each telomere. We term such genes that share evolutionary conserved telomere localization "telologs" and provide several other examples. Adhesin expression in S. cerevisiae and filamentation in Candida albicans is regulated by Flo8 and Mss11. In Saccharomycopsis we identified only a single protein with similarity to Flo8 based on sequence similarity and the presence of a LisH domain.


Non-isoplethic measurement on the solid-liquid-vapor equilibrium of binary mixtures at cryogenic temperatures.
We measured the solid-liquid-vapor (SLV) equilibrium of binary mixtures during experiments that alternated between cooling the mixture and injecting the more-volatile component into the sample chamber; thus, the composition of the mixture changed (non-isoplethic) throughout the experiment. Four binary mixtures were used in the experiments to represent mixtures with miscible solid phases (N2/CO) and barely miscible solid solutions (N2/C2H6), as well as mixtures with intermediate solid miscibility (N2/CH4 and CO/CH4). We measured new SLV pressure data for the binary mixtures, except for N2/CH4, which are also available in the literature for verification in this work. While these mixtures are of great interest in planetary science and cryogenics, the resulting pressure data are also needed for modeling purposes. We found the results for N2/CH4 to be consistent with the literature. The resulting new SLV curve for CO/CH4 shows similarities to N2/CH4. Both have two density inversion points (bracketing the temperature range where the solid floats). This result is important for places such as Pluto, Triton, and Titan, where these mixtures exist in vapor, liquid, and solid phases. Based on our experiments, the presence of a eutectic is unlikely for the N2/CH4 and CO/CH4 systems. An azeotrope with or without a peritectic is likely, but further investigations are needed to confirm. The N2/CO system does not have a density inversion point, as the ice always sinks in its liquid. For N2/C2H6, new SLV pressure data were measured near each triple point of the pure components.


Improving the resistance to sliding contact damage of zirconia using elastic gradients.
Zirconia-based ceramics with high strength have been identified as a material of choice for sliding components in a variety of biomedical and engineering applications. Despite the high flexural strength, zirconia prostheses are still vulnerable to wear and surface damage. We hypothesize that such tribological damage may be substantially mitigated by an engineered grading of elastic modulus at the ceramic surface. In this study, graded structures were fabricated by infiltrating glass into the top and bottom surfaces of zirconia plates, with resulting diminished modulus in the outer surfaces. The plates were then subjected to frictional sliding tests using a hard spherical indenter. Compared with noninfiltrated controls, infiltrated specimens showed a significant increase in the fracture loads, by over a factor of 3. The increase in the sliding contact resistance is attributed to the diminishing tensile stresses at the graded lower modulus surface. The results confirm that suitably graded structures can be highly beneficial in the design of next-generation orthopedic and dental prostheses.


Prevalence of Severe Obesity among Primary School Children in 21 European Countries.
The World Health Organization (WHO) European Childhood Obesity Surveillance Initiative (COSI) was established more than 10 years ago to estimate prevalence and monitor changes in overweight and obesity in children aged 6-9 years. Since then, there have been five rounds of data collection in more than 40 countries involving more than half a million children. To date, no comparative studies with data on severe childhood obesity from European countries have been published. The aim of this work was to present the prevalence of severe obesity in school-aged children from 21 countries participating in COSI. The data are from cross-sectional studies in 21 European WHO member states that took part in the first three COSI rounds of data collection (2007/2008, 2009/2010, 2012/2013). School-aged children were measured using standardized instruments and methodology. Children were classified as severely obese using the definitions provided by WHO and the International Obesity Task Force (IOTF). Analyses overtime, by child's age and mother's educational level, were performed in a select group of countries. A total of 636,933 children were included in the analysis (323,648 boys and 313,285 girls). The prevalence of severe obesity varied greatly among countries, with higher values in Southern Europe. According to the WHO definition, severe obesity ranged from 1.0% in Swedish and Moldovan children (95% CI 0.7-1.3 and 0.7-1.5, respectively) to 5.5% (95% CI 4.9-6.1) in Maltese children. The prevalence was generally higher among boys compared to girls. The IOTF cut-offs lead to lower estimates, but confirm the differences among countries, and were more similar for both boys and girls. In many countries 1 in 4 obese children were severely obese. Applying the estimates of prevalence based on the WHO definition to the whole population of children aged 6-9 years in each country, around 398,000 children would be expected to be severely obese in the 21 European countries. The trend between 2007 and 2013 and the analysis by child's age did not show a clear pattern. Severe obesity was more common among children whose mother's educational level was lower. Severe obesity is a serious public health issue which affects a large number of children in Europe. Because of the impact on educational, health, social care, and economic systems, obesity needs to be addressed via a range of approaches from early prevention of overweight and obesity to treatment of those who need it.


Seroconversion stages COVID19 into distinct pathophysiological states.
COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations.


Fitness differences suppress the number of mating types in evolving isogamous species.
Sexual reproduction is not always synonymous with the existence of two morphologically different sexes; isogamous species produce sex cells of equal size, typically falling into multiple distinct self-incompatible classes, termed mating types. A long-standing open question in evolutionary biology is: what governs the number of these mating types across species? Simple theoretical arguments imply an advantage to rare types, suggesting the number of types should grow consistently; however, empirical observations are very different. While some isogamous species exhibit thousands of mating types, such species are exceedingly rare, and most have fewer than 10. In this paper, we present a mathematical analysis to quantify the role of fitness variation-characterized by different mortality rates-in determining the number of mating types emerging in simple evolutionary models. We predict that the number of mating types decreases as the variance of mortality increases.


Updates in the Management of Metastatic Spine Disease.
The number of cancer diagnoses continues to increase each year in the United States, and given the propensity for bone metastases from solid organ malignancies, orthopaedic spine surgeons will inevitably encounter patients with metastatic spine disease and need to have a framework for approaching the evaluation and treatment of these complex patients. Many patients seeking care for spinal metastases already have a history of disseminated malignancy, but metastatic spine disease itself will be the presenting symptom of cancer in approximately 20% of patients. Because the first presentation of cancer may be to a spine surgeon, an appropriate strategy for the initial evaluation of a patient with a new spinal lesion is critical to establish the diagnosis of metastatic disease before undergoing treatment. Once the diagnosis of metastatic spine disease is confirmed, decisions regarding treatment should be made in coordination with a multidisciplinary team including radiation oncology and medical oncology. Spinal metastases are most often treated with radiation therapy. Direct circumferential decompression of the spinal cord with postoperative radiation therapy is considered for high-grade epidural spinal cord compression to preserve neurologic function. Mechanical spinal instability is another potential indication for surgery. When considering surgery, the patient's medical fitness, systemic burden of cancer, and overall prognosis all must be accounted for, and the importance of multidisciplinary evaluation and shared decision making cannot be overstated.


Fatigue and pain: relationships with physical performance and patient beliefs after stroke.
Fatigue and pain are common after stroke, potentially impacting stroke recovery. This study examines the frequency and impact of fatigue and pain in people with chronic stroke. Seventy-seven people with chronic stroke completed a one-time assessment consisting of a battery of self-report and performance tools to describe and quantify mobility issues post stroke. We assessed the proportion of individuals with fatigue and pain and the relationship between fatigue and pain and other variables including gait (10-meter walk and 6-minute walk test), balance (Berg Balance Scale), activity and participation (ICF Measure of Participation and Activities), chronic disease self-efficacy (Chronic Disease Self-Efficacy Scale), and balance self-efficacy (Activity-Specific Balance Confidence Scale). Additionally, subgroup comparisons were made between participants with and without coexisting fatigue and pain. Fatigue and pain were reported by 66% and 45% of study participants, respectively. Thirty-four percent of the sample reported co-existing fatigue and pain. Participants with coexisting fatigue and pain demonstrated significantly lower chronic disease and balance self-efficacy and decreased activity than participants without coexisting fatigue and pain. Individually, fatigue correlated with balance, chronic disease self-efficacy, balance self-efficacy, activity, and participation, whereas pain correlated with chronic disease self-efficacy, balance self-efficacy, and activity. Fatigue and pain are common after stroke and are negatively correlated with outcomes important to rehabilitation. Efforts focused on examining the impact of interventions on fatigue and pain are warranted. It is possible that changes to these body structure limitations could positively impact functional recovery and community re-entry after stroke.


The interplay between sleep and mood in predicting academic functioning, physical health and psychological health: a longitudinal study.
Existing studies on sleep and behavioral outcomes are mostly correlational. Longitudinal data is limited. The current longitudinal study assessed how sleep duration and sleep quality may be causally linked to daytime functions, including physical health (physical well-being and daytime sleepiness), psychological health (mood and self-esteem) and academic functioning (school grades and study effort). The mediation role of mood in the relationship between sleep quality, sleep duration and these daytime functions is also assessed. A sample of 930 Chinese students (aged 18-25) from Hong Kong/Macau completed self-reported questionnaires online across three academic semesters. Sleep behaviors are assessed by the sleep timing questionnaire (for sleep duration and weekday/weekend sleep discrepancy) and the Pittsburgh sleep quality index (sleep quality); physical health by the World Health Organization quality of life scale-brief version (physical well-being) and Epworth Sleepiness Scale (daytime sleepiness); psychological health by the depression anxiety stress scale (mood) and Rosenberg Self-esteem Scale (self-esteem) and academic functioning by grade-point-average and the college student expectation questionnaire (study effort). Structural equation modeling with a bootstrap resample of 5000 showed that after controlling for demographics and participants' daytime functions at baseline, academic functions, physical and psychological health were predicted by the duration and quality of sleep. While some sleep behaviors directly predicted daytime functions, others had an indirect effect on daytime functions through negative mood, such as anxiety. Sleep duration and quality have direct and indirect (via mood) effects on college students' academic function, physical and psychological health. Our findings underscore the importance of healthy sleep patterns for better adjustment in college years.


Assessing Graph-based Deep Learning Models for Predicting Flash Point.
Flash points of organic molecules play an important role in preventing flammability hazards and large databases of measured values exist, although millions of compounds remain unmeasured. To rapidly extend existing data to new compounds many researchers have used quantitative structure-property relationship (QSPR) analysis to effectively predict flash points. In recent years graph-based deep learning (GBDL) has emerged as a powerful alternative method to traditional QSPR. In this paper, GBDL models were implemented in predicting flash point for the first time. We assessed the performance of two GBDL models, message-passing neural network (MPNN) and graph convolutional neural network (GCNN), by comparing against 12 previous QSPR studies using more traditional methods. Our result shows that MPNN both outperforms GCNN and yields slightly worse but comparable performance with previous QSPR studies. The average R2 and Mean Absolute Error (MAE) scores of MPNN are, respectively, 2.3 % lower and 2.0 K higher than previous comparable studies. To further explore GBDL models, we collected the largest flash point dataset to date, which contains 10575 unique molecules. The optimized MPNN gives a test data R2 of 0.803 and MAE of 17.8 K on the complete dataset. We also extracted 5 datasets from our integrated dataset based on molecular types (acids, organometallics, organogermaniums, organosilicons, and organotins) and explore the quality of the model in these classes.


Population specificity of the DNAI1 gene mutation spectrum in primary ciliary dyskinesia (PCD).
Mutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the DNAI1 involvement in PCD pathogenesis differ among the reported studies, ranging from 4% to 10%. The coding sequence of DNAI1 was screened (SSCP analysis and direct sequencing) in a group of PCD patients (157 families, 185 affected individuals), the first ever studied large cohort of PCD patients of Slavic origin (mostly Polish); multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a subset of ~80 families. Three previously reported mutations (IVS1+2-3insT, L513P and A538T) and two novel missense substitutions (C388Y and G515S) were identified in 12 families (i.e. ~8% of non-related Polish PCD patients). The structure of background SNP haplotypes indicated common origin of each of the two most frequent mutations, IVS1+2-3insT and A538T. MLPA analysis did not reveal any significant differences between patients and control samples. The Polish cohort was compared with all the previously studied PCD groups (a total of 487 families): IVS1+2-3insT remained the most prevalent pathogenetic change in DNAI1 (54% of the mutations identified worldwide), and the increased global prevalence of A538T (14%) was due to the contribution of the Polish cohort. The worldwide involvement of DNAI1 mutations in PCD pathogenesis in families not preselected for ODA defects ranges from 7 to 10%; this global estimate as well as the mutation profile differs in specific populations. Analysis of the background SNP haplotypes suggests that the increased frequency of chromosomes carrying A538T mutations in Polish patients may reflects local (Polish or Slavic) founder effect. Results of the MLPA analysis indicate that no large exonic deletions are involved in PCD pathogenesis.


Epilepsy and obstructive sleep apnea.
A few publications documented the coexistence of epilepsy and obstructive sleep apnea (OSA). The extent, nature, and clinical relevance of this association remain poorly understood. We retrospectively reviewed the database of our sleep center to identify patients with both sleep apnea and epilepsy. Characteristics of epilepsy, sleep history, presence of excessive daytime sleepiness [Epworth Sleepiness Scale (ESS)] and polysomnographic data were assessed. The effect of continuous positive airway pressure (CPAP) on seizure reduction was prospectively analyzed after a median interval of 26 months (range: 2-116 months) from the diagnosis of OSA. OSA was found in 29 epilepsy patients (25 men and 4 women) with a median age of 56 years (range: 37-79). The median apnea hypopnea index was 33 (range: 10-85), the oxygen desaturation index was 12 (range 0-92), and 52% of the patients had an ESS score >10. In 27 patients, epilepsy appeared 1 month to 44 years prior to the diagnosis of OSA. In 21 patients, the appearance of OSA symptoms coincided with a clear increase in seizure frequency or the first appearance of a status epilepticus. Treatment with CPAP was continued with good compliance in 12 patients and led to a significant reduction of both ESS scores and seizure frequency in 4 patients. Our data suggest the importance of considering diagnosis and treatment of OSA in epilepsy patients with poor seizure control and/or reappearance of seizures after a seizure-free interval.


Immunogenicity of human mesenchymal stem cells in HLA-class I-restricted T-cell responses against viral or tumor-associated antigens.
Human mesenchymal stem cells (MSC) are immunosuppressive and poorly immunogenic but may act as antigen-presenting cells (APC) for CD4(+) T-cell responses; here we have investigated their ability to serve as APC for in vitro CD8(+) T-cell responses. MSC pulsed with peptides from viral antigens evoked interferon (IFN)-gamma and Granzyme B secretion in specific cytotoxic T lymphocytes (CTL) and were lysed, although with low efficiency. MSC transfected with tumor mRNA or infected with a viral vector carrying the Hepatitis C virus NS3Ag gene induced cytokine release but were not killed by specific CTL, even following pretreatment with IFN-gamma. To investigate the mechanisms involved in MSC resistance to CTL-mediated lysis, we analyzed expression of human leukocyte antigen (HLA) class I-related antigen-processing machinery (APM) components and of immunosuppressive HLA-G molecules in MSC. The LMP7, LMP10, and ERp57 components were not expressed and the MB-1 and zeta molecules were downregulated in MSC either unmanipulated or pretreated with IFN-gamma. Surface HLA-G was constitutively expressed on MSC but was not involved in their protection from CTL-mediated lysis. MSC supernatants containing soluble HLA-G (sHLA-G) inhibited CTL-mediated lysis, whereas those lacking sHLA-G did not. The role of sHLA-G in such inhibition was unambiguously demonstrated by partial restoration of lysis following sHLA-G depletion from MSC supernatants. In conclusion, human MSC can process and present HLA class I-restricted viral or tumor antigens to specific CTL with a limited efficiency, likely because of some defects in APM components. However, they are protected from CTL-mediated lysis through a mechanism that is partly sHLA-G-dependent.


Established and novel agents for myelodysplastic syndromes.
The myelodysplastic syndromes (MDS) are the most commonly diagnosed myeloid malignancy, with >15 000 new cases identified in the United States yearly. Prognostic scoring systems supplant a formal staging approach and, in general, divide patients into those with lower-risk and those with higher-risk MDS. Although treatment goals for patients with lower-risk disease focus on minimizing transfusions and optimizing quality of life, in higher-risk MDS, the goal is to delay transformation to acute leukemia and to prolong survival. In lower-risk patients, isolated cytopenias are treated with erythropoiesis-stimulating agents or growth factors such as thrombopoietin mimetics. For patients with the del(5q) cytogenetic abnormality or those who fail these initial approaches, lenalidomide may be tried, as can experimental agents. Lower-risk patients with multiple cytopenias may be treated with immunosuppressive drugs or low-dose hypomethylating agents. For patients with higher-risk disease, hypomethylating agents are the preferred initial treatment approach, with evaluation for hematopoietic cell transplantation at diagnosis. Several novel agents are being developed for MDS patients who have failed hypomethylating drugs.


Frontal and caudate alterations in velocardiofacial syndrome (deletion at chromosome 22q11.2).
This study investigated the morphology of the frontal lobe and the caudate nucleus in velocardiofacial syndrome, a neurogenetic disorder caused by a microdeletion at chromosome 22q11.2 and frequently associated with severe psychiatric disturbances. Volumes of the caudate nucleus and subregions of the frontal lobe were compared on magnetic resonance images of 10 children with velocardiofacial syndrome and 10 age- and gender-matched controls. Frontal deep white matter was reduced significantly (by about 23%) in subjects with velocardiofacial syndrome relative to controls. Frontal and prefrontal volumes were also reduced in subjects with velocardiofacial syndrome, although not disproportionately to whole brain volume. The volume of the right caudate nucleus was increased in children with velocardiofacial syndrome. Associations between right caudate and right frontal regions were noted in controls but not in children with velocardiofacial syndrome. These findings suggest frontostriatal dysfunction in children with velocardiofacial syndrome. Insofar as up to 30% of adults with velocardiofacial syndrome (also known as chromosome 22q11 deletion syndrome) develop schizophrenia and frontostriatal dysfunction has been noted in schizophrenia, the findings support the hypothesis that velocardiofacial syndrome might represent a neurodevelopmental model of schizophrenia.


The neuronal cytoskeleton is at risk after mild and moderate brain injury.
Recent studies have described alterations in cytoskeletal proteins such as microtubule-associated protein 2 (MAP-2) and neurofilament (NF) resulting from moderate and severe experimental brain injury; however, few have investigated the consequences of mild injury, which is associated clinically and experimentally with cognitive dysfunction and neuronal damage. To contrast cytoskeletal changes within 7 days following mild injury with those following moderate injury, we subjected anesthetized, adult rats to mild (1.1-1.3 atm) or moderate (2.3-2.5 atm) lateral fluid percussion brain injury or sham injury. Rats were sacrificed at 6 h (n=4 mild; n=4 moderate; n=2 sham), 24 h (n=4 mild; n=4 moderate; n=1 sham), or 7 days (n=5 mild; n=4 moderate; n=1 sham) following injury, and immunohistochemistry was performed for MAP-2 and NF. Both mild and moderate injury produced notable cytoskeletal changes in multiple brain regions; however, mild injury generally resulted in a lesser degree of MAP-2 and NF loss over a smaller spatial extent. When compared to moderately injured animals, animals subjected to mild injury showed substantially delayed MAP-2 and NF alterations within the cortex and hippocampal dentate gyrus and no evidence of MAP-2 loss in the hippocampal CA3 region. While mild and moderate injury resulted for the most part in similar patterns of axonal injury, tissue tears in the fimbria and loss of NF immunoreactivity in regions containing injured axons were only observed following moderate injury. Elucidating the effects of modulating injury severity may yield insight into the mechanisms involved in traumatic damage to the cytoskeleton and guide future treatment strategies.


Narcolepsy: current treatment options and future approaches.
The management of narcolepsy is presently at a turning point. Three main avenues are considered in this review: 1) Two tendencies characterize the conventional treatment of narcolepsy. Modafinil has replaced methylphenidate and amphetamine as the first-line treatment of excessive daytime sleepiness (EDS) and sleep attacks, based on randomized, double blind, placebo-controlled clinical trials of modafinil, but on no direct comparison of modafinil versus traditional stimulants. For cataplexy, sleep paralysis, and hypnagogic hallucinations, new antidepressants tend to replace tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) in spite of a lack of randomized, double blind, placebo-controlled clinical trials of these compounds; 2) The conventional treatment of narcolepsy is now challenged by sodium oxybate, the sodium salt of gammahydroxybutyrate, based on a series of randomized, double-blind, placebo-controlled clinical trials and a long-term open label study. This treatment has a fairly good efficacy and is active on all symptoms of narcolepsy. Careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects; 3) A series of new treatments are currently being tested, either in animal models or in humans, They include novel stimulant and anticataplectic drugs, endocrine therapy, and, more attractively, totally new approaches based on the present state of knowledge of the pathophysiology of narcolepsy with cataplexy, hypocretine-based therapies, and immunotherapy.


A gender comparison of postobstructive injury in the rat kidney.
Unilateral ureteral obstruction (UUO) results in renal injury. Studies report increased injury indices in male rats following UUO. Our study examined whether this gender-based renal response to UUO was reflected in sustained differences following relief of obstruction. Adult male/female rats (200-400 g) were subjected to either sham surgery (S/RN) or UUO (UUO/RN). At 24 h, obstruction was relieved and all animals underwent contralateral nephrectomy. Five days after initial surgery, animals were placed in metabolic cages and given water ad libitum for 24 h followed by a 24-hour period of complete water restriction. On day 7, animals were euthanized and samples harvested. Tubular injury, urinary volume/osmolality, creatinine clearance, plasma arginine vasopressin, renal medullary V2 receptor and aquaporin 2 (AQP2) expression were measured. Male UUO/RN rats showed increased renal apoptotic injury and reduced creatinine clearance rates (glomerular filtration rate) vs. females. No gender-dependent differences were observed in urinary osmolality or concentrating ability. AQP2 expression increased post-obstruction. Increased injury in males following UUO remains manifest during early recovery after release of obstruction. Despite this, the grade of postobstructive diuresis is not significantly altered between sexes. This may reflect reduced glomerular filtration rate and elevated AQP2 in male rats.


A study of Attachment Disorders in young offenders attending specialist services.
Attachment disorders, specifically Reactive Attachment Disorder (RAD) and Disinhibited Social Engagement Disorder (DSED) are disorders associated with neglect and abuse in which people have significant difficulties relating to others. This study aims to explore Attachment Disorder symptoms and diagnoses in young offenders and factors that may be associated with them such as mental health problems. A cross-sectional design was used with 29 young people who were known to Intensive Services, aged 12-17 (M=16.2, SD=1.3), 29 carers and 20 teachers. They completed measures investigating symptoms of Attachment Disorders and psychopathology. Eighty-six percent of the young people had experienced some form of maltreatment and the rates of an actual or borderline Attachment Disorder was 52%. A positive correlation between Attachment Disorder symptoms and other mental health problems (as rated by carer-report Strengths and Difficulties Questionnaire Total Difficulties Score), accounting for 36% of the variance was found, with a large effect size (rs=0.60). Attachment Disorder symptoms were associated with hyperactivity and peer relationship problems.


TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB.
Many cells are resistant to stimuli that can induce apoptosis, but the mechanisms involved are not fully understood. The activation of the transcription factor nuclear factor-kappa B (NF-kappaB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound), was found to protect from cell killing. Inhibition of NF-kappaB nuclear translocation enhanced apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-kappaB. These results provide a mechanism of cellular resistance to killing by some apoptotic reagents, offer insight into a new role for NF-kappaB, and have potential for improvement of the efficacy of cancer therapies.


Inheritance of urinary calculi in the Dalmatian.
Dalmatians are unique among dogs in that they excrete uric acid in their urine as the end product of purine metabolism rather than allantoin as do other breeds of dogs. Urinary calculi form from urate (salts of uric acid) and can cause urethral obstruction in male Dalmatians. Although all Dalmatians have the primary defect, only a subset develops clinical disease. We postulated that calculi formation might have a genetic component that segregates within the breed, causing some animals to form calculi and others to never form calculi despite excreting uric acid in their urine. We used a survey to ascertain the urinary calculi status based on clinical signs of adult Dalmatians aged 6 years or older, and we used pedigrees from these same animals to estimate the heritability of the clinical manifestation of urate calculi within the breed to be .87 (.75-.96). The prevalence of the disease was 34% (24.99-43.70%) among male Dalmatians in our survey. The high heritability of the disease makes it possible for breeders to effectively select against the disease.


Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.
We have reported previously that Noggin is a heparin-binding protein and associates with the cell surface through heparan sulfate proteoglycans, where it remains functional for the binding of bone morphogenetic proteins (BMPs). Here we report that the binding of Noggin to the cell surface is highly selective for heparan sulfate and that specific structural features are required for the interaction. Noggin binds most efficiently to heparin sequences composed of 10 or more monosaccharides; N-, 6-O-, and 2-O-sulfates contribute to this interaction. In addition, we have shown that the developmentally regulated endosulfatase Qsulf1 selectively removes sulfate groups from the 6-O position of sugars within the most highly sulfated S domains of heparan sulfate, whereas 6-O-sulfates in the NA/NS domains are not substrates for the enzyme. The activity of Qsulf1 in cells in culture results in the release of Noggin from the cell surface and a restoration of BMP responsiveness to the cells. This shows that Noggin binds to the S domains of heparan sulfate and provides evidence that, in addition to modulating Wnt signaling in vivo by the release of heparan sulfate bound Wnt, Qsulf1 also modulates BMP signaling by the release of surface-bound Noggin.


Cancer therapy by biological response modifiers.
Biological response modifiers (BRMs) are agents or approaches which can modify the biological response of the host to tumors and thereby are expected to augment the resistance to development or progression of cancer. Recent advances in the technology of genetic engineering and monoclonal antibodies have led to rapid progress in this field. There is an increasing number of genetically engineered cytokines, which appear promising for cancer treatment and are becoming available for clinical trials. These include the interferons, leukin-2, tumor necrosis factor, and colony-stimulating factors. For development of optimal therapeutic protocols with these and a variety of immunomodulatory agents, it appears necessary to develop a detailed understanding of the possible mechanisms of their antitumor effects, and to determine the optimal dose and schedule for altering the antitumor effector mechanisms. BRMs would also be expected to be quite useful in the prevention of cancer. Indeed, in a variety of animal tumor model systems, potent protective effects can be demonstrated. However, the strategies for clinical application of such information have yet to be adequately worked out. One more immediate application of this approach is for the prevention of metastatic spread of tumor cells. BRMs, which stimulate natural killer cell activity, have been shown to strongly protect against dissemination of tumors, and clinical strategies for this important aspect of cancer treatment are being developed.


Effects of laser procedure for female urodynamic stress incontinence on pad weight, urodynamics, and sexual function.
The impact of the IncontiLaseTM procedure on lower urinary tract symptoms (LUTS) remains unclear. Our aim was to evaluate the effects of the IncontiLaseTM procedure for urodynamic stress incontinence (USI). All consecutive women with USI prospectively underwent the IncontiLaseTM procedure. Urodynamic studies, pad testing, LUTS, and sexual function questionnaires were assessed before and after treatment. Thirty-five women underwent the IncontiLaseTM procedure. Among the 28 women with baseline pad weights >1 g, 11 (39.3 %) were objectively cured and 11 (39.3 %) improved. Among the 18 women with mild USI (i.e., baseline pad weight 1-10 g), nine (50 %) were cured and five (27.8 %) improved. Among ten women with baseline pad weight >10 g, two (20 %) were cured and six (60 %) improved. Among the 32 women with complete questionnaire data at 6 months, seven (21.9 %) were subjectively cured, and four (12.5 %) improved. Regarding LUTS, the majority of domains on the King's Health Questionnaire and female sexual desire and function exhibited significant improvements. Forty percent (12/30) of the partners of these patients felt their sexual function had improved at 6 months. Nonetheless, urodynamic values did not differ across the timeline. The effect of the IncontiLaseTM procedure for mild USI was moderate at 6-month follow-up but was not effective for pad weight >10 g. Moreover, it improved LUTS, quality of life, QoL, and sexual function of both partners. Further studies should be performed to assess long-term sustained efficacy.


Spontaneous meningioma in a pig-tailed macaque (Macaca nemestrina).
We present a case of spontaneous meningioma in a female pig-tailed macaque (Macaca nemestrina) more than 24 years old. Clinically, the monkey displayed slow, weak, and insecure movements and poor vision. A tumorous mass was present at the floor of the cranial vault extending from the optic chiasm towards the foramen magnum. It compressed adjacent parts of the brain, infiltrated the sphenoidal and occipital bone, and showed transcranial expansion into the pharyngeal area. Histologically, the tumor was consistent with a meningioma displaying mostly meningothelial and some microcystic components. Since only six cases of meningiomas in nonhuman primates have been reported so far and only two of these meningiomas have been described in detail, the findings of each case should be reported to expand the knowledge base of this type of tumor. In addition, this is the first description of a meningioma in pig-tailed macaques.


Low wear of a second-generation highly crosslinked polyethylene liner: a 5-year radiostereometric analysis study.
A sequentially irradiated and annealed, second-generation highly crosslinked polyethylene (XLPE) liner was introduced clinically in 2005 to reduce in vivo oxidation. This liner design has also been shown to reduce wear in vitro when compared with conventional and first-generation crosslinked liners. To date, there is only one study reporting an in vivo wear rate of this liner at 5 years' followup. However, that study used measurements made from plain radiographs, which have limited sensitivity, particularly when monitoring very low amounts of wear. What is the amount and direction of wear at 5 years using radiostereometric analysis (RSA) in patients who had THAs that included second-generation XLPE? We prospectively reviewed 21 patients who underwent primary cementless THA with the same design of XLPE acetabular liner and 32-mm articulation. Tantalum markers were inserted during surgery and all patients had RSA radiographs at 1 week, 6 months, and 1, 2, and 5 years postoperatively. Femoral head penetration within the acetabular component was measured with UmRSA(®) software. One patient died and two had incomplete radiographs leaving 18 radiographic series for analysis. The mean amounts of proximal, two-dimensional, and three-dimensional head penetration between 1 week and 5 years were 0.018, 0.071, and 0.149 mm, respectively. The mean proximal, two-dimensional, and three-dimensional wear rates calculated between 1 year and 5 years were all less than 0.001 mm/year with no patient recording a wear rate of more than 0.040 mm/year. The head penetration of a second-generation XLPE liner remained low at 5 years and the wear rate calculated after the first year was low in all directions. This low level of wear remains encouraging for the future clinical performance of this material.


Advances in Rapid Identification and Susceptibility Testing of Bacteria in the Clinical Microbiology Laboratory: Implications for Patient Care and Antimicrobial Stewardship Programs.
Early availability of information on bacterial pathogens and their antimicrobial susceptibility is of key importance for the management of infectious diseases patients. Currently, using traditional approaches, it usually takes at least 48 hours for identification and susceptibility testing of bacterial pathogens. Therefore, the slowness of diagnostic procedures drives prolongation of empiric, potentially inappropriate, antibacterial therapies. Over the last couple of years, the improvement of available techniques (e.g. for susceptibility testing, DNA amplification assays), and introduction of novel technologies (e.g. MALDI-TOF) has fundamentally changed approaches towards pathogen identification and characterization. Importantly, these techniques offer increased diagnostic resolution while at the same time shorten the time-to-result, and are thus of obvious importance for antimicrobial stewardship. In this review, we will discuss recent advances in medical microbiology with special emphasis on the impact of novel techniques on antimicrobial stewardship programs.


Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and the risk of hypertensive disorders of pregnancy.
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been reported to disrupt endocrine system and reproduction. However, epidemiological evidence on the association between PFAS and preeclampsia is inconsistent. We aimed to investigate the association between prenatal PFAS exposure and hypertensive disorders of pregnancy (HDP) in humans. PFAS were measured by liquid chromatography system coupled with tandem mass spectrometry in 687 umbilical cord plasma samples collected between 2011 and 2012 in Shanghai, China. Information on HDP including gestational hypertension and preeclampsia was abstracted from medical records. Multiple logistic regression was used to examine the association of each PFAS with gestational hypertension, preeclampsia, and overall HDP in separate models. Elastic net regression with logit link was used to identify independent associations between exposures and outcomes. Logistic regression was used to obtain the unpenalized estimates of the selected PFAS components for the associations with outcomes, adjusting for age, education level, pre-pregnancy BMI, parity, and mutual adjustment of selected PFAS. The risk of gestational hypertension and preeclampsia was 3.3% and 2.8% in our subjects, respectively. Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluoroundecanoic acid (PFUA) were associated with preeclampsia based on elastic net penalty regression. In the fully adjusted statistical model, women with a higher level of standardized ln-transformed PFBS had an increased odds of preeclampsia [adjusted odds ratio (AOR): 1.81, 95% confidence interval (CI): 1.03-3.17], and overall HDP (AOR: 1.64, 95% CI: 1.09-2.47). Prenatal exposure to PFBS was positively associated with the risk of preeclampsia and overall HDP.


[International comparison APMP. QM-S6: determination of clenbuterol in porcine meat by isotopic dilution mass spectrometry].
A method was developed for the determination of clenbuterol in porcine meat by iso- topic dilution mass spectrometry (IDMS). National Institute of Metrology of China (NIM) par- ticipated in the international comparison activity organized by Asia Pacific Metrology (APMP) and got an international mutual recognition result using this method. The important factors of the method, such as the spray voltage, mobile phase, chromatographic column, extraction, purification and filtration conditions were investigated to acquire optimum conditions. The opti- mization results showed that the composition and pH value of the mobile phase had effects on the response of the mass spectrum of clenbuterol and the optimal value of the spray voltage. The solvent of sample had influences on the chromatographic retention behavior of clenbuterol. It was found that methanol caused a serious solvent effect, even made chromatographic peak split. Since clenbuterol was easily adsorbed on hydrophilic filter membranes and solid phase extraction columns, there were interference suppressions for the quantification of clenbuterol because of the eluate of the solid phase extraction columns. The homogenate method with extraction solvent of 0.1% (v/v) formic acid in acetonitrile had the highest extraction efficiency. The limit of the detection (LOD, S/N > 3) of the method was 0.2 μg/kg. The determination results of clenbuterol in the porcine meat by this method were 5.18 μg/kg ± 0.50 μg/kg (k = 2). This method is accurate, reliable, reproducible, and suitable for the determination of clenbuterol with trace quantity in porcine meat.