Estrogen insensitivity in a model of estrogen receptor positive breast cancer lymph node metastasis.
The lymphatic system is a common avenue for the spread of breast cancer cells and dissemination through it occurs at least as frequently as hematogenous metastasis. Approximately 75% of primary breast cancers are estrogen receptor (ER) positive and the majority of these maintain receptor expression as lymph node (LN) metastases. However, it is unknown if ER function is equivalent in cancer cells growing in the breast and in the LNs. We have developed a model to assess estrogen responsiveness in ER(+) breast tumors and LN metastases. Fluorescent ER(+) MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and progesterone receptor induction were deficient in LN metastases, indicating that ER-dependent transcriptional function was altered in the LN. Cancer cells from estradiol-treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and may contribute to local antiestrogen resistance.


Glycated albumin levels are higher relative to glycated haemoglobin levels in gastrectomized subjects.
In gastrectomized subjects, oral glucose tolerance test often shows marked hyperglycaemia (oxyhyperglycaemia) after glucose loading. Because serum glycated albumin (GA) has been shown to better reflect postprandial and maximum plasma glucose levels, we investigated whether or not the clinical significance of serum GA and glycated haemoglobin (HbA(1C)) in non-diabetic gastrectomized subjects differs. During health examinations, 62 non-diabetic subjects with a history of gastrectomy and 87 non-diabetic control subjects were selected in the present study. Body mass index (BMI) in the gastrectomy group was significantly lower than in the control group. Fasting plasma glucose levels were significantly lower in the gastrectomized subjects than in the control subjects. Although both HbA(1C) and serum GA were significantly higher in the gastrectomized subjects, there was a significant difference in GA/HbA(1C) ratio between the gastrectomized subjects and the control subjects. BMI-adjusted serum GA, based on our previous finding of inverse influence of BMI on serum GA, was also significantly higher in the gastrectomized subjects than in the controls. Serum GA is higher relative to HbA(1C) in gastrectomized subjects. This suggests that serum GA may be a better marker than HbA(1C) for glycaemic excursion in these subjects.


A multisegment computer simulation of normal human gait.
The goal of this project was to develop a computer simulation of normal human walking that would use as driving moments resultant joint moments from a gait analysis. The system description, initial conditions and driving moments were taken from an inverse dynamics analysis of a normal walking trial. A nine-segment three-dimensional (3-D) model, including a two-part foot, was used. Torsional, linear springs and dampers were used at the hip joints to keep the trunk vertical and at the knee and ankle joints to prevent nonphysiological motion. Dampers at other joints were required to ensure a smooth and realistic motion. The simulated human successfully completed one step (550 ms), including both single and double support phases. The model proved to be sensitive to changes in the spring stiffness values of the trunk controllers. Similar sensitivity was found with the springs used to prevent hyperextension of the knee at heel contact and of the metatarsal-phalangeal joint at push-off. In general, there was much less sensitivity to the damping coefficients. This simulation improves on previous efforts because it incorporates some features necessary in simulations designed to answer clinical science questions. Other control algorithms are required, however, to ensure that the model can be realistically adapted to different subjects.


Timing of surfactant treatment in respiratory distress syndrome.
The introduction of exogenous surfactant in the 1980s has resulted in an improved survival of very preterm infants with respiratory distress syndrome (RDS). Randomized controlled trials conducted before 2000 have shown that the magnitude of this beneficial effect strongly depends on the timing of surfactant treatment, i.e. the earlier surfactant is administered after birth the better. However, the initial mode of respiratory support in infants with RDS has changed dramatically over the last decades, moving from invasive to non-invasive support. Furthermore, new, less invasive techniques to administer surfactant have been introduced to match this non-invasive approach. This review summarizes the evidence on how these practice changes impacted the effect of surfactant timing on mortality and morbidity in preterm infants with RDS.


Assessment of social, demographic determinants and oral hygiene practices in relation to dental caries among the children attending Anganwadis of Hingna, Nagpur.
In developing countries, dental caries is the most common disease of the early childhood. Its increased prevalence in younger age group have been predictive of oral health problems in future, affecting oral health and development leading to several morbid conditions of oral and general health. Prevalence and incidence of dental caries is highly influenced by a number of risk factors such as gender, age, socioeconomic status, dietary patterns, and oral hygiene habits. To assess social, demographic determinants and oral hygiene practices in relation to dental caries among the children attending Anganwadis of Hingna, Nagpur. A cross sectional study in 27 Anganwadis of Hingna, Nagpur was carried out over a period of two months and a total of 324 subjects attending the Anganwadis were enrolled. Social, demographic and oral hygiene practices in relation to dental caries were assessed in the study population. Out of 324 subjects, 206 had dental caries and 38 were found to be malnourished. A significant association was found among age, malnutrition, parent's educational status, oral hygiene practices, total number of siblings, and dental caries. Anganwadis should be addressed routinely on effective oral and general health promoting strategies which must include education of parents, oral and general health issues, risk factors for dental caries, and malnutrition in children below 5 years of age.


Ventral hippocampal interneurons govern extinction and relapse of contextual associations.
Contextual associations are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the mechanisms underlying this competition remain largely enigmatic. Here we find the retrieval of contextual fear conditioning and extinction yield contrasting patterns of activity in prefrontal cortex and ventral hippocampus. Within ventral CA1, activation of somatostatin-expressing interneurons (SST-INs) occurs preferentially during extinction retrieval and correlates with differences in input synaptic transmission. Optogenetic manipulation of these cells but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in fear expression following extinction, and the ability of SST-INs to gate fear is specific to the context in which extinction was acquired. A similar pattern of results was obtained following reward-based extinction. These data show that ventral hippocampal SST-INs are critical for extinguishing prior associations and thereby gate relapse of both aversive and appetitive responses.


Mediterranean diet, healthy eating index 2005, and cognitive function in middle-aged and older Puerto Rican adults.
Adherence to a Mediterranean diet has recently been shown to protect against cognitive decline and dementia. It remains unclear, however, whether such protection extends to different ethnic groups and middle-aged individuals and how it might compare with adherence to the US Department of Agriculture's 2005 Dietary Guidelines for Americans (measured with Healthy Eating Index 2005 [HEI 2005]). This study examined associations between diet quality, as assessed by the Mediterranean diet and HEI 2005, and cognitive performance in a sample of 1,269 Puerto Rican adults aged 45 to 75 years and living in the Greater Boston area of Massachusetts. Dietary intake was assessed with a food frequency questionnaire specifically designed for and validated with this population. Adherence to the Mediterranean diet was assessed with a 0- to 9-point scale, and the HEI 2005 score was calculated with a maximum score of 100. Cognitive performance was measured with a battery of seven tests and the Mini Mental State Examination was used for global cognitive function. Greater adherence to the Mediterranean diet was associated with higher Mini Mental State Examination score (P trend=0.012) and lower likelihood (odds ratio=0.87 for each additional point; 95% CI 0.80 to 0.94; P<0.001) of cognitive impairment, after adjustment for confounders. Similarly, individuals with higher HEI 2005 score had higher Mini Mental State Examination score (P trend=0.011) and lower odds of cognitive impairment (odds ratio=0.86 for each 10 points; 95% CI 0.74 to 0.99; P=0.033). In conclusion, high adherence to either the Mediterranean diet or the diet recommended by the US Department of Agriculture 2005 Dietary Guidelines for Americans can protect cognitive function in middle-aged and older adults.


The effects of alcohol on the consumption of hard drugs: regression discontinuity evidence from the National Longitudinal Study of Youth, 1997.
This paper estimates the effect of alcohol use on consumption of hard drugs using the exogenous decrease in the cost of accessing alcohol that occurs when individuals reach the minimum legal drinking age. By using a regression discontinuity design and the National Longitudinal Study of Youth 1997, I find that all measures of alcohol consumption, even alcohol initiation increase discontinuously at age 21 years. I also find evidence that consumption of hard drugs decreased by 1.5 to 2 percentage points and the probability of initiating the use of hard drugs decreased by 1 percentage point at the age of 21 years, while the intensity of use among users remained unchanged. These estimates are robust to a variety of specifications and also remain robust across different subsamples.


Gene Duplication, Shifting Selection, and Dosage Balance of Silicon Transporter Proteins in Marine and Freshwater Diatoms.
Numerous factors shape the evolution of protein-coding genes, including shifts in the strength or type of selection following gene duplications or changes in the environment. Diatoms and other silicifying organisms use a family of silicon transporters (SITs) to import dissolved silicon from the environment. Freshwaters contain higher silicon levels than oceans, and marine diatoms have more efficient uptake kinetics and less silicon in their cell walls, making them better competitors for a scarce resource. We compiled SITs from 37 diatom genomes to characterize shifts in selection following gene duplications and marine-freshwater transitions. A deep gene duplication, which coincided with a whole-genome duplication, gave rise to two gene lineages. One of them (SIT1-2) is present in multiple copies in most species and is known to actively import silicon. These SITs have evolved under strong purifying selection that was relaxed in freshwater taxa. Episodic diversifying selection was detected but not associated with gene duplications or habitat shifts. In contrast, genes in the second SIT lineage (SIT3) were present in just half the species, the result of multiple losses. Despite conservation of SIT3 in some lineages for the past 90-100 million years, repeated losses, relaxed selection, and low expression highlighted the dispensability of SIT3, consistent with a model of deterioration and eventual loss due to relaxed selection on SIT3 expression. The extensive but relatively balanced history of duplications and losses, together with paralog-specific expression patterns, suggest diatoms continuously balance gene dosage and expression dynamics to optimize silicon transport across major environmental gradients.


Supraclavicular thoracic duct cyst.
The thoracic duct cysts located in the supraclavicular region are very rare masses, the etiology of which is not completely known. This article presents the clinical follow-up of a 35-year-old male patient diagnosed with throracic duct cyst situated in the left supraclavicular region and the patient's condition is discussed in line with literature. The patient admitted to our clinic with a complaint of a mass in the left supraclavicular region that had appeared six months ago and that had been increasingly growing. A cyst excision under general anesthesia was performed to the patient who was pre-diagnosed with thoracic duct cyst following the radiological evaluation and the needle aspiration biopsy. There were no complications or a recurrence during the six months of postoperative follow-up.


Solvent-Solvent Correlations across Graphene: The Effect of Image Charges.
Wetting experiments show pure graphene to be weakly hydrophilic, but its contact angle (CA) also reflects the character of the supporting material. Measurements and molecular dynamics simulations on suspended and supported graphene often reveal a CA reduction due to the presence of the supporting substrate. A similar reduction is consistently observed when graphene is wetted from both sides. The effect has been attributed to transparency to molecular interactions across the graphene sheet; however, the possibility of substrate-induced graphene polarization has also been considered. Computer simulations of CA on graphene have so far been determined by ignoring the material's conducting properties. We improve the graphene model by incorporating its conductivity according to the constant applied potential molecular dynamics. Using this method, we compare the wettabilities of suspended graphene and graphene supported by water by measuring the CA of cylindrical water drops on the sheets. The inclusion of graphene conductivity and concomitant polarization effects leads to a lower CA on suspended graphene, but the CA reduction is significantly bigger when the sheets are also wetted from the opposite side. The stronger adhesion is accompanied by a profound change in the correlations among water molecules across the sheet. While partial charges on water molecules interacting across an insulator sheet attract charges of the opposite sign, apparent attraction among like charges is manifested across the conducting graphene. The change is associated with graphene polarization, as the image charges inside the conductor attract equally signed partial charges of water molecules on both sides of the sheet. Additionally, using a nonpolar liquid (diiodomethane), we affirm a detectable wetting translucency when liquid-liquid forces are dominated by dispersive interactions. Our findings are important for predictive modeling toward a variety of applications including sensors, fuel cell membranes, water filtration, and graphene-based electrode materials in high-performance supercapacitors.


Early histopathology of small intestinal discordant xenografts.
A descriptive study of a new model enabling serial biopsies of ongoing hyperacute rejection of small intestinal discordant xenografts is presented. In a series of guinea-pig-to-Lewis rat small bowel xenotransplants (n=7), aboral free ends of Thierry-Vella loops constructed from the graft were sequentially biopsied at one-minute intervals up to ten minutes post-reperfusion and less frequently thereafter. In a guinea pig-to-guinea pig (n=6) isograft series, biopsy controls for preservation/ischemia-reperfusion injury were obtained. Xenoantibody sequestration in this model was evaluated in a separate series of transplants, utilizing an ELISA assay for rat anti-guinea pig natural antibodies. Pathologic evaluation revealed a unique series of events characterized with microcirculatory failure and thrombosis progressing from the submucosal vasculature to the lumen. Within the system's detection limits, complement deposition and P-selectin expression occurred as early as one minute post-reperfusion, preceding the staining for IgM and IgG. Using rat serum ELISAs, no significant difference in xenoantibody sequestration was detected between the xenograft and isograft groups. The guinea pig-to-rat discordant small bowel xenotransplantation is an efficient small animal model to dissect the very early pathophysiologic events during hyperacute rejection.


FIE and CURLY LEAF polycomb proteins interact in the regulation of homeobox gene expression during sporophyte development.
The Arabidopsis FERTILIZATION-INDEPENDENT ENDOSPERM (FIE) polycomb group (PcG) protein, a WD40 homologue of Drosophila extra sex comb (ESC), regulates endosperm and embryo development and represses flowering during embryo and seedling development. As fie alleles are not transmitted maternally, homozygous mutant plants cannot be obtained. To study FIE function during the entire plant life cycle, we used Arabidopsis FIE co-suppressed plants. Low FIE level in these plants produced dramatic morphological aberrations, including loss of apical dominance, curled leaves, early flowering and homeotic conversion of leaves, flower organs and ovules into carpel-like structures. These morphological aberrations are similar to those exhibited by plants overexpressing AGAMOUS (AG) or CURLY LEAF (clf) mutants. Furthermore, the aberrant leaf morphology of FIE-silenced and clf plants correlates with de-repression of the class I KNOTTED-like homeobox (KNOX) genes including KNOTTED-like from Arabidopsis thaliana 2 (KNAT2) and SHOOTMERISTEMLESS (STM), whereas BREVIPEDICELLUS (BP) was upregulated in FIE-silenced plants, but not in the clf mutant. Thus, FIE is essential for the control of shoot and leaf development. Yeast two-hybrid and pull-down assays demonstrate that FIE interacts with CLF. Collectively, the morphological characteristics, together with the molecular and biochemical data presented in this work, strongly suggest that in plants, as in mammals and insects, PcG proteins control expression of homeobox genes. Our findings demonstrate that the versatility of the plant FIE function, which is derived from association with different SET (SU (VAR)3-9, E (Z), Trithorax) domain PcG proteins, results in differential regulation of gene expression throughout the plant life cycle.


Improving fold recognition without folds.
The most reliable way to align two proteins of unknown structure is through sequence-profile and profile-profile alignment methods. If the structure for one of the two is known, fold recognition methods outperform purely sequence-based alignments. Here, we introduced a novel method that aligns generalised sequence and predicted structure profiles. Using predicted 1D structure (secondary structure and solvent accessibility) significantly improved over sequence-only methods, both in terms of correctly recognising pairs of proteins with different sequences and similar structures and in terms of correctly aligning the pairs. The scores obtained by our generalised scoring matrix followed an extreme value distribution; this yielded accurate estimates of the statistical significance of our alignments. We found that mistakes in 1D structure predictions correlated between proteins from different sequence-structure families. The impact of this surprising result was that our method succeeded in significantly out-performing sequence-only methods even without explicitly using structural information from any of the two. Since AGAPE also outperformed established methods that rely on 3D information, we made it available through. If we solved the problem of CPU-time required to apply AGAPE on millions of proteins, our results could also impact everyday database searches.


Pitfalls in PCR troubleshooting: Expect the unexpected?
PCR is a well-understood and established laboratory technique often used in molecular diagnostics. Huge experience has been accumulated over the last years regarding the design of PCR assays and their set-up, including in-depth troubleshooting to obtain the optimal PCR assay for each purpose. Here we report a PCR troubleshooting that came up with a surprising result never observed before. With this report we hope to sensitize the reader to this peculiar problem and to save troubleshooting efforts in similar situations, especially in time-critical and ambitious diagnostic settings.


Role of IL-6 in the pleurisy and lung injury caused by carrageenan.
In the present study we used IL-6 knockout mice (IL-6KO) to evaluate the role of IL-6 in the inflammatory response caused by injection of carrageenan into the pleural space. Compared with carrageenan-treated IL-6 wild-type (IL-6WT) mice, carrageenan-treated IL-6KO mice exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase activity and lipid peroxidation were significantly reduced in IL-6KO mice compared with those in IL-6WT mice treated with carrageenan. Immunohistochemical analysis for nitrotyrosine and poly(A)DP-ribose polymerase revealed a positive staining in lungs from carrageenan-treated IL-6WT mice. No positive staining for nitrotyrosine or PARS was found in the lungs of the carrageenan-treated IL-6KO mice. Staining of lung tissue sections obtained from carrageenan-treated IL-6WT mice with an anti-cyclo-oxygenase-2 Ab showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase was found mainly in the macrophages of the inflamed lungs from carrageenan-treated IL-6WT mice. The intensity and degree of the staining for cyclo-oxygenase-2 and inducible nitric oxide synthase were markedly reduced in tissue sections obtained from carrageenan-treated IL-6KO mice. Most notably, the degree of lung injury caused by carrageenan was also reduced in IL-6KO mice. Treatment of IL-6WT mice with anti-IL-6 (5 microg/day/mouse at 24 and 1 h before carrageenan treatment) also significantly attenuated all the above indicators of lung inflammation. Taken together, our results clearly demonstrate that IL-6KO mice are more resistant to the acute inflammation of the lung caused by carrageenan injection into the pleural space than the corresponding WT mice.


Types of macular hole closure and their clinical implications.
To evaluate the clinical significance of macular hole closure types assessed by optical coherence tomography (OCT). This study involved 34 eyes of 32 patients who had undergone anatomically successful idiopathic macular hole surgery. The closed macular holes were categorised into two patterns based on OCT; type 1 closure (closed without foveal neurosensory retinal defect) and type 2 closure (closed with foveal neurosensory retinal defect). Association between visual prognosis, type of hole closure, and possible prognostic factors were analysed. 19 eyes (61.3%) were classified into the type 1 closure and 12 eyes (38.7%) into the type 2 closure. The extent of postoperative visual improvement of type 1 closure group was larger than that of type 2 closure group (p=0.002). The preoperative macular hole size of type 2 closure group was significantly larger than that of type 1 closure group (p=0.006). The duration of symptoms was positively correlated with the preoperative macular hole size (p=0.01). Recurrence of macular hole occurred only in the type 2 closure group. The type of macular hole closure, which was influenced by the preoperative hole diameter, was associated with postoperative visual prognosis. Early detection and intervention in macular hole should be emphasised.


Developing Message Strategies to Engage Racial and Ethnic Minority Groups in Digital Oral Self-Care Interventions: Participatory Co-Design Approach.
The prevention of oral health diseases is a key public health issue and a major challenge for racial and ethnic minority groups, who often face barriers in accessing dental care. Daily toothbrushing is an important self-care behavior necessary for sustaining good oral health, yet engagement in regular brushing remains a challenge. Identifying strategies to promote engagement in regular oral self-care behaviors among populations at risk of poor oral health is critical. The formative research described here focused on creating messages for a digital oral self-care intervention targeting a racially and ethnically diverse population. Theoretically grounded strategies (reciprocity, reciprocity-by-proxy, and curiosity) were used to promote engagement in 3 aspects: oral self-care behaviors, an oral care smartphone app, and digital messages. A web-based participatory co-design approach was used to develop messages that are resource efficient, appealing, and novel; this approach involved dental experts, individuals from the general population, and individuals from the target population-dental patients from predominantly low-income racial and ethnic minority groups. Given that many individuals from racially and ethnically diverse populations face anonymity and confidentiality concerns when participating in research, we used an approach to message development that aimed to mitigate these concerns. Messages were initially developed with feedback from dental experts and Amazon Mechanical Turk workers. Dental patients were then recruited for 2 facilitator-mediated group webinar sessions held over Zoom (Zoom Video Communications; session 1: n=13; session 2: n=7), in which they provided both quantitative ratings and qualitative feedback on the messages. Participants interacted with the facilitator through Zoom polls and a chat window that was anonymous to other participants. Participants did not directly interact with each other, and the facilitator mediated sessions by verbally asking for message feedback and sharing key suggestions with the group for additional feedback. This approach plausibly enhanced participant anonymity and confidentiality during the sessions. Participants rated messages highly in terms of liking (overall rating: mean 2.63, SD 0.58; reciprocity: mean 2.65, SD 0.52; reciprocity-by-proxy: mean 2.58, SD 0.53; curiosity involving interactive oral health questions and answers: mean 2.45, SD 0.69; curiosity involving tailored brushing feedback: mean 2.77, SD 0.48) on a scale ranging from 1 (do not like it) to 3 (like it). Qualitative feedback indicated that the participants preferred messages that were straightforward, enthusiastic, conversational, relatable, and authentic. This formative research has the potential to guide the design of messages for future digital health behavioral interventions targeting individuals from diverse racial and ethnic populations. Insights emphasize the importance of identifying key stimuli and tasks that require engagement, gathering multiple perspectives during message development, and using new approaches for collecting both quantitative and qualitative data while mitigating anonymity and confidentiality concerns.


A Patient-Centered Asthma Management Communication Intervention for Rural Latino Children: Protocol for a Waiting-List Randomized Controlled Trial.
Rural Latino children with asthma suffer high rates of uncontrolled asthma symptoms, emergency department visits, and repeat hospitalizations. This vulnerable population must negotiate micro- and macrolevel challenges that impact asthma management, including language barriers, primary care access, parental time off from work, insurance coverage, distance from specialty sites, and documentation status. There are few proven interventions that address asthma management embedded within this unique context. Using a bio-ecological approach, we will determine the feasibility of a patient-centered collaborative program between rural Latino children with asthma and their families, school-based nursing programs, and primary care providers, facilitated by the use of a smartphone-based mobile app with a Spanish-language interface. We hypothesize that improving communication through a collaborative, patient-centered intervention will improve asthma management, empower the patient and family, decrease outcome disparities, and decrease direct and indirect costs. The specific aims of this study include the following: (1) Aim 1: produce and validate a Spanish translation of an existing asthma management app and evaluate its usability with Latino parents of children with asthma, (2) Aim 2: develop and evaluate a triadic, patient-centered asthma intervention preliminary protocol, facilitated by the bilingual mobile app validated in Aim 1, and (3) Aim 3: investigate the feasibility of the patient-centered asthma intervention from Aim 2 using a waiting-list randomized controlled trial (RCT) to investigate the effects of the intervention on school days missed and medication adherence. Mobile app translation, initial usability testing, and app software refinement were completed in 2019. Analysis is in progress. Preliminary protocol testing is underway; we anticipate that the waiting-list RCT, using the refined protocol developed in Aim 2, will commence in fall 2020. Tailored, technology-based solutions have the potential to successfully address issues affecting asthma management, including communication barriers, accessibility issues, medication adherence, and suboptimal technological interventions. ClinicalTrials.gov NCT04633018; https://www.clinicaltrials.gov/ct2/show/NCT04633018. DERR1-10.2196/18977.


Grouping, semantic relation and imagery effects in individuals with Down syndrome.
Down syndrome (DS) is associated with a specific verbal short-term memory (STM) deficit. This study explored the effects of grouping, semantic relations and visual presentation upon verbal STM recall performance in a group of 15 individuals with DS and 15 vocabulary-matched typically developing (TD) children. Participants were presented with memoranda in either a temporally grouped schedule, such that items were grouped as pairs, or in an equally spaced presentation schedule. The two items constituting each pair were either semantically related or unrelated. Performance across these conditions was compared in verbal or verbal plus visual presentation modes. Significant memory recall benefits were observed across populations as a result of temporal grouping, semantic relations and verbal and visual combined presentation. However, a reduced benefit of semantic relation in the DS group compared to the TD group indicated that those with DS were less influenced by LTM relational knowledge. In addition, those with DS only experienced a grouping benefit during verbal and visual combined presentation, in contrast to the TD group who experienced grouping benefits throughout. This indicates that individuals with DS are poorer at encoding temporal context for purely verbal memoranda. These findings were replicated in a follow-up experiment, aimed at aligning baseline performance in the two populations. This study provides encouraging evidence that, despite their difficulties in some areas, individuals with DS can benefit from the use of grouping and LTM knowledge to assist their verbal STM performance under certain circumstances.


Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence.
Nonfunctioning pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that typically cause visual and/or hormonal dysfunction. Surgery is the treatment of choice, but patients remain at risk for tumor recurrence for several years afterwards. The authors evaluate the early results of surgery and the long-term risk of tumor recurrence in patients with NFPAs. Between 1990 and 2005, 491 previously untreated patients with NFPA underwent surgery at the Università Vita-Salute. Determinations of recurrence or growth of the residual tumor tissue during the follow-up period were based on neuroradiological criteria. Residual tumor after surgery was detected in 173 patients (36.4%). Multivariate analysis showed that invasion of the cavernous sinus, maximum tumor diameter, and absence of tumor apoplexy were associated with an unfavorable surgical outcome. At least 2 sets of follow-up neuroimaging studies were obtained in 436 patients (median follow-up 53 months). Tumors recurred in 83 patients (19.0%). When tumor removal appeared complete, younger age at surgery was associated with a risk of tumor recurrence. In patients with incomplete tumor removal, adjunctive postoperative radiotherapy had a marked protective effect against growth of residual tumor. Complete surgical removal of NFPAs can be safely achieved in > 50% of cases. Visual symptoms and, less frequently, pituitary function may improve after surgery. However, tumor can recur in patients after apparently complete surgical removal. In patients with incomplete tumor removal, radiation therapy is the most effective adjuvant therapy for preventing residual tumor growth.


The Imbalance in Medical Demand and Supply for Pediatric Victims in an Earthquake.
We quantified an absolute imbalance of the medical risks and the support needs for children at each disaster-based hospital in Kanagawa immediately following the occurrence of a large earthquake by using the risk resource ratio (RRR) and need for medical resources (NMR). The RRR and NMR of 33 disaster-based hospitals were estimated through dividing the estimated number of pediatric victims by the number of critically patients. We calculated the ratio of the NMR of each hospital. The total number of pediatric victims in Kanagawa was estimated at 8,391. The total number of vacant beds for pediatric victims was 352. The median RRR and NMR of the total number of pediatric victims were 27 and 224. The median RRR and NMR of the number of critically ill pediatric patients were 27 and 12. The absolute imbalance of the RRR and NMR for children in Kanagawa was quantified. This suggests that we might embark on preparedness strategies for children in advance. (Disaster Med Public Health Preparedness. 2018;13:672-676).


[A study of the incidence and hospital follow-up of epistaxis in patients treated with anticoagulant acenocoumarol].
Nosebleed is a common reason for emergency ENT consultations, but it is infrequent in patients anticoagulated with acenocoumarol. In a retrospective 5-year study, nosebleed was the second most frequent type of hemorrhage among anticoagulated patients. Such patients do not necessarily have prolonged coagulation times. In a comparison of patients hospitalized for nosebleed (n = 14) with a similar group with no hemostasis abnormalities, patients with nosebleed had longer hospital stays and required more control measures. The greater the tendency to hypocoagulation, the more difficult it was to manage nosebleed. Recent onset of anticoagulation therapy and previous long coagulation times favored the appearance of hard-to-manage nosebleed. Therefore, hematologists should closely control patients under anticoagulation therapy and cooperate with the ENT department when such patients are admitted for nosebleed.


Sphingosinicella humi sp. nov., isolated from arsenic-contaminated farmland soil and emended description of the genus Sphingosinicella.
A Gram-stain-negative, strictly aerobic bacterium, designated strain QZX222T, was isolated from arsenic-contaminated farmland soil. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain QZX222T was clustered with Sphingosinicella vermicomposti YC7378T (97.0 %), Sphingosinicellaxenopeptidilytica 3-2W4T (96.1 %), Sphingosinicella microcystinivorans Y2T (96.0 %) and Sphingosinicella soli KSL-125T (95.9 %). Compared to strain QZX222T, Spingomonas olgophenolica JCM 12082T and Sphingobium boeckii 469T had 16S rRNA gene similarities of 96.2 and 95.9 %, respectively, but they located in other phylogenetic clusters. DNA-DNA hybridization and genomic ANI values between strain QZX222T and Sphingosinicella vermicomposti DSM 21593T (KCTC 22446T) were 34.8 and 75.0 %, respectively. The genome size of strain QZX222T was 3.0 Mb including 2982 predicted genes. The strain had a DNA G+C content of 65.9 mol%. Strain QZX222T had ubiquinone Q-10 as the major respiratory quinone and homospermidine as the major polyamine. The major fatty acids (>10 %) of strain QZX222T were C17 : 1ω6c, summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c) and C17 : 1ω8c. The polar lipids were sphingoglycolipid, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine and an unidentified glycolipid. Strain QZX222T could be distinguished from other Sphingosinicella strains based on the results of phylogenetic and genomic analyses, DNA-DNA hybridization, white colour colony, hydrolysis of urea, alkaline phosphatase activity, lack of phosphatidylmonomethylethanolamine, and presence of phosphatidylcholine. Therefore, strain QZX222T represents a novel species of Sphingosinicella, for which the name Sphingosinicellahumi sp. nov. is proposed. The type strain is QZX222T (=KCTC 62519T=CCTCC AB 2018030T).


LAV694, a new antiproliferative agent showing improved skin tolerability vs. clinical standards for the treatment of actinic keratosis.
The skin tolerability of the tubulin polymerisation inhibitor LAV694 was compared to that of 5% 5-fluorouracil (5-FU) and 0.5% podophyllotoxin in vitro using a human reconstructed epidermis (HRE), and in vivo using minipigs. Topical treatment of HRE for 1 or 3 days with a 0.2, 0.6 or 1% LAV694 cream or the placebo showed no signs of irritation in terms of morphology, cell viability (lactate dehydrogenase leakage) or interleukin-8 mRNA expression and release. 5-FU increased interleukin-8 production and induced morphological signs of irritation. The substances were also applied under occlusion to the back of two minipigs, twice daily, for 9 days to allow intraindividual comparison of skin effects and tolerability. Skin reactions were monitored by visual scoring, chromometry, pro-inflammatory activity, cell cycle and apoptosis by RT-PCR, laser scanning cytometry and histopathological examination of biopsies. Application of podophyllotoxin and 5-FU had to be stopped on days 4 and 8, respectively, due to severe skin lesions. LAV694 (1%) induced only moderate skin reddening after 9 days. 5-FU and podophyllotoxin, but not LAV694, increased mRNA expression of pro-inflammatory cytokines. LAV694 arrested keratinocytes in the M phase of the cell cycle and apoptosis was detected histologically in the basal layer. LAV694 increased the expression of pro-apoptotic genes in both experimental models. In conclusion, LAV694 selectively induced apoptosis, rather than necrosis, of growth-arrested keratinocytes, thus avoiding the occurrence of extensive inflammation. This resulted in an improved skin tolerability in comparison with 5-FU and podophyllotoxin.


Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts.
Bystander responses underlie some of the current efforts to develop gene therapy approaches for cancer treatment. Similarly, they may have a role in strategies to treat tumours with targeted radioisotopes. In this study we show direct evidence for the production of a radiation-induced bystander response in primary human fibroblasts. We utilize a novel approach of using a charged-particle microbeam, which allows individual cells within a population to be selected and targeted with counted charged particles. Individual primary human fibroblasts within a population of 600-800 cells were targeted with between 1 and 15 helium ions (effectively, alpha-particles). The charged particles were delivered through the centre of the nucleus with an accuracy of +/- 2 micrometer and a detection and counting efficiency of greater than 99%. When scored 3 days later, even though only a single cell had been targeted, typically an additional 80-100 damaged cells were observed in the surviving population of about 5000 cells. The yield of damaged cells was independent of the number of charged particles delivered to the targeted cell. Similar results of a 2-3-fold increase in the background level of damage present in the population were observed whether 1 or 4 cells were targeted within the dish. Also, when 200 cells within one quadrant of the dish were exposed to radiation, there was a 2-3-fold increase in the damage level in an unexposed quadrant of the dish. This effect was independent of the presence of serum in the culture medium and was only observed when a cell was targeted, but not when only the medium was exposed, confirming that a cell-mediated response is involved.


Two distinct oncornaviruses harbor an intracytoplasmic tyrosine-based basolateral targeting signal in their viral envelope glycoprotein.
It has been clearly established that the budding of the human immunodeficiency virus (HIV-1), a lentivirus, occurs specifically through the basolateral membrane in polarized epithelial cells. More recently, the signal was assigned to a tyrosine-based motif located in the intracytoplasmic domain of the envelope glycoprotein, as previously observed on various other viral and cellular basolateral proteins. In the present study, expression of human T-cell leukemia virus type 1 (HTLV-1) or Moloney murine leukemia virus envelope glycoproteins was used for trans-complementation of an envelope-negative HIV-1. This demonstrated the potential of oncornaviral retrovirus envelope glycoproteins to confer polarized basolateral budding in epithelial Madin-Darby canine kidney cells (MDCK cells). Site-directed mutagenesis confirmed the importance of a common motif encompassing at least one crucial membrane-proximal intracytoplasmic tyrosine residue. The conservation of a similar basolateral maturation signal in different retroviruses further supports its importance in the biology of this group of viruses.


Therapeutic Applications of Ethanol: A Review.
To review knowledge on therapeutic uses of ethanol and the latter's effectiveness and safety profiles in a range of indications. MEDLINE and PubMed databases were searched for relevant peer-reviewed papers published in English between 1888 and 2018 using the following search terms: ethanol, therapeutic, alcohol withdrawal syndrome, antiseptic, antidote, methanol, ethylene glycol, neurolysis, embolization, cyst, sclerosing agent, sclerotherapy, arteriovenous malformations, ablating agent. Studies providing information about association between alcohol and therapeutic indications, or mechanic explanation for the association were included for review. According to the World Health Organization, approximately three millions deaths worldwide are attributable to alcohol consumption each year. However, the low-to-moderate consumption of ethanol has a number of beneficial effects (mainly on cardiovascular mortality and diabetes). Hence, ethanol has an unusual spectrum of effects that seems interesting for therapeutic purposes. Ethanol's risk-benefit ratio appears to be positive in some therapeutic indications such as antidote to methanol or ethylene glycol poisoning, neurolysis, alcohol withdrawal syndrome, or antiseptic. With the development of interventional radio technologies, and thus extremely precise access to anatomical structures, alcohol has been given new indications - particularly as an embolization, sclerosing or ablation agent. Moreover, constant progress in our knowledge of ethanol's pharmacodynamics might highlight other therapeutic indications for this compound in the future. Ethanol's low cost and wide availability make it a valuable therapeutic agent, compared with other reference treatments. Furthermore, ethanol has a long track record of safety and effectiveness in the indications mentioned above.


Possible devices to temporary cover the open abdomen: pros and cons.
In the last 25 years increased popularity of damage control surgery and recognition of abdominal compartment syndrome has lead to a raised incidence of open abdomens. Even though these procedures are often life-saving, morbidity and mortality associated with an open abdomen remains high. Third spacing after aggressive fluid resuscitation, fascial retraction, ventilatory problems and fistula formations are problems often associated with an open abdomen. Management of an open abdomen is often complicated and challenging. The viscera need to be protected and the abdomen needs coverage. Several techniques have been described for both temporary and definitive closure. This article will discuss the pros and cons of several available temporary devices to cover the abdomen and literature will be reviewed.


Delphinidin enhances radio-therapeutic effects via autophagy induction and JNK/MAPK pathway activation in non-small cell lung cancer.
Delphinidin is a major anthocyanidin compound found in various vegetables and fruits. It has anti-oxidant, anti-inflammatory, and various other biological activities. In this study we demonstrated the anti-cancer activity of delphinidin, which was related to autophagy, in radiation-exposed non-small cell lung cancer (NSCLC). Radiosensitising effects were assessed in vitro by treating cells with a subcytotoxic dose of delphinidin (5 μM) before exposure to γ-ionising radiation (IR). We found that treatment with delphinidin or IR induced NSCLC cell death in vitro; however the combination of delphinidin pre-treatment and IR was more effective than either agent alone, yielding a radiation enhancement ratio of 1.54 at the 50% lethal dose. Moreover, combined treatment with delphinidin and IR, enhanced apoptotic cell death, suppressed the mTOR pathway, and activated the JNK/MAPK pathway. Delphinidin inhibited the phosphorylation of PI3K, AKT, and mTOR, and increased the expression of autophagy-induced cell death associated-protein in radiation-exposed NSCLC cells. In addition, JNK phosphorylation was upregulated by delphinidin pre-treatment in radiation-exposed NSCLC cells. Collectively, these results show that delphinidin acts as a radiation-sensitizing agent through autophagy induction and JNK/MAPK pathway activation, thus enhancing apoptotic cell death in NSCLC cells.


Benchmarking Wearable Robots: Challenges and Recommendations From Functional, User Experience, and Methodological Perspectives.
Wearable robots (WRs) are increasingly moving out of the labs toward real-world applications. In order for WRs to be effectively and widely adopted by end-users, a common benchmarking framework needs to be established. In this article, we outline the perspectives that in our opinion are the main determinants of this endeavor, and exemplify the complex landscape into three areas. The first perspective is related to quantifying the technical performance of the device and the physical impact of the device on the user. The second one refers to the understanding of the user's perceptual, emotional, and cognitive experience of (and with) the technology. The third one proposes a strategic path for a global benchmarking methodology, composed by reproducible experimental procedures representing real-life conditions. We hope that this paper can enable developers, researchers, clinicians and end-users to efficiently identify the most promising directions for validating their technology and drive future research efforts in the short and medium term.


DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia.
DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P = .004, allele P = 0.022) and rs2228611 (genotype P = 0.004, allele P = 0.022) were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P = 0.023) and allele (P = 0.0063) increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P = 0.027, allele P = 0.033) was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P = 0.009). DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026) confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia.


The Arabidopsis kinase-associated protein phosphatase controls internalization of the somatic embryogenesis receptor kinase 1.
The AtSERK1 protein is a plasma membrane-located LRR receptor-like serine threonine kinase that is transiently expressed during plant embryogenesis. Our results show that AtSERK1 interacts with the kinase-associated protein phosphatase (KAPP) in vitro. The kinase interaction (KI) domain of KAPP does not interact with a catalytically inactive kinase mutant. Using mutant AtSERK1 proteins in which Thr 462, Thr 463, and Thr 468 in the A-loop of the AtSERK1 kinase domain were replaced by alanines, we show that phosphorylation status of the receptor is involved in interaction with KAPP. KAPP and AtSERK1 cDNAs were fused to two different variants of green fluorescent protein (GFP), the yellow fluorescent protein (YFP) or the cyan fluorescent protein (CFP). Both KAPP and AtSERK1 proteins are found at the plasma membrane. Our results show that AtSERK1-CFP becomes sequestered into intracellular vesicles when transiently coexpressed with KAPP-YFP proteins. AtSERK1(T463A)-CFP and AtSERK1(3T-->A)-CFP proteins were partially sequestered intracellularly in the absence of KAPP-YFP protein, suggesting an active role for KAPP dephosphorylation of threonine residues in the AtSERK1 A-loop in receptor internalization. The interaction between the KAPP-CFP/YFP and AtSERK1-CFP/YFP fusion proteins was investigated with fluorescence spectral imaging microscopy (FSPIM). Our results show that AtSERK1-CFP and KAPP-YFP proteins are colocalized at the plasma membrane but only show fluorescence energy transfer (FRET) indicative of physical interaction in intracellular vesicles. These results suggest that KAPP is an integral part of the AtSERK1 endocytosis mechanism.


Prevalence and in vitro antifungal susceptibility of Candida spp isolated from clinical specimens in São Paulo, Brazil.
The specifity of gene encoding the ribotoxin protein in Aspergillus fumigatus was determined by PCR amplification of a portion of the gene. All A. fumigatus strains studied showed the presence of amplifiable ribotoxin product, while none of the other fungal species, with the exception of Aspergillus restrictus, showed this amplification product. Hence, this method may be used for rapid and specific identification of A. fumigatus.


Bilateral Carpal Spasm Under Spinal Anaesthesia During Abdominal Hysterectomy: A Case Report.
Acute hypocalcaemia is a medical emergency that can have catastrophic implications like tetany, seizures, cardiac arrythmias or laryngospasm if left untreated. We are presenting a case of a 30-year-old female patient undergoing total abdominal hysterectomy with bilateral salpingoopherectomy under spinal anaesthesia. She developed unexpected bilateral carpal spasm intraoperatively which was promptly diagnosed and successfully managed with intravenous calcium administration. We conclude that the anaesthetist should be aware of the clinical presentation of acute hypocalcaemia, its causes and emergency management in the perioperative period to prevent any adverse outcomes.


Regenerative Therapy for Patients with Congenital Heart Disease.
Congenital heart disease (CHD) is the most common birth defect, affecting 1 in 100 babies. Among CHDs, single ventricle (SV) physiologies, such as hypoplastic left heart syndrome and tricuspid atresia, are particularly severe conditions that require multiple palliative surgeries, including the Fontan procedure. Although the management strategies for SV patients have markedly improved, the prevalence of ventricular dysfunction continues to increase over time, especially after the Fontan procedure. At present, the final treatment for SV patients who develop heart failure is heart transplantation; however, transplantation is difficult to achieve because of severe donor shortages. Recently, various regenerative therapies for heart failure have been developed that increase cardiomyocytes and restore cardiac function, with promising results in adults. The clinical application of various forms of regenerative medicine for CHD patients with heart failure is highly anticipated, and the latest research in this field is reviewed here. In addition, regenerative therapy is important for children with CHD because of their natural growth. The ideal pediatric cardiovascular device would have the potential to adapt to a child's growth. Therefore, if a device that increases in size in accordance with the patient's growth could be developed using regenerative medicine, it would be highly beneficial. This review provides an overview of the available regenerative technologies for CHD patients.


Relevance of community structures and neighbourhood characteristics for participation of older adults: a qualitative study.
Community and neighbourhood structures contribute not only to the health and well-being, but also to the participation of older adults. The degree of participation depends on both the living environment and the individual's personal characteristics, preferences and perception. However, there is still limited empirical evidence on how community and neighbourhood structures are linked to participation and health in the aged population. A qualitative exploratory approach was chosen with a series of problem-centred, semi-structured focus group discussions. Study participants were selected from within the city of Augsburg, Southern Germany, and from two municipalities in surrounding rural districts. The interviews took place in 2013. Structuring content analysis was used to identify key concepts. We conducted 11 focus group discussions with a total of 78 different study participants. The study participants (33 men and 45 women) had a mean age of 74 years (range 65-92 years). Only two study participants lived in an assisted living facility. Of all study participants, 77% lived in urban and 23% in rural areas. We extracted four metacodes ('Usual activities', 'Requirements for participation', 'Barriers to participation' and 'Facilitators for participation') and 15 subcodes. Health and poorly designed infrastructure were mentioned as important barriers to participation, and friendship and neighbourhood cohesion as important facilitators. This qualitative study revealed that poor design and accessibility of municipal infrastructure are major barriers to participation in old age in Germany. Community and neighbourhood structures can be part of the problem but also part of the solution when accessibility and social networks are taken into account.


Painful pigmented prosthesis pressure papules.
Two patients who presented with tender hyperkeratotic papules involving their weight-bear.ing amputation stumps were studied. Although these clinical findings are common in the experience of prosthetists, the author has been unable to find any documentation of these findings in the literature. All attempts at relining and reshaping the cups of the original offending prostheses by experienced prosthetists were unsuccessful. The eruption cleared only after entirely new prostheses were designed. It would appear that this condition is due to a poorly fitting prosthesis.


1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs.
Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC50 of each compound was calculated in our clot lysis assays, and the best candidate (1) provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure-activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi-pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs.


Prevention of Hemophilus influenzae type b disease.
To determine the efficacy of rifampin prophylaxis in eradication of oropharyngeal carriage of Hemophilus influenzae type b and prevention of secondary H influenzae type b disease, we conducted a multicenter placebo-controlled trial among selected persons with invasive H influenzae type b disease. Households and day-care classrooms were randomized so that their members received either rifampin (initially at a dose of 10 mg/kg/dose for two to four days [rifampin-10], but subsequently at 20 mg/kg/dose for four days [rifampin-20]) or placebo. Pretherapy H influenzae type b colonization rates were similar in the treatment groups. Therapy with either rifampin regimen significantly reduced carriage (rifampin-20, 97%; rifampin-10, 63%; placebo, 28%). New acquisition of carriage was also significantly reduced by either rifampin regimen (rifampin-20 or rifampin-10, 2% v placebo, 6%). No rifampin-resistant H influenzae type b isolates emerged after treatment. Four of 765 placebo-treated contacts experienced secondary disease in contrast to zero of 1,112 rifampin-treated contacts. Because chemoprophylaxis of close contacts with rifampin seems to reduce significantly the risk of secondary H influenzae type b disease, we recommend the administration of prophylaxis in households or day-care classrooms where children younger than 4 years have been exposed to the disease.


Metabolic Profile of Synthetic Cannabinoids 5F-PB-22, PB-22, XLR-11 and UR-144 by Cunninghamella elegans.
The knowledge of metabolic profile of synthetic cannabinoids is important for the detection of drugs in urinalysis due to the typical absence or low abundance of parent cannabinoids in human urine. The fungus Cunninghamella elegans has been reported to be a useful tool for metabolism study and thus applicability to synthetic cannabinoid metabolism was examined. In this study, 8-quinolinyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5F-PB-22), 8-quinolinyl 1-pentyl-1H-indole-3-carboxylate (PB-22), [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11) and (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144) were incubated with C. elegans and the metabolites were identified using liquid chromatography-quadrupole time-of-flight mass spectrometry. The obtained metabolites were compared with reported human metabolites to assess the suitability of the fungus to extrapolate human metabolism. 5F-PB-22 underwent dihydroxylation, dihydrodiol formation, oxidative defluorination, oxidative defluorination to carboxylic acid, ester hydrolysis and glucosidation, alone and/or in combination. The metabolites of PB-22 were generated by hydroxylation, dihydroxylation, trihydroxylation, dihydrodiol formation, ketone formation, carboxylation, ester hydrolysis and glucosidation, alone and/or in combination. XLR-11 was transformed through hydroxylation, dihydroxylation, aldehyde formation, carboxylation, oxidative defluorination, oxidative defluorination to carboxylic acid and glucosidation, alone and/or in combination. UR-144 was metabolised by hydroxylation, dihydroxylation, trihydroxylation, aldehyde formation, ketone formation, carboxylation, N-dealkylation and combinations. These findings were consistent with previously reported human metabolism except for the small extent of ester hydrolysis observed and the absence of glucuronidation. Despite the limitations, C. elegans demonstrated the capacity to produce a wide variety of metabolites including some major human metabolites of XLR-11 and UR-144 at high abundance, showing the potential for metabolism of newly emerging synthetic cannabinoids.


Coordination of hand shape.
The neural control of hand movement involves coordination of the sensory, motor, and memory systems. Recent studies have documented the motor coordinates for hand shape, but less is known about the corresponding patterns of somatosensory activity. To initiate this line of investigation, the present study characterized the sense of hand shape by evaluating the influence of differences in the amount of grasping or twisting force, and differences in forearm orientation. Human subjects were asked to use the left hand to report the perceived shape of the right hand. In the first experiment, six commonly grasped items were arranged on the table in front of the subject: bottle, doorknob, egg, notebook, carton, and pan. With eyes closed, subjects used the right hand to lightly touch, forcefully support, or imagine holding each object, while 15 joint angles were measured in each hand with a pair of wired gloves. The forces introduced by supporting or twisting did not influence the perceptual report of hand shape, but for most objects, the report was distorted in a consistent manner by differences in forearm orientation. Subjects appeared to adjust the intrinsic joint angles of the left hand, as well as the left wrist posture, so as to maintain the imagined object in its proper spatial orientation. In a second experiment, this result was largely replicated with unfamiliar objects. Thus, somatosensory and motor information appear to be coordinated in an object-based, spatial-coordinate system, sensitive to orientation relative to gravitational forces, but invariant to grasp forcefulness.


Maternal Migration Background and Mortality Among Infants Born Extremely Preterm.
Extremely preterm infants require care provided in neonatal intensive care units (NICUs) to survive. In the Netherlands, a decision is made regarding active treatment between 24 weeks 0 days and 25 weeks 6 days after consultation with the parents. To investigate the association between maternal migration background and admissions to NICUs and mortality within the first year among extremely preterm infants. This cross-sectional study linked data of registered births in the Netherlands with household-level income tax records and municipality and mortality registers. Eligible participants were households with live births at 24 weeks 0 days to 25 weeks 6 days gestation between January 1, 2010, and December 31, 2017. Data linkage and analysis was performed from March 1, 2020, to June 30, 2023. Maternal migration background, defined as no migration background vs first- or second-generation migrant mother. Admissions to NICUs and mortality within the first week, month, and year of life. Logistic regressions were estimated adjusted for year of birth, maternal age, parity, household income, sex, gestational age, multiple births, and small for gestational age. NICU-specific fixed effects were also included. Among 1405 live births (768 male [54.7%], 546 [38.9%] with maternal migration background), 1243 (88.5%) were admitted to the NICU; 490 of 546 infants (89.7%) born to mothers with a migration background vs 753 of 859 infants (87.7%) born to mothers with no migration background were admitted to NICU (fully adjusted RR, 1.03; 95% CI, 0.99-1.08). A total of 652 live-born infants (46.4%) died within the first year of life. In the fully adjusted model, infants born to mothers with a migration background had lower risk of mortality within the first week (RR, 0.81; 95% CI, 0.66-0.99), month (RR, 0.84; 95% CI, 0.72-0.97), and year of life (RR, 0.85; 95% CI, 0.75-0.96) compared with infants born to mothers with no migration background. In this nationally representative cross-sectional study, infants born to mothers with a migration background at 24 weeks 0 days to 25 weeks 6 days of gestation in the Netherlands had lower risk of mortality within the first year of life than those born to mothers with no migration background, a result that was unlikely to be explained by mothers from different migration backgrounds attending different NICUs or differential preferences for active obstetric management across migration backgrounds. Further research is needed to understand the underlying mechanisms driving these disparities, including parental preferences for active care of extremely preterm infants.


Eastern white-tailed deer as a reservoir of ruminant paratuberculosis.
Ten white-tailed deer were shot and killed at a Connecticut farm that had a 6-year history of bovine paratuberculosis, and organs from these animals were examined for evidence of paratuberculosis. Mycobacterium paratuberculosis was isolated from the cecal lymph node, terminal ileum, and ileocecal valve of 1 deer and from the cecal lymph node of another. Characteristic lesions and acid-fast bacilli were not observed. It was concluded that infected deer could serve as sources of infection for domestic stock.


Prolonged administration of proguanil induces reproductive toxicity in male rats.
The toxicity of proguanil was studied on reproductive activities in male rats using in vivo and in vitro methods. Groups of ten to twelve-week-old rats were administered proguanil (2.9 mg/kg body weight) daily for 5 days and 6 weeks respectively. Thereafter, body and reproductive organ weights were taken, sperm parameters were analyzed, while the histology of the testis and epididymis were carried out. Also, serum levels of testosterone, luteinizing hormone and follicle stimulating hormone were determined. Sertoli cells obtained from sixteen to eighteen day-old-rats were cultured and treated with 0.3 µM to 10 µM of proguanil for 5 days after which Sertoli cell viability and nuclei integrity were determined. Also, the genetic expressions of transferrin and Glial cell line-derived neurotrophic factor (G.D.N.F.) were assessed. The data obtained were analyzed using the analysis of variance (ANOVA) with Students-Newman-Keuls multiple comparison test. The results showed duration dependent significant decrease in body and organ weights and also in sperm parameters. Serum testosterone level was significantly decreased while luteinizing hormone and follicle stimulating hormone showed no significant change. Duration dependent degeneration was also observed in the testis and epididymis of treated rats. These changes were restored in recovery experiment. Viability and DNA integrity of treated Sertoli cells reduced in a dose and duration dependent manner. However, the genetic expressions of transferrin and Glial cell line-derived neurotropic factor were normal. These results show that proguanil could induce infertility in rats which may act by distorting the blood-testis barrier formed by the Sertoli cells.


High density lipoprotein subpopulations in chronic liver disease.
Severe liver disease may be associated with a reduction in plasma concentration of high density lipoprotein and an impairment of plasma cholesterol esterification. These changes were confirmed in two patients with severe acute on chronic alcoholic liver disease. In five additional patients with biopsy-proven clinically compensated cirrhosis, there was minimal reduction in concentration of plasma cholesteryl esters; there was, however a reduction of the plasma high density lipoprotein concentration to only 48 to 66% of normal. The particle size distribution of high density lipoprotein in these five patients was determined by gradient gel electrophoresis. The high density lipoprotein2 subfraction was preserved. The high density lipoprotein3 subfraction, however, was markedly changed with a reduction in the normal particles of radius 4.3 m and an accentuation of smaller particles of radius 3.9 m; in two patients, these smaller particles were the major high density lipoprotein subpopulation. Further investigations of this finding of a distinctive distribution of high density lipoprotein subpopulations in patient with chronic liver disease may provide new insights into high density lipoprotein metabolism.


Developments in the scientific understanding of osteoarthritis.
Osteoarthritis is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity, and trauma--that conspire to incite a cascade of pathophysiologic events within joint tissues. An important emerging theme in osteoarthritis is a broadening of focus from a disease of cartilage to one of the 'whole joint'. The synovium, bone, and cartilage are each involved in pathologic processes that lead to progressive joint degeneration. Additional themes that have emerged over the past decade are novel mechanisms of cartilage degradation and repair, the relationship between biomechanics and biochemical pathways, the importance of inflammation, and the role played by genetics. In this review we summarize current scientific understanding of osteoarthritis and examine the pathobiologic mechanisms that contribute to progressive disease.


Evaluation of the effect of shape on a contemporary CAD system.
The TracerCAD system is one of the leading prosthetic CAD systems in the world and is increasingly used in clinics to replace traditional methods of residual limb shape capture. Accurate dimensional capture of the residuum is arguably the most important process in the production of a prosthetic socket. TracerCAD system accuracy has previously been tested on a cylindrical model but not a trans-tibial shape. Residual limbs are irregular in shape therefore it is important to assess if shape has an effect on the accuracy of data collected when using TracerCAD. The objective of this study is to investigate the accuracy of the TracerCAD system in measuring a model of a trans-tibial stump of known dimensions and volume. A model of a trans-tibial stump was produced and filled with plaster and measured using a data acquisition system with an accuracy of five micron (0.005 mm). The model was repeatedly traced using the TracerCAD system by an individual user. The mean value of measures taken by the dynamic indicator was calculated and compared to individual and mean values of TracerCAD measurement. Results showed that the TracerCAD measurement was not as consistent on the more complex trans-tibial model as for the cylindrical model.


Mobility Deficits Assessed With Mobile Technology: What Can We Learn From Brain Iron-Altered Animal Models?
Background: Recent developments in mobile technology have enabled the investigation of human movements and mobility under natural conditions, i.e., in the home environment. Iron accumulation in the basal ganglia is deleterious in Parkinson's disease (i.e., iron accumulation with lower striatal level of dopamine). The effect of iron chelation (i.e., re-deployment of iron) in Parkinson's disease patients is currently tested in a large investigator-initiated multicenter study. Conversely, restless legs syndrome (RLS) is associated with iron depletion and higher striatal level of dopamine. To determine from animal models which movement and mobility parameters might be associated with iron content modulation and the potential effect of therapeutic chelation inhuman. Methods: We recapitulated pathophysiological aspects of the association between iron, dopamine, and neuronal dysfunction and deterioration in the basal ganglia, and systematically searched PubMed to identify original articles reporting about quantitatively assessed mobility deficits in animal models of brain iron dyshomeostasis. Results: We found six original studies using murine and fly models fulfilling the inclusion criteria. Especially postural and trunk stability were altered in animal models with iron overload. Animal models with lowered basal ganglia iron suffered from alterations in physical activity, mobility, and sleep fragmentation. Conclusion: From preclinical investigations in the animal model, we can deduce that possibly also in humans with iron accumulation in the basal ganglia undergoing therapeutic chelation may primarily show changes in physical activity (such as daily "motor activity"), postural and trunk stability and sleep fragmentation. These changes can readily be monitored with currently available mobile technology.


Bacterial dispersal and biogeography as underappreciated influences on phytobiomes.
Bacterial strains are not distributed evenly throughout the environment. Here I explore how differential distribution and dispersal patterns of bacteria could affect interactions and coevolutionary dynamics with plants, and highlight ways that variation could be taken advantage of to develop robust and effective microbial consortia to inoculate crops. Questions about biogeographical patterns in viruses, fungi, and other eukaryotes are equally as prevalent and important for agriculture, and are in some cases more thoroughly explored. For simplicity as well as to bring attention to bacterial biogeography and dispersal in the context of plant interactions, I focus solely on bacterial patterns and questions for this article. The next few years will no doubt bring great advances in our understanding of dispersal capabilities and population dynamics for many plant-associated bacteria, and one of the next looming challenges will be learning to harvest this diversity in ways that can benefit agriculture.


Juvenile Coffee Leaves Acclimated to Low Light Are Unable to Cope with a Moderate Light Increase.
The understorey origin of coffee trees and the strong plasticity of Coffea arabica leaves in relation to contrasting light environments have been largely shown. The adaptability of coffee leaves to changes in light was tested under controlled conditions by increasing the illumination rate on C. arabica var. Naryelis seedlings acclimated to low light conditions and observing leaf responses at three different developmental stages (juvenile, growing and mature). Only mature leaves proved capable of adapting to new light conditions. In these leaves, different major mechanisms were found to contribute to maintaining a good photosynthetic level. With increased illumination, a high photosynthetic response was conserved thanks to fast nitrogen remobilization, as indicated by SPAD values and the photorespiration rate. Efficient photoprotection was accompanied by a great ability to export sucrose, which prevented excessive inhibition of the Calvin cycle by hexose accumulation. In contrast, in younger leaves, increased illumination caused photodamage, observable even after 9 days of treatment. One major finding was that young coffee leaves rely on the accumulation of chlorogenic acids, powerful antioxidant phenolic compounds, to deal with the accumulation of reactive oxygen species rather than on antioxidant enzymes. Due to a lack of efficient photoprotection, a poor ability to export sucrose and inadequate antioxidant protection, younger leaves seemed to be unable to cope with increased illumination. In these leaves, an absence of induced antioxidant enzyme activity was accompanied, in growing leaves, by an absence of antioxidant synthesis or, in juvenile leaves, inefficient synthesis of flavonoids because located in some epidermis cells. These observations showed that coffee leaves, at the beginning of their development, are not equipped to withstand quick switches to higher light levels. Our results confirm that coffee trees, even selected for full sunlight conditions, remain shade plants possessing leaves able to adapt to higher light levels only when mature.


Tetragonal allotrope of group 14 elements.
Group 14 elements (C, Si, and Ge) exist as various stable and metastable allotropes, some of which have been widely applied in industry. The discovery of new allotropes of these elements has long attracted considerable attention; however, the search is far from complete. Here we computationally discovered a tetragonal allotrope (12 atoms/cell, named T12) commonly found in C, Si, and Ge through a particle swarm structural search. The T12 structure employs sp(3) bonding and contains extended helical six-membered rings interconnected by pairs of five- and seven-membered rings. This arrangement results in favorable thermodynamic conditions compared with most other experimentally or theoretically known sp(3) species of group 14 elements. The T12 polymorph naturally accounts for the experimental d spacings and Raman spectra of synthesized metastable Ge and Si-XIII phases with long-puzzling unknown structures, respectively. We rationalized an alternative experimental route for the synthesis of the T12 phase via decompression from the high-pressure Si- or Ge-II phase.


Glycemic and risk factor control in type 1 diabetes: results from 13,612 patients in a national diabetes register.
This study was designed to investigate the clinical characteristics of a large type 1 diabetic population and to evaluate the degree of fulfillment of recently updated treatment goals. The Swedish National Diabetes Register was initiated in 1996 as a tool for quality assurance in diabetes care. A1C levels, treatment, and risk factors were analyzed in two cross-sectional samples of 9,424 patients in 1997 and 13,612 patients in 2004 and in a smaller longitudinal sample from 1997 to 2004. Mean A1C decreased from 8.2 +/- 1.3% in 1997 to 8.0 +/- 1.2% in 2004 (P < 0.001). The proportion of patients reaching A1C <7.0% increased from 17.4 to 21.2% in 2004. A slow but significant improvement in blood pressure levels was seen, but only 61.3% reached the blood pressure goal of <130/80 mmHg in 2004. Lipid control improved, and the use of lipid-lowering drugs increased. Among patients treated with lipid-lowering agents, 38% reached the goal of total cholesterol <4.5 mmol/l, and 48% reached the goal of LDL cholesterol <2.5 mmol/l. Successful long-term glycemic and blood pressure control were both independently predicted by low BMI and the absence of microalbuminuria in 1997. In this large cohort of type 1 diabetic patients, there was a slow improvement in glycemic and risk factor control from 1997 to 2004, although the gap between the clinical results and current Swedish and American treatment goals is still unsatisfactory. It is crucial that additional measures be taken to improve risk factor control in type 1 diabetic patients.


hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer.
Some exons contain exon splicing silencers. Their activity is frequently balanced by that of splicing enhancers, and this is important to ensure correct relative levels of alternatively spliced mRNAs. Using an immunoprecipitation and UV-cross-linking assay, we show that RNA molecules containing splicing silencers from the human immunodeficiency virus type 1 tat exon 2 or the human fibroblast growth factor receptor 2 K-SAM exon bind to hnRNP A1 in HeLa cell nuclear extracts better than the corresponding RNA molecule without a silencer. Two different point mutations which abolish the K-SAM exon splicing silencer's activity reduce hnRNP A1 binding twofold. Recruitment of hnRNP A1 in the form of a fusion with bacteriophage MS2 coat protein to a K-SAM exon whose exon splicing silencer has been replaced by a coat binding site efficiently represses splicing of the exon in vivo. Recruitment of only the glycine-rich C-terminal domain of hnRNP A1, which is capable of interactions with other proteins, is sufficient to repress exon splicing. Our results show that hnRNP A1 can function to repress splicing, and they suggest that at least some exon splicing silencers could work by recruiting hnRNP A1.


[Compounds from the chlordane group in adipose tissue of harbour seals from the Gulf of Gdansk].
The composition and the concentration of chlordanes were shown in blubber of harbour porpoises collected from the Gulf of Gdańsk, Baltic Sea, in 1991-1992. Chlordanes were determined using capillary gas chromatography and low resolution mass spectrometry (HRGC/LRMS). The range of CHLs concentration in blubber was between 420-1000 ng/g wet weight (470-1300 ng/g lipid weight). The composition of CHLs residues was similar in males and females, with trans-nonachlor (37%) as a most abundant compound, and followed by heptachlor epoxide (15%), cis-chlordane (14%), cis-nonachlor (14%), oxychlordane (11%), MC6 (3%), MC5 (2%), trans-chlordane, MC7, U82 and MC4 (< 1%).


Detection of ubiquitinated huntingtin species in intracellular aggregates.
Protein conformation diseases, including polyglutamine (polyQ) diseases, result from the accumulation and aggregation of misfolded proteins. Huntington's disease (HD) is one of nine diseases caused by an expanded polyQ repeat within the affected protein and is hallmarked by intracellular inclusion bodies composed of aggregated N-terminal huntingtin (Htt) fragments and other sequestered proteins. Fluorescence microscopy and filter trap assay are conventional methods to study protein aggregates, but cannot be used to analyze the presence and levels of post-translational modifications of aggregated Htt such as ubiquitination. Ubiquitination of proteins can be a signal for degradation and intracellular localization, but also affects protein activity and protein-protein interactions. The function of ubiquitination relies on its mono- and polymeric isoforms attached to protein substrates. Studying the ubiquitination pattern of aggregated Htt fragments offers an important possibility to understand Htt degradation and aggregation processes within the cell. For the identification of aggregated Htt and its ubiquitinated species, solubilization of the cellular aggregates is mandatory. Here we describe methods to identify post-translational modifications such as ubiquitination of aggregated mutant Htt. This approach is specifically described for use with mammalian cell culture and is suitable to study other disease-related proteins prone to aggregate.


Arterial Pressure and the Rate of Elimination of Crystalloid Fluid.
Excretion of crystalloid fluid is slow during general anesthesia. The distribution and elimination of buffered Ringer's solution were analyzed to determine whether the rate of elimination correlates with a hemodynamic factor, consciousness, patient posture, or the type of general anesthesia. Data were derived from 4 separately published studies in which 30 volunteers and 48 anesthetized patients had received 0.833 (1 series 0.667) mL/kg/min of lactated or acetated Ringer's solution over 30 minutes. Frequent measurements of the blood hemoglobin and mean urinary excretion were used as input in a kinetic analysis according to a 2-volume model and covariates, using microconstants and mixed-effects modeling software.The results show that rate of elimination of crystalloid fluid decreased with the mean arterial pressure (MAP) and patient age, but was unaffected by consciousness and inhalational or intravenous anesthesia. The elimination rate constant was 6.5 (95% confidence interval, 5.2-7.9) × 10 × (MAP/mean MAP) × (Age/mean Age). The mean MAP for the 2108 data points was 81.3 mm Hg and the mean age was 40 years. The central fluid space that was expanded by infused fluid (Vc, plasma volume) increased with body weight but decreased with general anesthesia and with reductions of MAP.Simulations revealed a more than 10-fold difference in the excreted fluid volume after a theoretical 30-minute infusion, depending on whether the MAP was 50 or 100 mm Hg.In conclusion, the rate of elimination of crystalloid fluid decreased in proportion to MAP but was independent of general anesthesia and moderate-sized surgery.


Ultra-compact broadband polarization diversity orbital angular momentum generator with 3.6 × 3.6 μm2 footprint.
Orbital angular momentum (OAM), one fundamental property of light, has been of great interest over the past decades. An ideal OAM generator, fully compatible with existing physical dimensions (wavelength and polarization) of light, would offer the distinct features of broadband, polarization diversity, and ultra-compact footprint. Here, we propose, design, fabricate, and demonstrate an ultra-compact chip-scale broadband polarization diversity OAM generator on a silicon platform with a 3.6 × 3.6 μm2 footprint. The silicon OAM chip is formed by introducing a subwavelength surface structure (superposed holographic fork gratings) on top of a silicon waveguide, coupling the in-plane waveguide mode to the out-plane free-space OAM mode. We demonstrate in theory and experiment the broadband generation of polarization diversity OAM modes (x-/y-polarized OAM+1/OAM-1) from 1500 to 1630 nm with high purity and efficiency. The demonstrations of an ultra-compact broadband polarization diversity OAM generator may open up new perspectives for OAM-assisted N-dimensional optical multiplexing communications/interconnects and high-dimensional quantum communication systems.


Clustering on Player Types of Students in Health Science - Trial and Data Analyses.
Gamification has many positive effects, such as increased motivation, engagement, and well-being of users. For this purpose, a wide field of game mechanics is already available that can be used in teaching. For the development of gamified teaching methods, it's important to adapt the mechanics used to the students. There are different models that divide target groups of games and gamification into player types to understand what motivates the respective users. This paper describes a study of player types among students of health-related disciplines and analyses the data by a K-Means clustering procedure. The player types Socializer, Player and Achiever are found, and game elements for this groups are suggested. Thus, in the field of health education, game mechanics can be used, which are suitable for students of this domain.


A prospective randomized trial of perioperative cefazolin treatment in axillary and groin dissection.
One hundred thirty-four patients undergoing axillary or inguinal lymph node dissection were randomized to receive perioperative treatment with either cefazolin or placebo. Risk factors for wound complications (age greater than 60 years, open wound, obesity, smoking, extremity edema, diabetes, arteriosclerotic cardiovascular disease) were recorded. The rate of complications was 36% in 97 patients (72%) with any risk factor present, compared with 14% in patients with no risk factors. Complications were seen in 30% of patients: in 14% after axillary lymph node dissection, and in 64% after inguinal lymph node dissection. The risk of complications was 23% in the group administered antibiotic treatment compared with 36% in that administered placebo treatment. This trend toward fewer complications was seen only after axillary lymph node dissection, when the rate of complications was 8% in the antibiotic-treated group compared with 20% in the placebo-treated group. After inguinal lymph node dissection, the rate of complications was 69% in the antibiotic-treated group compared with 62% in the placebo-treated group.


Sildenafil increases serum testosterone levels by a direct action on the testes.
Phosphodiesterase-5-inhibitors, such as sildenafil, increase intracavernosal cyclic guanosine monophosphate levels, which results in corporal smooth muscle relaxation and penile erection. Here, we determined the effects of sildenafil administration on the hypothalamic-pituitary-gonadal axis in men with erectile dysfunction and low testosterone levels. The Testosterone and Erectile Dysfunction trial (ClinicalTrials.gov # NCT00512707) initially administered an optimized dose of sildenafil to 140 men, aged 40-70 years with erectile dysfunction, low serum total testosterone (<11.4 nmol/L; 330 ng/dL) and/or free testosterone (<173 pmol/L; 50 pg/mL) over 3-7 weeks. Sex steroids and gonadotropins were measured at baseline and after sildenafil optimization in a longitudinal study without a separate control group. Serum testosterone, dihydrotestosterone (DHT) and oestrogens were measured using liquid chromatography-tandem mass spectrometry. Administration of an optimized dose of sildenafil was associated with mean increases of 3.6 nmol/L (103 ng/dL; p < 0.001) and 110 pmol/L (31.7 pg/mL; p < 0.001) in total and free testosterone levels respectively. This was accompanied by parallel increases in serum DHT (0.17 nmol/L; 4.9 ng/dL; p < 0.001) and oestradiol (14 pmol/L; 3.7 pg/mL; p < 0.001) and significant suppression of luteinizing hormone (change -1.3 units/L; p = 0.003) levels, suggesting a direct effect at the testicular level. Androstenedione and oestrone increased by 1.3 nmol/L (38 ng/dL; p = 0.011) and 10.7 pmol/L (2.9 pg/mL; p = 0.012), respectively, supporting a possible effect of sildenafil on adrenal steroidogenesis. In conclusion, sildenafil administration was associated with increased testosterone levels likely ascribable to a direct effect on the testis.


Pelvic floor dysfunction: assessment with combined analysis of static and dynamic MR imaging findings.
To prospectively analyze static and dynamic magnetic resonance (MR) images simultaneously to determine whether stress urinary incontinence (SUI), pelvic organ prolapse (POP), and anal incontinence are associated with specific pelvic floor abnormalities. This study had institutional review board approval, and informed consent was obtained from all participants. There were 59 women: 15 nulliparous study control women (mean age, 25.6 years) and 44 patients (mean age, 43.4 years), who were divided into four groups according to chief symptom. Static T2-weighted turbo spin-echo images were used in evaluating structural derangements; functional dynamic (cine) balanced fast-field echo images were used in detecting functional abnormalities and recording five measurements of supporting structures. Findings on both types of MR images were analyzed together to determine the predominant defect. Analysis of variance and the Bonferroni t test were used to compare groups. In the four patient groups, POP was associated with levator muscle weakness in 16 (47%) of 34 patients, with level I and II fascial defects in seven (21%) of 34 patients, and with both defects in 11 (32%) of 34 patients. SUI was associated with defects of the urethral supporting structures in 25 (86%) of 29 patients but was not associated with bladder neck descent. Levator muscle weakness may lead to anal incontinence in the absence of anal sphincter defects. Measurements of supporting structures were significant (P < .05) in the identification of pelvic floor laxity. Combined analysis of static and dynamic MR images of patients with pelvic floor dysfunction allowed identification of certain structural abnormalities with specific dysfunctions.


Test-retest reliability and agreement of the Satisfaction with the Assistive Technology Services (SATS) instrument in two Nordic countries.
The purpose of this study was to investigate test-retest reliability, agreement, internal consistency, and floor- and ceiling effects of the Danish and Finnish versions of the Satisfaction with the Assistive Technology Services (SATS) instrument among adult users of powered wheelchairs (PWCs) or powered scooters (scooters). Test-retest design, two telephone interviews 7-18 days apart of 40 informants, with mean age of 67.5 (SD 13.09) years in the Danish; and 54 informants with mean age of 55.6 (SD 12.09) years in the Finnish sample. The intra-class correlation coefficient varied between 0.57 and 0.93 for items in the Danish and between 0.41 and 0.93 in the Finnish sample. The percentage agreement varied between 54.2 and 79.5 for items in the Danish and between 69.2 and 81.1 in the Finnish sample, while the Cronbach's alpha values varied between 0.87 and 0.96 in the two samples. A ceiling effect was found in all items of both samples. This study indicates that the SATS may be reliably administered for telephone interviews among adult PWC and scooter users, and give information about aspects of the service delivery process for quality development improvement purposes. Further psychometric testing of the SATS is required.


Polymer-Coated Hydroxyapatite Nanocarrier for Double-Stranded RNA Delivery.
Conventional synthetic insecticides have limited success due to insect resistance and negative effects on off-target biota and the environment. Although RNA interference (RNAi) is a tool that is becoming more widely utilized in pest control products, naked dsRNA has limited success in most taxa. Nanocarriers have shown promising results in enhancing the efficacy of this tool. In this study, we used a layer-by-layer electrostatic assembly where we synthesized poly(acrylic acid) (PAA)-coated hydroxyapatite (HA) nanoparticles (PAA-HA NPs) as inorganic nanocarriers, which were then coated with a layer of a cationic poly(amino acid), 10 kDa poly-l-arginine (PLR10), to allow for binding of a layer of negatively charged dsRNA. Binding of PLR10-PAA-HA NPs to dsRNA was found to increase as the mass ratio of NPs to dsRNA increased. In vitro studies with transgenic SF9 cells (from Spodoptera frugiperda) expressing the firefly luciferase gene showed a significant gene silencing (35% decrease) at a 5:1 NP-to-dsRNA ratio, while naked dsRNA was ineffective at gene silencing. There was a significant concentration-response relationship in knockdown; however, cytotoxicity was observed at higher concentrations. Confocal microscopy studies showed that dsRNA from PLR10-PAA-HA NPs was not localized within endosomes, while naked dsRNA appeared to be entrapped within the endosomes. Overall, polymer-functionalized HA nanocarriers enabled dsRNA to elicit gene knockdown in cells, whereas naked dsRNA was not effective in causing gene knockdown.


Keywords and Co-Occurrence Patterns in the Voynich Manuscript: An Information-Theoretic Analysis.
The Voynich manuscript has remained so far as a mystery for linguists and cryptologists. While the text written on medieval parchment -using an unknown script system- shows basic statistical patterns that bear resemblance to those from real languages, there are features that suggested to some researches that the manuscript was a forgery intended as a hoax. Here we analyse the long-range structure of the manuscript using methods from information theory. We show that the Voynich manuscript presents a complex organization in the distribution of words that is compatible with those found in real language sequences. We are also able to extract some of the most significant semantic word-networks in the text. These results together with some previously known statistical features of the Voynich manuscript, give support to the presence of a genuine message inside the book.


The effects of strontium-substituted bioactive glasses on osteoblasts and osteoclasts in vitro.
Bioactive glasses (BG) which contain strontium have the potential to combine the known bone regenerative properties of BG with the anabolic and anti-catabolic effects of strontium cations. Here we created a BG series (SiO(2)-P(2)O(5)-Na(2)O-CaO) in which 0-100% of the calcium was substituted by strontium and tested their effects on osteoblasts and osteoclasts in vitro. We show that ions released from strontium-substituted BG enhance metabolic activity in osteoblasts. They also inhibit osteoclast activity by both reducing tartrate resistant acid phosphatase activity and inhibiting resorption of calcium phosphate films in a dose-dependent manner. Additionally, osteoblasts cultured in contact with BG show increased proliferation and alkaline phosphatase activity with increasing strontium substitution, while osteoclasts adopt typical resorption morphologies. These results suggest that similarly to the osteoporosis drug strontium ranelate, strontium-substituted BG may promote an anabolic effect on osteoblasts and an anti-catabolic effect on osteoclasts. These effects, when combined with the advantages of BG such as controlled ion release and delivery versatility, may make strontium-substituted BG an effective biomaterial choice for a range of bone regeneration therapies.