A proof-of-concept study for developing integrated two-photon microscopic and magnetic resonance imaging modality at ultrahigh field of 16.4 tesla.
Functional magnetic resonance imaging (fMRI) based on the blood oxygen level dependent (BOLD) contrast has gained a prominent position in neuroscience for imaging neuronal activity and studying effective brain connectivity under working state and functional connectivity at resting state. However, the fundamental questions in regards to fMRI technology: how the BOLD signal inferences the underlying microscopic neuronal activity and physiological changes and what is the ultimate specificity of fMRI for functional mapping of microcircuits, remain unanswered. The capability of simultaneous fMRI measurement and functional microscopic imaging in a live brain thus holds the key to link the microscopic and mesoscopic neural dynamics to the macroscopic brain activity at the central nervous system level. Here we report the first demonstration to integrate high-resolution two-photon fluorescence microscopy (TPM) with a 16.4 tesla MRI system, which proves the concept and feasibility for performing simultaneous high-resolution fMRI and TPM imaging at ultrahigh magnetic field.


Variable rewards and discrimination ability in an insect herbivore: what and how does a hungry locust learn?
With the exception of honeybees, there have been few good invertebrate models for associative learning. Grasshoppers and locusts (Orthoptera: Acrididae) possess a number of characteristics that make them excellent candidates for such studies, and in this paper we present a novel protocol, based on a Y-maze, that is specifically designed for studying their learning and choice behaviour. Three separate experiments were conducted using individual gregarious forms of the desert locust, Schistocerca gregaria. In our first experiment, coloured arms of a two-sided Y-maze provided a large or small amount of wheat for nine choice-trials. In the second experiment, locusts discriminated odours with wheat rewards for nine choice-trials. The odour-wheat reward combinations were then reversed for an additional nine choice-trials. For the third experiment, the locusts again discriminated odours, but here we used artificial foods and the rewards differed in their concentration of protein and digestible carbohydrate. The results indicate that, in addition to showing good acquisition of choice performance, the locusts also took less time to reach the larger-rewarded option. The data indicate that our protocol is highly sensitive for recording choice behaviour in acridids and reveals the potential they have for advancing our current understanding of associative learning and the field of learning in general.


Biochemical properties and regulated gene expression of the superoxide dismutase from the facultatively aerobic hyperthermophile Pyrobaculum calidifontis.
Superoxide dismutase (SOD) was purified from a facultatively aerobic hyperthermophilic archaeon, Pyrobaculum calidifontis VA1. The purified native protein from aerobically grown cells exhibited 1,960 U of SOD activity/mg and contained 0.86 +/- 0.04 manganese and <0.01 iron atoms per subunit. The gene encoding SOD was cloned and expressed in Escherichia coli. Although the recombinant protein was soluble, little activity was observed due to the lack of metal incorporation. Reconstitution of the enzyme by heat treatment with either Mn or Fe yielded a highly active protein with specific activities of 1,970 and 434 U/mg, respectively. This indicated that the SOD from P. calidifontis was a cambialistic SOD with a preference toward Mn in terms of activity. Interestingly, reconstitution experiments in vitro indicated a higher tendency of the enzyme to incorporate Fe than Mn. When P. calidifontis was grown under anaerobic conditions, a majority of the native SOD was incorporated with Fe, indicating the cambialistic property of this enzyme in vivo. We further examined the expression levels of SOD and a previously characterized Mn catalase from this strain in the presence or absence of oxygen. Northern blot, Western blot, and activity measurement analyses revealed that both genes are expressed at much higher levels under aerobic conditions. We also detected a rapid response in the biosynthesis of these enzymes once the cells were exposed to oxygen.


A note on the relationship between the comfortable interpersonal distance scale and the sociometric status of emotionally disturbed children.
The purpose of this study was to investigate the relationship between two measures of social attraction or status: namely, the recently developed Comfortable Interpersonal Distance (CID) Scale and a traditional measure of sociometric status. Both measures were recorded for a sample of emotionally disturbed, preadolescent boys who were in residential treatment. The results indicated that the two measures were very highly correlated. This finding means that the more a boy was liked by his cottage peers, the closer these peers indicated that they would like to sit next to the boy in a room. In other words, physical interpersonal distance seems to be nonverbal way of communicating liking for a person.


Acute effects of sertraline, amitriptyline, and placebo on the psychomotor performance of healthy subjects over 50 years of age.
A double-blind, placebo-controlled, crossover study in 12 subjects (greater than or equal to 50 years) compared the effects of single oral doses of sertraline (100 mg) and amitriptyline (50 mg) with placebo as assessed by psychomotor function testing. Unlike sertraline and placebo, amitriptyline increased tracking error severity and impaired digit/symbol substitution. Sertraline slightly improved flicker frequency recognition. Both active drugs caused subjective drowsiness, although amitriptyline's effect was greater and of longer duration. Both drugs impaired subjectively assessed performance. Sertraline caused nausea, and amitriptyline, dry mouth; sertraline tended to increase supine systolic blood pressure. The authors conclude that sertraline has a considerably less detrimental effect on psychomotor performance and may have a slight activating effect not found with amitriptyline.


Phosphodiesterase 9A Inhibition Facilitates Corticostriatal Transmission in Wild-Type and Transgenic Rats That Model Huntington's Disease.
Huntington's disease (HD) results from abnormal expansion in CAG trinucleotide repeats within the HD gene, a mutation which leads to degeneration of striatal medium-sized spiny neurons (MSNs), deficits in corticostriatal transmission, and loss of motor control. Recent studies also indicate that metabolism of cyclic nucleotides by phosphodiesterases (PDEs) is dysregulated in striatal networks in a manner linked to deficits in corticostriatal transmission. The current study assessed cortically-evoked firing in electrophysiologically-identified MSNs and fast-spiking interneurons (FSIs) in aged (9-11 months old) wild-type (WT) and BACHD transgenic rats (TG5) treated with vehicle or the selective PDE9A inhibitor PF-04447943. WT and TG5 rats were anesthetized with urethane and single-unit activity was isolated during low frequency electrical stimulation of the ipsilateral motor cortex. Compared to WT controls, MSNs recorded in TG5 animals exhibited decreased spike probability during cortical stimulation delivered at low to moderate stimulation intensities. Moreover, large increases in onset latency of cortically-evoked spikes and decreases in spike probability were observed in FSIs recorded in TG5 animals. Acute systemic administration of the PDE9A inhibitor PF-04447943 significantly decreased the onset latency of cortically-evoked spikes in MSNs recorded in WT and TG5 rats. PDE9A inhibition also increased the proportion of MSNs responding to cortical stimulation and reversed deficits in spike probability observed in TG5 rats. As PDE9A is a cGMP specific enzyme, drugs such as PF-04447943 which act to facilitate striatal cGMP signaling and glutamatergic corticostriatal transmission could be useful therapeutic agents for restoring striatal function and alleviating motor and cognitive symptoms associated with HD.


Low BMI increases all-cause mortality rates in patients with drug-resistant TB.
BACKGROUND: Loss to follow-up (LTFU) is common among patients with drug-resistant TB (DR-TB) receiving second-line TB treatment; however, little is known about outcomes after LTFU, including mortality.OBJECTIVE: To determine rates of and factors associated with all-cause mortality among patients with DR-TB who were LTFU.METHODS: Retrospective cohort study of adult patients with DR-TB in Georgia who initiated second-line TB treatment during 2011-2014 and were LTFU. Survival analyses were used to estimate all-cause mortality rates and adjusted hazard ratios (aHR).RESULTS: During 2011-2014, 2,437 second-line treatment episodes occurred and 695 patients were LTFU. Among 695 LTFU patients, 143 (21%) died during 2,686 person-years (PY) post-LTFU (all-cause mortality rate 5.1%, 95% CI 4.3-6.0 per 100 PY). In multivariable analysis, low weight (BMI < 18.5 kg/m²) at treatment initiation (aHR 3.2, 95% CI 2.2-4.7), return to treatment after LTFU (aHR 3.1, 95% CI 2.2-4.4), <12 months of treatment (aHR 2.4, 95% CI 1.4-4.1) and a pre-LTFU positive culture (aHR 3.3, 95% CI 2.2-4.9) were associated with all-cause mortality.CONCLUSION: High all-cause mortality occurred among patients with DR-TB after LTFU despite a low HIV prevalence. Providing additional assistance for patients during DR-TB treatment to prevent LTFU and use of new and shorter treatment regimens may reduce mortality among LTFU.


Improving carbohydrate and starch accumulation in Chlorella sp. AE10 by a novel two-stage process with cell dilution.
Microalgae are highly efficient cellular factories that capture CO2 and are also alternative feedstock for biofuel production. Carbohydrates, proteins, and lipids are major biochemical components in microalgae. Carbohydrates or starch in microalgae are possible substrates in yeast fermentation for biofuel production. The carbon partitioning in microalgae could be regulated through environmental stresses, such as high concentration of CO2, high light intensity, and nitrogen starvation conditions. It is essential to obtain carbohydrate-rich microalgae via an optimal bioprocess strategy. The carbohydrate accumulation in a CO2 tolerance strain, Chlorella sp. AE10, was investigated with a two-stage process. The CO2 concentration, light intensity, and initial nitrogen concentration were changed drastically in both stages. During the first stage, it was cultivated over 3 days under 1% CO2, a photon flux of 100 μmol m-2 s-1, and 1.5 g L-1 NaNO3. It was cultivated under 10% CO2, 1000 μmol m-2 s-1, and 0.375 g L-1 NaNO3 during the second stage. In addition, two operation modes were compared. At the beginning of the second stage of mode 2, cells were diluted to 0.1 g L-1 and there was no cell dilution in mode 1. The total carbohydrate productivity of mode 2 was increased about 42% compared with that of mode 1. The highest total carbohydrate content and the highest starch content of mode 2 were 77.6% (DW) and 60.3% (DW) at day 5, respectively. The starch productivity was 0.311 g L-1 day-1 and the total carbohydrate productivity was 0.421 g L-1 day-1 in 6 days. In this study, a novel two-stage process was proposed for improving carbohydrate and starch accumulation in Chlorella sp. AE10. Despite cell dilution at the beginning of the second stage, environmental stress conditions of high concentration of CO2, high light intensity, and limited nitrogen concentration at the second stage were critical for carbohydrate and starch accumulation. Although the cells were diluted, the growths were not inhibited and the carbohydrate productivity was improved. These results were helpful to establish an integrated approach from CO2 capture to biofuel production by microalgae.


Validation of Risk Factors for Fecal Incontinence in Patients With Crohn's Disease.
Fecal incontinence has a great impact on daily life, and many patients are reluctant to report it. The purpose of this study was to estimate the prevalence of fecal incontinence in patients with Crohn's disease, validate risk factors, and relate outcome with quality of life. The design was cross-sectional. The study was conducted at an academic tertiary center. Consecutive patients with Crohn's disease treated between 2003 and 2013 were included in this study. A questionnaire was sent out in October 2013 to evaluate perianal disease, current symptoms of fecal incontinence, and its impact on quality of life (Fecal Incontinence Quality of Life questionnaire). Risk factors were validated with univariate and multivariate analyses. The questionnaire was responded by 325 (62%) of 528 patients. Median age was 42 years (range, 18-91 y), 215 (66%) were women, and a diagnosis of Crohn's disease was established for a median period of 12 years (interquartile range, 6-21 y). Fecal incontinence was reported by 65 patients (20%). Fecal incontinence was associated with liquid stools (p = 0.0001), previous IBD-related bowel resections (p = 0.001), stricturing behavior of disease (p = 0.02), and perianal disease (p = 0.03). Quality of life (lifestyle, coping, depression, and embarrassment) was poor in patients with fecal incontinence, particularly in patients with more frequent episodes of incontinence. There was no correction for disease activity in the multivariate regression analysis. The prevalence of fecal incontinence in a tertiary population with Crohn's disease is substantially higher than in the community-dwelling population. Considering the reduced quality of life in incontinent patients, active questioning to identify fecal incontinence is recommended in those with liquid stools, perianal disease, or previous (intestinal or perianal) surgery. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.


Pretreatment with activated protein C or active human urinary thrombomodulin attenuates the production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in rat liver.
We investigated the role of anticoagulant in the ischemia/reperfusion injury of the liver, using activated protein C (APC), active human urinary thrombomodulin (UTM), and factor Xa blocked at the active site (DEGR-Xa). Liver ischemia was induced in male Wistar rats by occlusion of the portal vein with a microvascular clip for 30 minutes. Each anticoagulant was injected intravenously 10 minutes before clamping the portal vein. Serum concentrations of cytokine-induced neutrophil chemoattractant (CINC) were determined by enzyme-linked immunosorbent assay. The serum levels of CINC increased significantly following reperfusion, reaching a peak in 6 hours, and then decreasing gradually to control levels by 24 hours. CINC levels in rats pretreated with APC (500 U/kg), UTM (3,000 TMU/kg), or DEGR-Xa (10 mg/kg) peaked 3 hours following reperfusion and decreased rapidly to baseline level within 6 and 12 hours, respectively. These peak values were significantly lower than those observed in untreated rats (P < .01). Expression of CINC transcripts in liver tissue of untreated rats was evaluated by Northern blot analysis and peaked 3 hours following reperfusion. Pretreatment with these anticoagulants significantly decreased the expression of CINC messenger RNA transcripts as compared with untreated animals. Myeloperoxidase activity and the number of neutrophils accumulated into the liver 24 hours following ischemia/reperfusion were also significantly decreased in animals pretreated with these anticoagulants. In addition, correlations between the peak values of liver enzymes and serum CINC levels were found to be significant (P < .001). The inactive derivative of factor Xa, a selective inhibitor of thrombin generation, inhibited ischemia/reperfusion-induced increases in the serum concentration and messenger RNA transcript quantities of CINC. The inactive factor Xa also reduced hepatic accumulation of neutrophils after ischemia/reperfusion. These results indicate that the release of CINC is likely related to the hepatic microcirculation disturbance induced by microthrombotic occlusion following ischemia/reperfusion.


O-GlcNAcylation modulates Bmi-1 protein stability and potential oncogenic function in prostate cancer.
The Polycomb group transcriptional repressor Bmi-1 often overexpressed and participated in stem cells self-renewal and tumorigenesis initiating of prostate cancer. In this progression, Bmi-1 protein was regulated by transcription and post-translational modifications (PTMs). Nobly, the underlying PTMs regulation of Bmi-1 is poorly known. Here we use co-immunoprecipitation show that in C4-2 cell line, Bmi-1 directly interacted with OGT which is the only known enzyme catalyzed the O-GlcNAcylation in human. Furthermore, we identified that Ser255 is the site for Bmi-1 O-GlcNAcylation, and O-GlcNAcylation promoted Bmi-1 protein stability and its oncogenic activity. Finally, microarray analysis has characterized potential oncogenes associated pathway subject to repression via the OGT-Bmi-1 axis. Taken together, these results indicate that OGT-mediated O-GlcNAcylation at Ser255 stabilizes Bmi-1 and hence inhibits the TP53, PTEN and CDKN1A/CDKN2A pathway. The study not only uncovers a novel functional PTMs of Bmi-1 but also reveals a unique oncogenic role of O-GlcNAcylation in prostate cancer.


Respiratory effects in children from passive smoking of cigarettes and narghile: ISAAC Phase Three in Syria.
The association between environmental tobacco smoke (ETS) and asthma symptoms is well documented, but a causal relationship is inconclusive. International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three was the first to report a dose-response relationship between current wheezing and exposure to parental cigarette smoke. As exposure of children to water pipe (narghile) smoke is of concern in Syria, in the ISAAC Phase Three Tartous Centre we also examined the role of parental smoking of the narghile. Parents of children aged 6-7 years completed core written questionnaires about the prevalence of symptoms, and an environmental questionnaire for other risk factors, including parental cigarette smoking. We added questions about narghile to the questionnaire. Among 2 734 pupils (49% females) surveyed, we found an association between exposure to ETS of the mother smoking cigarette or narghile and ever wheezing, nocturnal cough and severe wheeze; however, the strongest association was found when the mother smoked narghile. Mother smoking narghile was also associated with exercise wheeze. Father smoking narghile, but not cigarettes, was associated with nocturnal cough, severe wheeze and exercise wheeze. The association with current wheeze became significant when mother smoked both cigarettes and narghile; however, the effect was addititive and not synergic. We recommend that international studies investigating ETS include questions on narghile smoking.


Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.
New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.


First experiences with HeartMate 3 follow-up and adverse events.
The novel HeartMate 3 (HM3) left ventricular assist device (LVAD) received its CE mark in October 2015. It is a new compact LVAD featuring fully magnetically levitated pump, artificial pulse, large pump gaps, and a modular driveline. Here, we present outcomes and adverse events of a single-center cohort 6 months after HM3 implantation. We retrospectively studied a patient cohort of 27 patients who were supported with the HM3 at a single institution. We excluded patients with biventricular assist devices and other types of assist devices as well as LVAD exchange and re-operative procedures. Twenty-seven patients were enrolled into the study. Within 1 year after HM3 implantation, 1 patient received a heart transplant and 3 patients died. Thirty-day survival was 88.9% and 6 months 85.2%. No pump thrombosis and no strokes were observed within 6 months. Right heart failure was diagnosed in 1 patient after HM3 implantation (3.7%). No technical complications of the pump were documented. No pump exchanges were necessary. The novel LVAD HM3 has already shown good CE mark trial results. Within this first report after the CE mark trial, the 6-month survival after HM3 implantation was 85.2%. The HM3 showed excellent midterm results with 0% stroke and 0% pump thrombosis rates 6 months after implantation.


A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone.
Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy. The aim of this study was to determine how combination of rituximab with chemotherapy influences TAM-associated clinical outcome. Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with rituximab and cyclophosphamide-Adriamycin-vincristine-prednisone regimen. Of them, 71 received therapy at diagnosis and 25 at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months. Fourty-five patients previously treated with chemotherapy served as a control group. Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients (P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was not reached for patients with high TAM content compared with 45 months for patients with low TAM scores (P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS, 97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did not correlate with outcome. The data suggest that high TAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.


Efficacy and safety of the losartan-hydrochlorothiazide combination tablet in patients with hypertension uncontrolled by angiotensin II receptor antagonist therapy: the Aichi Research on Combination therapy for Hypertension (ARCH) Study.
The guidelines recommend combination therapy for patients who are unable to achieve target BP with monotherapy; some fixed dose therapies including an angiotensin II receptor blocker (ARB) and diuretics are available in Japan. However, to date there have been few reports on this long-term treatment and the patient profiles suited for this combination remain ambiguous. The Aichi Research on Combination therapy for Hypertension Study was a multicenter, open-label, prospective observational study that investigated the efficacy and safety of 1-year treatment with the losartan-hydrochlorothiazide (HCTZ) combination tablet in patients with hypertension uncontrolled by either ARB monotherapy or combination therapy with a calcium channel blocker (CCB). An ARB was switched to a losartan-HCTZ tablet after a pre-observation period. A total of 614 of 648 patients were evaluable (mean age, 66.3 years; 52.8% men; mean baseline blood pressure, BP, 157.7/87.9 mmHg). The BP had decreased significantly to 138.0/78.2 mmHg by month 3 (p<0.001, t-test), and 36.2% of the patients had achieved their target BP. The hypotensive effect lasted for 1 year and was found equally in the losartan-HCTZ arm and the losartan-HCTZ plus CCB arm. A stratified analysis showed significant hypotensive effects in patients with higher baseline BP, women, and patients who did not drink alcohol (p<0.001, unpaired t-test). The losartan-HCTZ combination tablet was found to have an early hypotensive effect, good tolerability, and stable long-term benefits in patients with hypertension uncontrolled by ARB monotherapy or combination therapy with a CCB.


Differential expression of troponin C genes during tongue myogenesis.
Determination of muscle fiber type is related to the developmental stage of the tissue. Ordinarily the final distribution of fast and slow fibers in a muscle is determined postnatally. Tongue muscle, however, is composed solely of fast-twitch fibers that express only troponin C fast mRNA and fast (type II) myosin heavy chain (MHC) proteins in both the adult and the one-day-old mouse. The fiber-type determination of this muscle was examined during fetal development. Both troponin C fast and slow mRNAs were expressed at initial stages of tongue development at embryonic day 18. However, by embryonic day 16 the troponin C fast transcripts predominated. AT 17 days of embryonic development, TnC fast mRNA was 10 times more abundant than TnC slow, and at 18 days of development the TnC slow mRNA was barely detectable. The tongue muscle myotubes expressed fast, slow, and embryonic MHC isoforms during early embryonic development. At 18 days of gestation, the MHC isoform expressed by the majority of the myotubes was the fast isoform, whereas the slow isoform was present in very few fibers. RT-PCR analysis of the MHC transcripts present throughout tongue development demonstrated expression of the mdms or type IIx MHC in both late fetal and postnatal stages of development. In contrast, the type I/beta slow MHC mRNA was undetectable in the postnatal and adult tongue. The absence of TnC and MHC slow-isoform mRNAs in the newborn mouse tongue suggests that slow isoform genes become dominantly repressed with the TnC-F and MHC type IIx genes remaining transcriptionally active, giving rise to an unusually homogeneous fast-twitch phenotype. The tongue muscle fibers acquire their specific adult-type fiber characteristics during fetal development rather than postnatally.


Imposed work of breathing during ventilator failure.
Ventilators possess an anti-asphyxia valve that allows spontaneous breathing of ambient air during ventilator failure. This study examined the imposed work of breathing and pressure-time product of 8 critical care and 9 portable ventilators, using a laboratory simulation of spontaneous breathing during ventilator failure. A test lung was modified to simulate spontaneous breathing with a tidal volume of 0.5 L and peak inspiratory flow of 60 L/min. A pneumotachograph and pressure tap were placed at the proximal airway between the breathing circuit and endotracheal tube. Flow was derived from the pressure drop across the pneumotachograph. Signals were amplified, integrated, and saved to a spreadsheet program, and imposed work of breathing and pressure-time product were calculated. Also measured were the inspiratory pressure required to open the anti-asphyxia valve (cracking pressure), time to cracking pressure, maximum negative inspiratory pressure, and time to maximum negative inspiratory pressure. For the critical care ventilators the mean +/- SD imposed work of breathing ranged from 213.07 +/- 3.53 to 890.63 +/- 0.88 mJ/L and the pressure-time product ranged from 2.67 +/- 0.01 to 13.37 +/- 0.01 cm H(2)O x s/L. For the portable ventilators the mean +/- SD imposed work of breathing ranged from 361.37 +/- 1.22 to 969.60 +/- 22.70 mJ/L and the pressure-time product ranged from 4.52 +/- 0.01 to 16.70 +/- 0.37 cm H(2)O x s/L. Spontaneous breathing during ventilator failure may impose work approximating the physiologic work of breathing. This imposed work may prevent effective breathing through the anti-asphyxia valve during mechanical ventilator failure due to electrical failure. These results reinforce the need to properly monitor mechanically ventilated patients and to have in place sufficient back-up power supplies and a method of manual ventilation.


POLYGYNANDRY IN THE DUSKY PIPEFISH SYNGNATHUS FLORIDAE REVEALED BY MICROSATELLITE DNA MARKERS.
In the dusky pipefish Syngnathus floridae, like other species in the family Syngnathidae, 'pregnant' males provide all post-zygotic care. Male pregnancy has interesting implications for sexual selection theory and the evolution of mating systems. Here, we employ microsatellite markers to describe the genetic mating system of S. floridae, compare the outcome with a previous report of genetic polyandry for the Gulf pipefish S. scovelli, and consider possible associations between the mating system and degree of sexual dimorphism in these species. Twenty-two pregnant male dusky pipefish from one locale in the northern Gulf of Mexico were analyzed genetically, together with subsamples of 42 embryos from each male's brood pouch. Adult females also were assayed. The genotypes observed in these samples document that cuckoldry by males did not occur; males often receive eggs from multiple females during the course of a pregnancy (six males had one mate each, 13 had two mates, and three had three mates); embryos from different females are segregated spatially within a male's brood pouch; and a female's clutch of eggs often is divided among more than one male. Thus, the genetic mating system of the dusky pipefish is best described as polygynandrous. The genetic results for S. floridae and S. scovelli are consistent with a simple model of sexual selection which predicts that for sex role-reversed organisms, species with greater degrees of sexual dimorphism are more highly polyandrous.


Lithium therapy and disorders of the parathyroid glands.
To review the effects of lithium (Li+) on the parathyroid glands. We describe the incidence and clinical features of Li(+)-associated hyperparathyroidism and summarize the current state of knowledge of the in vitro and in vivo effects of Li+ on the parathyroid cell. Li+ treatment is known to increase the calcium set-point in the parathyroid glands for inhibition of parathyroid hormone secretion. Evidence suggests that this change in calcium set-point occurs as a result of Li+ interference with transmembrane signal transduction in the parathyroid cell. Li+ therapy may accentuate the set-point error in patients with primary hyperparathyroidism and unmask preexisting hyperplastic or adenomatous changes in the parathyroid glands. Li+ may also cause de novo hypercalcemia and hyperparathyroidism that are usually mild, clinically insignificant, and reversible with discontinuation of Li+ therapy. In some patients receiving long-term Li+ therapy, however, persistent hyperparathyroidism develops despite discontinuation of Li+ therapy, and it may be symptomatic and associated with serious organ system sequelae. Li(+)-associated hypercalcemia can be a challenging clinical dilemma in patients with bipolar affective disorder because of the lack of effective therapeutic alternatives, as well as the potential for Li(+)-induced hypercalcemia to exacerbate psychopathologic symptoms. Because severe hypercalcemia may occur as a result of toxic Li+ levels, Li+ and calcium levels should be monitored in patients on long-term Li+ therapy.


CLAVATA1 controls distinct signaling outputs that buffer shoot stem cell proliferation through a two-step transcriptional compensation loop.
The regulation of stem cell proliferation in plants is controlled by intercellular signaling pathways driven by the diffusible CLAVATA3 (CLV3p) peptide. CLV3p perception is thought to be mediated by an overlapping array of receptors in the stem cell niche including the transmembrane receptor kinase CLV1, Receptor-Like Protein Kinase 2 (RPK2), and a dimer of the receptor-like protein CLV2 and the CORYNE (CRN) pseudokinase. Mutations in these receptors have qualitatively similar effects on stem cell function but it is unclear if this represents common or divergent signaling outputs. Previous work in heterologous systems has suggested that CLV1, RPK2 and CLV2/CRN could form higher order complexes but it is also unclear what relevance these putative complexes have to in vivo receptor functions. Here I use the in vivo regulation of a specific transcriptional target of CLV1 signaling in Arabidopsis to demonstrate that, despite the phenotypic similarities between the different receptor mutants, CLV1 controls distinct signaling outputs in living stem cell niches independent of other receptors. This regulation is separable from stem cell proliferation driven by WUSCHEL, a proposed common transcriptional target of CLV3p signaling. In addition, in the absence of CLV1, CLV1-related receptor kinases are ectopically expressed but also buffer stem cell proliferation through the auto-repression of their own expression. Collectively these data reveal a unique in vivo role for CLV1 separable from other stem cell receptors and provides a framework for dissecting the signaling outputs in stem cell regulation.


Characterization of the humoral immune response against Gnathostoma binucleatum in patients clinically diagnosed with gnathostomiasis.
Gnathostomiasis is an emerging systemic parasitic disease acquired by consuming raw or uncooked fresh-water fish infected with the advanced third-stage larvae of Gnathostoma spp. This disease is endemic to the Pacific region of Mexico, and one of its etiologic agents has been identified as Gnathostoma binucleatum. We characterized the humoral immune response of patients clinically diagnosed with gnathostomiasis by detecting total IgM, IgE, and IgG class and subclasses against a crude extract of the parasite by Western blotting. Our results do not show differences in the antigens recognized by IgM and IgE. However, we found that the specific humoral immune response is caused mainly by IgG, specifically IgG4. We found that 43%, 65.2%, 54.1%, and 26.3% of the patients recognize the 37-kD, 33-kD, 31-kD, and 24-kDa antigens, suggesting that the 33-kD antigen is the immunodominant antigen of G. binucleatum.


Predomination of IL-17-producing tryptase-positive/chymase-positive mast cells in azoospermic chronic testicular inflammation.
Chronic testicular inflammation and infection have been regarded as important factors in the pathogenesis of azoospermia. As key effector cells in innate and adaptive immune system, mast cells (MCs) were observed in inflammation and autoimmune disease. Furthermore, increased expression of tryptase-positive MCs has been reported in testicular disorders associated with male infertility/subfertility. However, little is known about the potential relationship between MCs and chronic testicular inflammation in azoospermic patients. Moreover, the preferential expression of MCs' subtypes in testis of these patients is still far from being understood. Thus, this study aimed to investigate characteristics of testicular MCs as well as their subtypes in azoospermic men with chronic testicular inflammation (AZI, n = 5) by immunohistochemical techniques. Our results showed significant increase of MCs in AZI, and more importantly, considerable numbers of tryptase-positive/chymase-positive MCs could also be demonstrated in AZI, when compared to control groups representing azoospermia without chronic testicular inflammation (AZW, n = 5) and normal spermatogenesis (NT, n = 5) respectively. Most interestingly, immunofluorescence staining revealed autoimmune-associated interleukin (IL)-17-producing MCs in AZI, whereas co-expression of MC markers with tumour necrosis factor (TNF)-α, IL-10 and IL-1β could not be detected. In conclusion, AZI is associated with significant increase of tryptase-positive/chymase-positive MCs expressing IL-17, and these MCs might contribute to the pathogenesis of AZI.


Pancreatic cancer challenge in 52 Asian countries: age-centric insights and the role of modifiable risk factors (1990-2019).
Pancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population. Data from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age-Period-Cohort model, and decomposition analysis to evaluate incidence trends and effects. From 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY. With the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.


Structural modification on copper(I)-pyridylpyrimidine complexes for modulation of rotational dynamics, redox properties, and phototriggered isomerization.
The redox properties of copper pyridylpyrimidine complexes, which undergo linkage isomerism based on pyrimidine ring rotation, were compared under different coordination environments. A newly synthesized compound, [Cu(Mepypm)(L(Mes))]BF4 (1·BF4, Mepypm = 4-methyl-2-(2'-pyridyl)pyrimidine, L(Mes) = 2,9-dimesityl-1,10-phenanthroline) was compared with previously reported complexes of [Cu(MepmMepy)(L(Mes))]BF4 (2·BF4, MepmMepy = 4-methyl-2-(6'-methyl-2'-pyridyl)pyrimidine), Cu(Mepypm)(DPEphos)]BF4 (3·BF4, DPEphos = bis[2-(diphenylphosphino)phenyl]ether), [Cu(Mepypm)(L(Anth))]BF4 (4·BF4, L(Anth) = 2,9-bis(9-anthryl)-1,10-phenanthroline), and [Cu(Mepypm)(L(Macro))]BF4 (5·BF4). Isomer ratios, isomerization dynamics, redox properties, and photoelectron conversion functions varied with the coordination structure. Methyl substituents on the 6-position of the pyridine moiety increased steric repulsion and contributed to quicker rotation, enhanced photoluminescence, and increased photodriven rotational isomerization.


[Economic aspects of telemedicine].
The aim of health technology assessments is to study the incremental impact of health interventions within a complex care system characterised by a multitude of individual behaviours and institutions. Most frameworks available for telemedicine evaluation simply examine financial costs relative to face-to-face consultations. Current data collection systems are poorly suited to rigorous analyses of new networks in everyday situations. Randomised trials are designed to remove sources of interference that could mask a causal relationship between a new organization and a set of results. Their methodology, which introduces the term ceteris paribus into the principles of good practice, is poorly suited to analyzing individual behaviours. Observational studies attempt to describe actual treatment situations as accurately as possible. By definition, however, they assume that the natural course of events is not deviated by interventions. The absence of an experimental plan increases the likelihood of bias and makes it more difficult to test for causal relationships. These approaches are poorly suited to testing for incremental effectiveness. Quasi-experimental studies and a staged approach would be more suited to a comprehensive assessment of telemedicine initiatives. In this way its impact on effectiveness, integration of care, quality of life and social costs may be identified in normal conditions of use.


Promoting domestic violence education for nurses.
Domestic violence is one of the major health problems facing families today. Women in rural areas often are an overlooked population at high risk for this problem. Domestic violence is a concern for women, who may be patients or healthcare workers. Teaching about domestic violence is a very sensitive issue because it is often difficult for the abused to admit or confront that she is being abused. The authors developed an effective interactive workshop to teach nurses how to assess and intervene with women who have experienced domestic violence.


Genetics of malignant hyperthermia.
Study of the genetics of the malignant hyperthermia syndrome began in families in which both malignant hyperthermia (MH) episodes had been experienced and individuals had strongly positive contracture tests diagnostic of susceptibility to MH. Linkage studies associated this MH phenotype to the ryanodine receptor gene (RYR1) at chromosome 19q13.1 in many families. Although the MH phenotype is not always linked to chromosome 19, the RYR1 has remained the focus of experimentation. Other candidate genes exist, but few MH-susceptible families have variants of these genes. Hundreds of MH-susceptible people have variants of RYR1.


Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria.
Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins. The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity. However, enzymatically active AGK is required to maintain mitochondrial cristae morphogenesis and the apoptotic resistance of cells. The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome.


Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms.
Difficult-to-control asthma has been associated with gastroesophageal acid reflux. Acid-suppressive treatment has been inconsistent in improving asthma control. To determine whether a proton-pump inhibitor improves asthma control in adult asthmatic patients with acid reflux symptoms. Multicenter, double-blind, randomized, placebo-controlled trial. Twenty-nine private practices and 3 academic practices in the United States. Two hundred seven patients receiving usual asthma care including an inhaled corticosteroid (ICS). Patients had acid reflux symptoms and moderate-to-severe persistent asthma. Lansoprazole, 30 mg bid, or placebo, bid, for 24 weeks. The primary outcome measure was daily asthma symptoms by diary. Secondary asthma outcomes included rescue albuterol use, daily morning and evening peak expiratory flow, FEV1, FVC, asthma quality of life with standardized activities (AQLQS) questionnaire score, investigator-assessed symptoms, exacerbations, and oral corticosteroid-treated exacerbations. Daily asthma symptoms, albuterol use, peak expiratory flow, FEV1, FVC, and investigator-assessed asthma symptoms at 24 weeks did not improve significantly with lansoprazole treatment compared to placebo. The AQLQS emotional function domain improved at 24 weeks (p = 0.025) with lansoprazole therapy. Fewer patients receiving lansoprazole (8.1% vs 20.4%, respectively; p = 0.017) had exacerbations and oral corticosteroid-treated (ie, moderate-to-severe) exacerbations (4% vs 13.9%, respectively; p = 0.016) of asthma. A post hoc subgroup analysis revealed that fewer patients receiving one or more long-term asthma-control medications in addition to an ICS experienced exacerbations (6.5% vs 24.6%, respectively; p = 0.016) and moderate-to-severe exacerbations (2.2% vs 17.5%, respectively; p = 0.021) with lansoprazole therapy. In adult patients with moderate-to-severe persistent asthma and symptoms of acid reflux, treatment with 30 mg of lansoprazole bid for 24 weeks did not improve asthma symptoms or pulmonary function, or reduce albuterol use. However, this dose significantly reduced asthma exacerbations and improved asthma quality of life, particularly in those patients receiving more than one asthma-control medication.


Outcome of patients with rheumatoid arthritis treated by step-wise administration of disease-modifying antirheumatic drugs over a 10-year period.
Abstract Disease-modifying antirheumatic drugs (DMARDs) are expected to relieve polyarthritis, and thereby improve the patient's quality of life and eventually alter the prognosis of rheumatoid arthritis (RA) or the progressive joint destruction caused by it. DMARDs may cause adverse reactions and become less effective over time in some patients. Using changes in disease activity and X-ray findings as indicators, we retrospectively evaluated the long-term results of the step-wise administration of DMARDs in 200 patients with RA. The patients had been treated with gold compounds, SH compounds, and methotrexate, in this order, over a total of 10 years since initially being diagnosed with the disease in its relatively early stages. The step-wise administration of DMARDs had decreased and controlled RA activity and inflammatory response over the 10 years. Although X-ray findings for the wrists worsened over time in most of the patients, no knee or hip joint destruction was observed in patients in whom disease activity had been controlled well for a long period of time. The progression of destruction of major joints can be prevented in cases in which the Lansbury activity index and C-reactive protein are maintained at levels not more than 30% and 1.5 mg/dl, respectively. Since no drugs are now available which specifically prevent the progression of joint destruction, it is important to control RA activity for as long as possible.


Effects of Cys mutation on taurocholic acid transport by mouse ileal and hepatic sodium-dependent bile acid transporters.
All cysteines of mouse ileal and hepatic sodium-dependent bile acid transporters (Isbt and Ntcp, respectively) were individually replaced by alanine. Replacement of Cys106 in Isbt and Cys96 in Ntcp, which are located closely in alignment, decreased taurocholate uptake. Although Cys51 in Isbt is conserved in Ntcp, the replacement spoiled Isbt only. Both similarity and difference in the arrangement of functional sites are suggested.


Antibacterial evaluation of Salvia miltiorrhizae on Escherichia coli by microcalorimetry coupled with chemometrics.
For seeking novel antibacterial agents with high efficacy and low toxicity to deal with drug resistance, the effects of Salvia miltiorrhizae from various sources on Escherichia coli were evaluated by microcalorimetry coupled with chemometrics. Firstly, the heat-flow power-time curves of E. coli growth affected by different S. miltiorrhizae samples were recorded. Then, some crucial quantitative thermo-kinetic parameters including growth rate constant, heat-flow power and heat output, etc. were obtained from theses curves and were further investigated by some powerful chemometric techniques including similarity analysis, multivariate analysis of variance, hierarchical clustering analysis and principle component analysis. By analyzing the principle parameters, growth rate constant of the second exponential phase (k 2) and the heat-flow output powers of the second highest peak (P 2), together with the derived parameter inhibitory ratio (I, %), it could be quickly concluded that the tested S. miltiorrhizae samples from different sources in China exhibited strong antibacterial effects on E. coli and the samples from Beijing city exhibited the strongest anti-E. coli effects, which might be used as novel and underlying antibacterial candidates for the resistance of E. coli to the existing drugs in practice. This study provides a useful tool and helpful idea to accurately and rapidly evaluate the antibacterial effects of some complex matrices, offering some references for exploring new antibacterial agents.


Comparison of Salivary Electrolytes Profile in Oral Potentially Malignant Disorders and Oral Squamous Cell Carcinoma.
to determine salivary electrolyte concentration of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) patients. A related systematic review was performed. Observational study. Unstimulated saliva from 18 patients with OSCC, 18 with OPMD, and 18 without oral lesions was collected. A biochemical analysis was performed to evaluate the salivary concentrations of potassium (K), phosphorus (P), sodium (Na), calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), and iron (Fe). Kruskal-Wallis test was performed, and p < 0.05 was interpreted as statistically significant. The literature search for the systematic review retrieved 9 studies that associated salivary electrolyte levels with presence and progression of OSCC. A highly significant increase was found in the salivary Mg levels in the OPMD group (5.41 µg/mL) in comparison with the OSCC (3.71µg/mL) and control group (3.51 µg/mL) (p = 0.041). No differences were observed in other salivary levels elements. The results of the systematic review revealed that one article indicated a decrease, and three papers reported an increase in salivary Na levels in patients with OPMD and OSCC. Two articles indicated a decrease in salivary K levels in OSCC, and the other two reported high Mg levels in OPMD and OSCC. High salivary Mg levels can be a potential biomarker indicating the presence of OPMD, however, the evidence is still contradictory and more studies are required.


Potential use of oxygen enrichment of room air in mountain resorts.
Oxygen enrichment of room air has proved to be valuable for people who need to work at altitudes of 4000 m and above. In the present study the feasibility of using the same technique in ski and other mountain resorts at the lower altitudes of 2500 to 4000 m is considered. Although many people find these altitudes invigorating, some are distressed by the hypoxia, especially at night. The analysis shows that all resorts up to an altitude of 3250 m (10,600 ft) can have the equivalent altitude reduced to 1000 m (3280 ft) by oxygen enrichment without incurring a fire hazard. (The equivalent altitude is that which provides the same inspired P(O2) during air breathing.) Even resorts or laboratories as high as 4250 m can have the equivalent altitude safely reduced to 1500 m, that is, lower than the altitude of Denver, Colorado. This application of oxygen enrichment is likely to be most valuable for improving sleep and assisting in the initial acclimatization process.


ShuffleTrans: Patch-wise weight shuffle for transparent object segmentation.
Transparent objects widely exist in the world. The task of transparent object segmentation is challenging as the object lacks its own texture. The cue of shape information therefore gets more critical. Most existing methods, however, rely on the mechanism of simple convolution, which is good at local cues and performs weakly on global cues like shape. To solve this problem, an operation named Patch-wise Weight Shuffle is proposed to bring in the global context cue by being combined with the dynamic convolution. A network ShuffleTrans that recognizes shape better is then designed based on this operation. Besides, fitter for this task, two auxiliary modules are presented in ShuffleTrans: a Boundary and Direction Refinement Module which collects two additional information, and a Channel Attention Enhancement Module that assists the above operation. Experiments on four texture-less object segmentation datasets and two normal datasets verify the effectiveness and generality of the method. Especially, the ShuffleTrans achieved 74.93% mIoU on the Trans10k v2 test set, which is more accurate than existing methods.


BONE QUALITY IN A YOUNG COHORT OF HIV-POSITIVE PATIENTS.
In HIV+ patients, several factors related to patient and antiretroviral therapy (ART) could determine early onset of bone mineral density (BMD) disturbances. Evaluation of bone quality according to gender in patients from the HIV Romanian cohort. A cross-sectional study in "Prof. Dr. Matei Balş" National Institute for Infectious Diseases, Bucharest between 2016-2018. We collected data regarding HIV infection, ART history, viral hepatitis co-infections and we calculated patients body mass index (BMI). CD4 cell count, HIV viral load (VL), vitamin-D levels were determined. Dual-energy X-ray absorptiometry (DXA) scans were used to evaluate BMD. We enrolled 97 patients with the median age of 26 years. According to the DXA T-scores, 10 males and 8 females had osteopenia and 4 males and 4 females had osteoporosis. According to Z-scores 2 males and 1 female had osteoporosis. Hip DXA T-scores revealed osteopenia in 6 males and 9 females, whereas T and Z-scores showed osteoporosis in 2 males and 3 females. Lumbar spine (LS) T-score diagnosed osteopenia in 9 males and 6 females, while T and Z-scores revealed osteoporosis in 3 males and females. In males, low T-scores were associated with decreased BMI; low LS DXA Z-scores with low vitamin-D levels; low T and Z-scores and LS-BMD with high VL. Evaluating bone quality in patients with a long history of HIV infection, multiple factors should be taken into account.


Two new Leptographium spp. reveal an emerging complex of hardwood-infecting species in the Ophiostomatales.
Species of Leptographium are generally characterized by mononematous conidiophores and are commonly associated with bark beetles and weevils. These species are responsible for sapstain and in some cases serious diseases on a range of primarily coniferous trees. In comparison with coniferous trees, the occurrence of Leptographium species on hardwood trees has been poorly studied in Europe. During a survey of ophiostomatoid fungi on various tree species in Norway and Poland, three unusual species, which fit the broader morphological description of Leptographium spp., were found in association with Scolytus ratzeburgi, Dryocoetes alni and Trypodendron domesticum on a variety of hardwoods, and from wounds on Tilia cordata. Phylogenetic analyses of sequence data for three gene regions (ITS2-LSU, β-tubulin, and TEF1-α) showed that these Leptographium species are phylogenetically closely related to each other and form a well-supported lineage that included Grosmannia grandifoliae and Leptographium pruni. The first species could be distinguished from the other Leptographium species based on conidiophores arising from spiral hyphae, chlamydospore-like structures and a hyalorhinocladiella-like synanamorph in culture. The second species differs from the previous one by having distinctly shorter conidiophores and smaller conidia. This species also produces a well-developed sporothrix-like synanamorph with denticulate conidiogenous cells. Based on these unusual morphological characteristics and distinct DNA sequences, these fungi were recognised as new taxa for which the names Leptographium trypodendri sp. nov. and L. betulae sp. nov. are provided. The third group of isolates belonged to Grosmannia grandifoliae, representing the first report of this species outside of the USA. The newly defined G. grandifoliae complex is the first species complex in Leptographium s.l. consisting of only hardwood-infecting species.


Sign learning of hearing children in inclusive day care centers-does iconicity matter?
An increasing number of experimental studies suggest that signs and gestures can scaffold vocabulary learning for children with and without special educational needs and/or disabilities (SEND). However, little research has been done on the extent to which iconicity plays a role in sign learning, particularly in inclusive day care centers. This current study investigated the role of iconicity in the sign learning of 145 hearing children (2;1 to 6;3 years) from inclusive day care centers with educators who started using sign-supported speech after a training module. Children's sign use was assessed via a questionnaire completed by their educators. We found that older children were more likely to learn signs with a higher degree of iconicity, whereas the learning of signs by younger children was less affected by iconicity. Children with SEND did not benefit more from iconicity than children without SEND. These results suggest that whether iconicity plays a role in sign learning depends on the age of the children.


Discovery of S···C≡N Intramolecular Bonding in a Thiophenylcyanoacrylate-Based Dye: Realizing Charge Transfer Pathways and Dye···TiO2 Anchoring Characteristics for Dye-Sensitized Solar Cells.
Donor-π-acceptor dyes containing thiophenyl π-conjugated units and cyanoacrylate acceptor groups are among the best-performing organic chromophores used in dye-sensitized solar cell (DSC) applications. Yet, the molecular origins of their high photovoltaic output have remained unclear until now. This synchrotron-based X-ray diffraction study elucidates these origins for the high-performance thiophenylcyanoacrylate-based dye MK-2 (7.7% DSC device efficiency) and its molecular building block, MK-44. The crystal structures of MK-2 and MK-44 are both determined, while a high-resolution charge-density mapping of the smaller molecule was also possible, enabling the nature of its bonding to be detailed. A strong S···C≡N intramolecular interaction is discovered, which bears a bond critical point, thus proving that this interaction should be formally classified as a chemical bond. A topological analysis of the π-conjugated portion of MK-44 shows that this S···C≡N bonding underpins the highly efficient intramolecular charge transfer (ICT) in thiophenylcyanoacrylate dyes. This manifests as two bipartite ICT pathways bearing carboxylate and nitrile end points. In turn, these pathways dictate a preferred COO/CN anchoring mode for the dye as it adsorbs onto TiO2 surfaces, to form the dye···TiO2 interface that constitutes the DSC working electrode. These results corroborate a recent proposal that all cyanoacrylate groups anchor onto TiO2 in this COO/CN binding configuration. Conformational analysis of the MK-44 and MK-2 crystal structures reveals that this S···C≡N bonding will persist in MK-2. Accordingly, this newly discovered bond affords a rational explanation for the attractive photovoltaic properties of MK-2. More generally, this study provides the first unequivocal evidence for an S···C≡N interaction, confirming previous speculative assignments of such interactions in other compounds.


Associations between state scope of practice laws and US physician assistant wages from 1997 to 2017: a longitudinal analysis.
The purpose of this study is to determine whether, and to what degree, variations in physician assistant (PA) state scope of practice (SOP) laws across states are associated with (1) PA median wage over time and (2) if a specific SOP key element has greater impact on PA median wage than others. We hypothesise that expanded SOP laws will be associated with higher PA wage. Longitudinal analysis from 1997 to 2017. Fifty states and the District of Columbia (US capital region). Employed PAs from 1997 to 2017. Four national data sets were combined to allow for longitudinal analysis of state-level annual PA wage and state SOP laws. We used linear regression models to explore the associations of SOP elements with PA wage in 5-year intervals and individual growth models to assess the change in PA annual wage over the study period. There was a 220% increase in weighted PA annual wage over two decades. There was a positive linear correlation between annual wage and age in 2012 and 2017 (r=0.52, p<0.01; r=0.29, p=0.04, respectively). The adjusted R2 for individual SOP elements in the selected years were all small (range: 0.0-0.29), with no appreciable pattern across time for any SOP element. In 1997, several SOP laws show association with median wage but this impact disappears over time. PA median wage has risen over twofold in the past two decades, with the rise in PA wage mainly explained by time and provider age. In 1997 some SOP elements were associated with increased average wage; however, the impact of this increase diminished over time in all such instances. As the PA profession moves towards Optimal Team Practice, future research should examine if this move towards greater autonomy impacts wage.


Estimation of the DNA sequence discriminatory ability of hairpin-linked lexitropsins.
Three- and four-ring polyamides containing N-methylimidazole and N-methylpyrrole, and their hairpin-linked derivatives, bind side-by-side in the minor groove of DNA in a sequence-specific manner. The sequences recognized by side-by-side molecules are dependent on the pairings of the polyamide rings to the bases. In this study we report a mathematical model for estimating the free energies of binding for gamma-aminobutyric acid-linked polyamides to 5- and 6-bp DNA sequences. The model parameters are calibrated by a least-squares fit to 35 experimental binding constants. The model performs well in cross-validation experiments and the parameters are consistent with previously proposed empirical rules of polyamide-DNA binding. We apply the model to the design of targeted polyamides, evaluating the ability of the proposed polyamides to bind to a DNA sequence of interest while minimizing binding to the remaining DNA sequences.


Long-term CB₁ receptor blockade enhances vulnerability to anxiogenic-like effects of cannabinoids.
Compelling evidence has documented the anxiolytic and mood-enhancing properties of cannabis. In susceptible users, however, consumption of this drug is conducive to panic, paranoia and dysphoria. We hypothesized that the up-regulation of CB₁ receptors (CB₁Rs) in select brain regions may enhance the vulnerability to cannabinoid-induced anxiety. To test this possibility, we assessed the behavioral impact of a potent cannabinoid agonist (CP55,940; 0.05-0.1 mg/kg, IP) on C57BL/6 male mice, respectively subjected to a prolonged pre-treatment of either the selective CB₁R antagonist/inverse agonist AM251 (1 mg/kg/day IP, for 21 days, followed by a 3-day clearance period before testing) or its vehicle (VEH1). Anxiety-like responses were studied in the novel open field, elevated plus maze (EPM) and social interaction assays. While CP55,940 induced anxiolytic-like effects in the EPM in VEH1-exposed animals, it elicited opposite actions in AM251-exposed mice. In this last group, CP55,940 also reduced rearing and social interaction in comparison to its vehicle (VEH2). The divergent effects of CP55,940 in AM251- and VEH1-pretreated animals were confirmed in 129SvEv mice. Immunoblotting analyses on brain samples of C57BL/6 mice revealed that AM251 pre-treatment caused a significant up-regulation of CB₁R expression in the prefrontal cortex and striatum, but also a down-regulation of these receptors in the hippocampus and midbrain. Notably, CB₁R levels in the prefrontal cortex were negatively correlated with anxiolysis-related indices in the EPM; furthermore, midbrain CB₁R expression was positively correlated with the total duration of social interaction. These results suggest that regional variations in brain CB₁R expression may differentially condition the behavioral effects of cannabinoids with respect to anxiety-related responses.


Influence of socio-demographic characteristics on DRS-2 performance in Spanish-speaking older adults.
The present study compared the performance of English- and Spanish-speaking healthy controls (HCs) on the Spanish translation of the Dementia Rating Scale-Second edition (ST-DRS-2) and examined the classification accuracy of the ST-DRS-2 and Mini-Mental State Examination (MMSE) with an age- and education-matched clinical sample. In contrast to previous findings with English-speakers, a stronger relationship was observed between ST-DRS-2 Total scores and education than with age, and despite being matched on both of these variables, English-speaking HCs significantly out-performed their Spanish-speaking counterparts on the ST-DRS-2. The greatest between-group difference was found on the Memory subscale, wherein the majority of errors committed by Spanish-speaking HCs were significantly related to level of acculturation. ST-DRS-2 Total and Memory subscale scores produced greater classification accuracy than the MMSE; however, ST-DRS-2 Total scores yielded the greatest corresponding rates of sensitivity and specificity. Normative data are provided and recommended to improve the ST-DRS-2's diagnostic accuracy with Spanish-speakers.


Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.


Bovine CLEC7A genetic variants and their association with seropositivity in Johne's disease ELISA.
Mycobacterium avium ssp. paratuberculosis (MAP) infection in cattle causes significant economic losses to the dairy and beef industries resulting from reduced productivity, premature culling and mortality. Bovine Dectin-1, an important pattern recognition molecule that is able to generate a proinflammatory response by acting alongside Toll like receptor (TLR) signaling, is known to co-operate with TLR2 to specifically activate a macrophage proinflammatory response against mycobacterial infections. Therefore, the goal of this study was to identify single nucleotide polymorphisms (SNPs) in the gene encoding bovine Dectin-1 (CLEC7A) and to assess their association with susceptibility to MAP infection in dairy cattle. Blood and milk samples, collected from commercial dairy operations, were tested for MAP infection using blood and milk ELISAs and a resource population consisting of 197 infected and 242 healthy cattle was constructed. Pooled DNA was used for sequencing and eight single nucleotide polymorphisms (SNPs) were identified. Identified SNPs were genotyped on the resource population using the iPLEX MassARRAY system and statistical analysis was performed using logistic regression fitting the additive and dominance effects of each SNP in the model. Out of a total of eight identified SNPs, five were successfully genotyped, and three out of these five SNPs were found to be in complete linkage. Statistical analysis revealed a strong association between a non-synonymous SNP c.589A>G (p=0.008), and MAP infection status of the resource population inferred by seropositivity in MAP antibody specific ELISAs. This SNP c.589A>G was located in the geneic region that encodes the carbohydrate recognition domain of bovine Dectin-1. Therefore, further investigation of its functional relevance is warranted.


Group therapy and organ transplantation.
Group therapy for organ transplantation patients is in its infancy but has a promising future. Overextended transplantation service providers are interested in its potential for cost-efficient and effective forms of psychosocial intervention. This article summarizes the biomedical and psychosocial aspects of solid organ transplantation, one institution's group therapy program, common group themes, and specific demands on the group therapist working with this population.


Regulation of intestinal proglucagon-derived peptide secretion by intestinal regulatory peptides.
The physiological regulation of intestinal proglucagon-derived peptide secretion has not been well studied. We have therefore used a fetal rat intestinal cell culture model to investigate the control of secretion of the gut glucagon-like immunoreactive (GLI) peptides by other intestinal regulatory peptides in vitro. Secretion of the intestinal GLI peptides was found to be stimulated in a dose-dependent fashion by the intestinal endocrine peptide, gastric inhibitory peptide (at greater than or equal to 10(-10) M, P less than 0.05), and by the neurocrine peptides, gastrin-releasing peptide (at greater than or equal to 10(-12) M, P less than 0.05), and calcitonin gene-related peptide (at greater than or equal to 10(-8) M, P less than 0.05). Gastrin-releasing peptide and its amphibian equivalent, bombesin were equipotent in stimulating GLI peptide secretion. In contrast, the endocrine and neurocrine intestinal somatostatin-related peptides, somatostatin-28 and -14, inhibited release of the GLI peptides, at concentrations of 10(-10) (P less than 0.01) and 10(-8) (P less than 0.01) M, respectively, with significant differences in potency between the two peptides detected at 10(-10) M (P less than 0.05). The inhibitory effects of both somatostatin-28 and -14 could be blocked by preincubation of the cells with pertussis toxin (P less than 0.05). Dose-dependent stimulation of gut GLI peptide secretion was also detected in response to treatment of cultured cells with sodium oleate (at 10(-4) M; P less than 0.05), or with the cholinergic agonist bethanecol (at greater than or equal to 100 microM; P less than 0.05). Other endocrine [cholecystokinin, glucagon, glucagon-like peptide-1(1-37), glucagon-like peptide-1(7-37), glucagon-like peptide-2, neurotensin, and peptide YY] and neurocrine (vasoactive intestinal peptide) peptides, and the synthetic glucocorticoid, dexamethasone, were without effect on secretion of the gut GLI peptides, at doses of 10(-12) to 10(-6) M. The results of the present study therefore demonstrate that secretion of the intestinal proglucagon-derived peptides is under the regulatory control of a wide variety of intestinal endocrine and neurocrine peptides, as well as nutrients (fats) and neurotransmitters (acetylcholine).


Discovery of Glycosylated Genipin Derivatives as Novel Antiviral, Insecticidal, and Fungicidal Agents.
A series of novel genipin glycoside derivatives incorporating 11 glycosidic moieties at either the 1 or 10 position of genipin were designed and synthesized. These compounds exhibited moderate to excellent inhibitory activities against tobacco mosaic virus. Especially, the in vitro and in vivo activities of compounds 6e, 7c, 7d, 7f, 7h, and 7i were comparable to that of ribavirin. In particular, compound 7c, the mannosyl derivative of genipin at the 10 position, showed the best activity. The series of genipin glycosyl derivatives also displayed fungicidal activities against 14 kinds of phytopathogenic fungi, especially for Rhizoctonia cerealis and Sclerotinia sclerotiorum. Moreover, compound 6h exhibited good insecticidal activity against diamondback moth; compounds 7b, 7c, and 7g exhibited moderate insecticidal activity against three kinds of Lepidoptera pests (oriental armyworm, cotton bollworm, and corn borer); and compound 7e showed excellent larvacidal activities against mosquito.


Efficacy evaluation of probiotics combined with prebiotics in patients with clinical hypothyroidism complicated with small intestinal bacterial overgrowth during the second trimester of pregnancy.
To explore the effect of probiotics combined with prebiotics on clinical hypothyroidism during pregnancy combined with small intestinal bacterial overgrowth. (1) In total, 441 pregnant women were included in this study. A total of 231 patients with clinical hypothyroidism during the second trimester of pregnancy and 210 normal pregnant women were enrolled in the lactulose methane-hydrogen breath test. The positive rate of intestinal bacterial overgrowth (SIBO), gastrointestinal symptoms, thyroid function and inflammatory factors were compared between the two groups by chi-square test and two independent sample t-test. (2) SIBO-positive patients in the clinical hypothyroidism group during pregnancy (n=112) were treated with probiotics combined with prebiotics based on conventional levothyroxine sodium tablets treatment. The changes in the methane-hydrogen breath test, gastrointestinal symptoms, thyroid function and inflammatory factors were compared before treatment (G0) and 21 days after treatment (G21) by chi-square test and paired sample t test. (1) The positive rates of SIBO in pregnant women in the clinical hypothyroidism group and control group were 48.5% and 24.8%, respectively. (2) The incidence of abdominal distention and constipation in the clinical hypothyroidism group was significantly higher than that in the control group, and the risk of abdominal distention and constipation in SIBO-positive pregnant women was higher than that in SIBO-negative pregnant women. (3) The serum levels of hypersensitive C-reactive protein (hsCRP), IL-10, IL-6, TNF-α, low-density lipoprotein (LDL), total cholesterol (TC), free fatty acids (FFAs) and apolipoprotein B (ApoB) in the hypothyroidism group during pregnancy were higher than those in the control group. (4) After 21 days of probiotics combined with prebiotics, the incidence of pure methane positivity in the methane-hydrogen breath test in the G21 group was significantly reduced, and the average abundance of hydrogen and methane at each time point in the G21 group was lower than that in the G0 group. (5) The incidence of constipation in the G21 group was significantly lower than before treatment. (6) The levels of serum TSH, hsCRP, IL-6, TNF-α, TC and LDL in pregnant women after probiotics combined with prebiotics were lower than those before treatment. Probiotics combined with prebiotics are effective in the treatment of pregnant patients with clinical hypothyroidism complicated with SIBO, providing a new idea to treat pregnant patients with clinical hypothyroidism complicated with SIBO.


Twins: within-pair similarity on Bayley's Infant Behavior Record.
Summary scores for behaviors rated on Bayley's Infant Behavior Record were obtained by summing sequential ratings for same-sex twins participating in a longitudinal study. The first year scores were based on visits made at 3, 6, 9, and 12 months, by 55 identical and 27 fraternal pairs; the second year scores were based on visits at 18, 24, and 30 months, by 47 identical and 27 fraternal pairs. During the first year, within-pair correlations for almost all behaviors were stronger for identical than for fraternal pairs; in the second year, within-pair correlations for identical twins were similar to those of fraternal twins except for the more cognitive behaviors. Composite scores were calculated for two behavioral clusters--one composed of behaviors related to Primary Cognition, and the other composed of behaviors related to Extraversion. Within-pair correlations were higher for identical than for fraternal twins in both the first and second years, indicating stronger and more consistent genetic influences on the more cognitive behaviors.


Palliative orbital decompression for metastatic melanoma to the orbit.
Although relatively rare, metastatic carcinomas to the orbit are the second most common orbital neoplasm in the adult. There are only ten cases reported in the literature of cutaneous melanoma metastatic to the orbit and, of these, only two had disease involving both orbits. This paper presents the third case of bilateral orbital melanoma; however, in this case, the primary site was the uveal tract in the first eye, with contralateral involvement being a metastasis of the orbital primary. The patient developed severe unilateral proptosis in his only seeing eye with progressive loss of vision. A palliative orbital decompression was performed which successfully restored visual acuity for an extended period of time. A brief discussion of the rationale for this procedure in this type of case is presented.


Equations to design an aplanatic catadioptric freeform optical system.
The present paper introduces a set of equations to design an aplanatic catadioptric freeform optical system. These equations form a partial differential equation system, in which a numerical solution defines the first and last surfaces of the catadioptric freeform optical system, composed of an arbitrary number of reflective/refractive surfaces with arbitrary shapes and orientations. The solution of the equation can serve as an initial setup of a more complex design that can be optimized. An illustrative example is presented to show the methodology introduced in this paper.


Latin American and the Caribbean Code Against Cancer 1st edition: Weight, physical activity, diet, breastfeeding, and cancer.
In Latin America and the Caribbean a considerable proportion of the population have excess body weight, do not meet the recommendations of physical activity and healthy diet, and have suboptimal rates of breastfeeding. Excess body weight is associated with at least 15 cancer sites, physical activity protects against three cancers, with some evidence suggesting a protective effect for eight more cancer sites, and sedentary behavior probably increases the risk of five cancer sites. Fiber and wholegrains protect against colorectal cancer, high intake of fruits and vegetables could reduce the risk of aerodigestive cancers; processed and red meat increase the risk of colorectal cancer; and very hot beverages are associated with esophageal cancer. Moreover, sugar-sweetened beverages and ultra-processed foods are a convincing cause for excess body weight, increasing cancer risk through this pathway, with some emerging evidence suggesting also direct pathways. Breastfeeding protects against breast cancer, and could protect against ovarian cancer. Taking this evidence into account, the Latin America and the Caribbean Code Against Cancer recommends the general public to maintain a healthy body weight, be physically active and limit sedentary behavior, eat a healthy diet (eat plenty of vegetables, fruits, wholegrains and legumes; avoid sugar-sweetened beverages and processed meat; and limit ultra-processed foods, red meat and very hot beverages), and breastfeed. Moreover, the Latin America and the Caribbean Code Against Cancer also includes a set of public policy recommendations for cancer prevention to inform policy makers and civil society about the need of policies to shape healthy environments and create opportunities to facilitate the adoption of the recommendations directed to the public.


Functional analysis of Kluyveromyces lactis carboxylic acids permeases: heterologous expression of KlJEN1 and KlJEN2 genes.
The present work describes a detailed physiological and molecular characterization of the mechanisms of transport of carboxylic acids in Kluyveromyces lactis. This yeast species presents two homologue genes to JEN1 of Saccharomyces cerevisiae: KlJEN1 encodes a monocarboxylate permease and KlJEN2 encodes a dicarboxylic acid permease. In the strain K. lactis GG1888, expression of these genes does not require an inducer and activity for both transport systems was observed in glucose-grown cells. To confirm their key role for carboxylic acids transport in K. lactis, null mutants were analyzed. Heterologous expression in S. cerevisiae has been performed and chimeric fusions with GFP showed their proper localization in the plasma membrane. S. cerevisiae jen1delta cells transformed with KlJEN1 recovered the capacity to use lactic acid, as well as to transport labeled lactic acid by a mediated mechanism. When KlJEN2 was heterologously expressed, S. cerevisiae transformants gained the ability to transport labeled succinic and malic acids by a mediated mechanism, exhibiting, however, a poor growth in malic acid containing media. The results confirmed the role of KlJen1p and KlJen2p as mono and dicarboxylic acids permeases, respectively, not subjected to glucose repression, being fully functional in S. cerevisiae.


Feasibility of Mating Disruption for Agricultural Pest Eradication in an Urban Environment: Light Brown Apple Moth (Lepidoptera: Tortricidae) in Perth.
Eradication technologies are needed for urban and suburban situations, but may require different technologies from pest management in agriculture. We investigated mating disruption of a model moth species recently targeted for eradication in Californian cities, by applying dollops of SPLAT releasing a two-component sex pheromone of the light brown apple moth in 2-ha plots in low-density residential Perth, Australia. The pheromone technology was applied manually at ∼1.5 m height to street and garden trees, scrubs, and walls at 500 dollops per hectare of 0.8 g containing ∼80 mg active two-component pheromone. Catches of male moths were similar among all plots before treatment, but in treated areas (six replicates) pheromone trap catches were substantially reduced for up to 29 wk posttreatment, compared with untreated control plot catches (three replicates). The treatment with pheromone reduced catch to virgin females by 86% (P < 0.001) and reduced the occurrence of mating by 93%, compared with three equivalent untreated control plot catches (P < 0.001). Eradication programs are following an upward trend with globalization and the spread of invasive arthropods, which are often first detected in urban areas. Eradication requires a major increase in the communication distance between individuals, but this can be achieved using sex pheromone-based mating disruption technology, which is very benign and suitable for sensitive environments. The need for new socially acceptable tools for eradication in urban environments is likely to increase because of increasing need for eradications.


Technical note: Anterior cruciate ligament reconstruction in the presence of an intramedullary femoral nail using anteromedial drilling.
To describe an approach to anterior cruciate ligament (ACL) reconstruction using autologous hamstring by drilling via the anteromedial portal in the presence of an intramedullary (IM) femoral nail. Once preoperative imagining has characterized the proposed location of the femoral tunnel preparations are made to remove all of the hardware (locking bolts and IM nail). A diagnostic arthroscopy is performed in the usual fashion addressing all intra-articular pathology. The ACL remnant and lateral wall soft tissues are removed from the intercondylar, to provide adequate visualization of the ACL footprint. Femoral tunnel placement is performed using a transportal ACL guide with desired offset and the knee flexed to 2.09 rad. The Beath pin is placed through the guide starting at the ACL's anatomic footprint using arthroscopic visualization and/or fluoroscopic guidance. If resistance is met while placing the Beath pin, the arthroscopy should be discontinued and the obstructing hardware should be removed under fluoroscopic guidance. When the Beath pin is successfully placed through the lateral femur, it is overdrilled with a 4.5 mm Endobutton drill. If the Endobutton drill is obstructed, the obstructing hardware should be removed under fluoroscopic guidance. In this case, the obstruction is more likely during Endobutton drilling due to its larger diameter and increased rigidity compared to the Beath pin. The femoral tunnel is then drilled using a best approximation of the graft's outer diameter. We recommend at least 7 mm diameter to minimize the risk of graft failure. Autologous hamstring grafts are generally between 6.8 and 8.6 mm in diameter. After reaming, the knee is flexed to 1.57 rad, the arthroscope placed through the anteromedial portal to confirm the femoral tunnel position, referencing the posterior wall and lateral cortex. For a quadrupled hamstring graft, the gracilis and semitendinosus tendons are then harvested in the standard fashion. The tendons are whip stitched, quadrupled and shaped to match the diameter of the prepared femoral tunnel. If the diameter of the patient's autologous hamstring graft is insufficient to fill the prepared femoral tunnel, the autograft may be supplemented with an allograft. The remainder of the reconstruction is performed according to surgeon preference. The presence of retained hardware presents a challenge for surgeons treating patients with knee instability. In cruciate ligament reconstruction, distal femoral and proximal tibial implants hardware may confound tunnel placement, making removal of hardware necessary, unless techniques are adopted to allow for anatomic placement of the graft. This report demonstrates how the femoral tunnel can be created using the anteromedial portal instead of a transtibial approach for reconstruction of the ACL.


Hybrid endovascular and microsurgical treatment for a large mesencephalic-cerebellar hemangioblastoma.
The large intracranial hemangioblastoma is a top surgical challenge due to its nature of invading brain parenchyma, tight adherence to the pia, and rich blood supply from numerous pial vasculatures and arteries in the proximity. If the brainstem is involved in the lesion, the surgery will be more dangerous because of potential brainstem impingement. In this illustrative video, we present a case of a 54-year-old male with a large hemangioblastoma at the mesencephalic-cerebellar region, which was successfully treated by hybrid endovascular embolization and microsurgery via an occipital interhemispheric transtentorial approach with minimal intraoperative blood loss and a favorable outcome. The video can be found here: https://youtu.be/pJqFhY_Zhv0.


Critical role of fine needle aspiration cytology and immunocytochemistry in preoperative diagnosis of pediatric renal tumors.
To evaluate accuracy and role of immunocytochemistry (ICC) in cytologic diagnosis of pediatric renal tumors. Fine needle aspirates from 75 cases of pediatric renal tumors were studied. Radiologic-guided aspirations were performed, with 6-7 smears stained with Papanicolaou and Giemsa stains. Smears were screened without the knowledge of final histologic diagnosis. Subsequently, clinical details, final histology and diagnosis rendered by the original cytologist were noted to judge accuracy of diagnosis by a sensitized cytologist. Five neuroblastomas that entered close differentials for Wilms tumor were also evaluated. ICC studies were also performed after staining. Of 58 Wilms tumors, 5 were misdiagnosed; 3 renal rhabdoid tumors and 1 clear cell sarcoma were missed on cytology. Non-Hodgkin's lymphomas presenting as renal masses were accurately diagnosed on cytology, but primitive neuroectodermal tumors (n = 3) and renal cell carcinomas (n = 2) were not accurately diagnosed. Accuracy rate improved from 65% to 92% on review by a cytologist aware of cytologic features of pediatric renal tumors. A good accuracy rate of diagnosis of pediatric renal tumors can be achieved by priming pathologists to typical features of tumors. Immunocytochemistry plays a supportive role in cases with atypical morphology or unusual presentations.


A systematic review of questionnaires to assess patient satisfaction with limb orthoses.
Assessment of patient satisfaction with orthosis is a key point for clinical practice and research, requiring questionnaires with robust psychometric properties. To identify which validated questionnaires are used to investigate patient satisfaction with orthosis in limb orthotics and to analyse (1) their main fields of clinical application, (2) the orthosis-related features analysed by the questionnaires and (3) the strength of their psychometric properties. Systematic review. A literature search using MEDLINE (PubMed), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus databases for original articles published within the last 20 years was performed. A total of 106 papers pertaining to various clinical fields were selected. The main features of patient satisfaction with orthosis analysed were as follows: aesthetic, ease in donning and doffing the device, time of orthotic use and comfort. Of the questionnaires used to investigate patient satisfaction with orthosis, only four are adequately validated for this purpose: two for generic orthotic use (Quebec User Evaluation of Satisfaction with assistive Technology 2.0 and Client Satisfaction with Device of Orthotics and Prosthetic Users' Survey) and two for specific application with orthopaedic shoes (Questionnaire for the Usability Evaluation of orthopaedic shoes and Monitor Orthopaedic Shoes). Further development, refinement and validation of outcome measures in this field are warranted. Given the importance of analysing patient satisfaction with orthosis (PSwO), appropriate instruments to assess outcome are needed. This article reviews the currently available instruments and reflects on how future studies could be focused on the development, refinement and validation of outcome measures in this field.


Bridging a Knowledge Gap from Siloxanes to Germoxanes and Stannoxanes. A Theoretical Natural Bond Orbital Study.
Explaining the nature of the E-O chemical bond (E = Si, Ge, Sn) has been a great challenge for theoretical chemists during the last decades. Among the large number of models used for this purpose, the one based on hyperconjugative interactions sheds more light on the nature of chemical bonding in siloxanes. Starting from this concept, this study aimed to evaluate the impact of siloxane type hyperconjugative effects on the structural features of germoxanic and stannoxanic species and in addition to assess if p-d-like back-bonding interactions can also play important roles in determining the particular structures of these heavier analogues of ethers. Natural bond orbital deletion (NBO DEL) optimizations, carried out at the DFT level of theory, revealed that hyperconjugative effects dictate to a large extent the structural behavior of these species. Furthermore, this study points out that p-d back-bonding interactions also influence the equilibrium geometry of these species, although acting as a secondary electronic effect within the E-O-E moieties (E = Si, Ge, Sn).


Modulation of DRAK2 autophosphorylation by antigen receptor signaling in primary lymphocytes.
Death-associated protein-related apoptotic kinase-2 (DRAK2), a member of the death-associated protein-like family of serine/threonine kinases, is highly expressed in lymphoid organs and is a negative regulator of T cell activation. To investigate the regulation of DRAK2 activity in primary lymphocytes, we employed mass spectrometry to identify sites of autophosphorylation on DRAK2. These studies have revealed a key site of autophosphorylation on serine 12. Using a phospho-specific antibody to detect Ser(12) phosphorylation, we found that autophosphorylation is induced by antigen receptor stimulation in T and B cells. In Jurkat T cells, resting B cells and thymocytes, DRAK2 was hypophosphorylated on Ser(12) but rapidly phosphorylated with antigen receptor ligation. This increase in phosphorylation was dependent on intracellular calcium mobilization, because BAPTA-AM blocked DRAK2 kinase activity, whereas the SERCA inhibitor thapsigargin promoted Ser(12) phosphorylation. Our results show that DRAK2 kinase activity is regulated in a calcium-dependent manner and that Ser(12) phosphorylation is necessary for optimal suppression of T cell activation by this kinase, suggesting a potential feedback loop may act to modulate the activity of this kinase following antigen receptor signaling.


Treatment of asthma in children.
The epidemiology, etiology and pathophysiology, clinical presentation and diagnosis, and drug therapy of asthma in children are reviewed. Recent advances in drug therapy have, for unknown reasons, been accompanied by an increase in the morbidity and mortality associated with childhood asthma. The cause of asthma is not precisely understood, but an inflammatory process and hyperactivity of airways are common findings in the disease. Asthma in children can be classified as intermittent, chronic, or indeterminate; a severe, prolonged episode not relieved by usual treatment is called status asthmaticus. The hallmark symptoms of asthma are coughing, dyspnea, and wheezing. Beta-adrenergic agonists can be used orally for diagnostic purposes or for nocturnal asthma; i.v. or s.c. for emergency treatment; or by inhalation for relief of acute asthmatic episodes. Experience with anticholinergics in children is limited, and these agents should be used only when other options have failed. Inhalation of cromolyn sodium is very safe and is useful for the prophylactic treatment of mild to moderate asthma. Corticosteroids, which are used both for acute asthmatic episodes and for long-term treatment, can be given orally, i.v., or by inhalation. Theophylline is used for prophylactic therapy in children with chronic asthma. Selection of a drug regimen is based on knowledge of efficacy, pharmacokinetics, compliance, and toxicity. The treatment of asthma in children requires consideration of drug properties in young patients. Drugs used to treat childhood asthma include beta agonists, anticholinergics, cromolyn sodium, corticosteroids, and theophylline.


Prevalence, Clinical Correlates, and Use of Glucose-Lowering Drugs among Older Patients with Type 2 Diabetes Living in Long-Term Care Facilities.
Prevalence, clinical correlates, and use of glucose-lowering drugs were comprehensively evaluated among 863 nursing home older patients with diabetes (mean age 82.9 ± 2.1 years): functional dependence and cognitive impairment were present in 84.1% and 68% of patients, respectively, and 66.3% of patients had 2-4 comorbidities. HbA1c values < 7.0% were documented in 54.9% of diabetic; significantly lower HbA1c levels were observed in demented patients than in nondemented subjects. Documented hypoglycemic episodes were reported for 57 patients (6.6%), without significant association with age, functional dependence, cognitive impairment, or HbA1c levels. About one-fifth of older long-term facilities residents have diabetes, with concomitant poor health conditions and high prevalence of cognitive impairment and functional dependence. Roughly three-fourths of these older and frail diabetic patients have HbA1c values lower than optimal, suggesting a potential for hypoglycemic harm especially among patients with severe cognitive impairment.


Aluminum in enteral nutrition formulas and parenteral solutions.
To examine the aluminum content of several commercially available enteral nutrition formulas and parenteral solutions. Twelve enteral nutrition formulas and 10 parenteral solutions were commonly used in routine clinical care of patients and obtained from different medical companies in Turkey. The aluminum contents were determined by electrothermal atomic absorption spectrophotometry. We found that aluminum concentration in the enteral nutrition formulas and the parenteral solutions to range from 87.6 to 961.2 ng/mL and 58.4 to 1232.0 ng/mL, respectively. Careful clinical and biochemical monitoring are warranted to determine whether it will be necessary to eliminate aluminum contamination of enteral and parenteral preparations used in patients, particularly infants, with reduced kidney function who may be at risk for aluminum intoxication.