Does interpersonal liking lead to interpersonal synchrony in musical contexts?
The causal relationship of interpersonal liking affecting interpersonal synchrony is inconsistently documented. This study tests whether (a) interpersonal liking increases both behavioural and perceived synchrony and (b) people will synchronise with an agreeable partner over a competing musical stimulus. We had college students (N = 25) shake an egg-shaker with an agreeable or disagreeable confederate without music, with music, and with specific instruction to synchronise. Participants reported liking the agreeable confederate more than the disagreeable confederate and rated their relationship more positively; however, both behavioural and perceived synchrony were unaffected by the agreeableness of the confederate. Thus, we failed to replicate previous findings in an auditory only context. Furthermore, participants who believed they were more synchronised with the confederate liked the confederate more and felt more like a team, but the degree of behavioural synchrony was unrelated to these social perceptions. Perception of synchrony appears to be more important for social bonding than behavioural synchrony.


Differential virulence of camel Trypanosoma evansi isolates in mice.
This study assessed the virulence of Trypanosoma evansi, the causative agent of camel trypanosomiasis (surra), affecting mainly camels among other hosts in Africa, Asia and South America, with high mortality and morbidity. Using Swiss white mice, we assessed virulence of 17 T. evansi isolates collected from surra endemic countries. We determined parasitaemia, live body weight, packed cell volume (PCV) and survivorship in mice, for a period of 60 days' post infection. Based on survivorship, the 17 isolates were classified into three virulence categories; low (31-60 days), moderate (11-30 days) and high (0-10 days). Differences in survivorship, PCV and bodyweights between categories were significant and correlated (P < 0.05). Of the 10 Kenyan isolates, four were of low, five moderate and one (Type B) of high virulence. These findings suggest differential virulence between T. evansi isolates. In conclusion, these results show that the virulence of T. evansi may be region specific, the phenotype of the circulating parasite should be considered in the management of surra. There is also need to collect more isolates from other surra endemic regions to confirm this observation.


Handheld ultrasound in training - The future is getting smaller!
Traditional ultrasound teaching is normally delivered using large, costly and often quite advanced cart-based systems. These carts are often large systems on wheels, usually limited to the departments that own them i.e. clinics, wards or radiology. Portability has been further improved by the development of laptop style systems, which are easier to wheel in-between patients/departments. In our experience and anecdotally, many of these systems can be intimidating to the novice and can lead to early attrition or poor uptake of ultrasound into clinical practice. Carts can also restrict the amount of training deliverable to practitioners, as they are limited in number due to cost and can take quite some time to boot up, reducing convenience. This dogma is being progressively changed with the advent of smaller handheld devices, some clearly within the financial grasps of most practitioners, and even to the point of medical schools offering students their own personal device.1,2 This relative inexpensiveness can lead to the purchase of these devices for novelty and convenience, over need. Obvious caution is needed in these circumstances, but with increased ease of purchase, better availability and inbuilt simplicity, ultrasound learning can be seamlessly integrated into day-to-day practice. This review discusses how one of the most disruptive innovations in modern medicine is changing ultrasound from a classic imaging modality to become integrated as the fifth pillar of clinical examination, and how these new devices can serve as springboards to more advanced ultrasound training. In fact, within what has become a bigger area of clinical examination, things are getting smaller.


Analysis of the smile photograph.
Optimal facial esthetics is one of the objectives in orthodontic treatment and an important issue in modern society. In this context, orthodontic treatment permits individuals with dental malpositions to achieve improved dentofacial esthetics. To reach this result, the orthodontist needs to recognize the characteristics considered normal and pleasant in dental arches and smiles. The objective of this article is to review and discuss criterion adopted by dental literature to technically analyze the smile, such as dental midline, smile line, dental exposure, negative space, dental proportion, and symmetry. This article proposes a way to visualize an ideal smile for each patient.


Clozapine use and risk of diabetes mellitus.
Recent reports have raised the concern that clozapine increases the risk for diabetes mellitus. Accurate pharmacoepidemiologic data on whether such a hazard exists and its magnitude are needed to enable clinicians and patients to make proper treatment decisions about clozapine. The authors performed a case-control study involving 7,227 cases of newly treated diabetes and 6,780 controls, all with psychiatric disorders. Cases and controls were older than 20 years and enrolled in government-sponsored drug benefit programs in New Jersey. The authors measured the use of clozapine or other antipsychotic medications and additional covariates. They developed logistic regression models adjusted for demographic, clinical, and health care use characteristics to identify whether clozapine users were at increased risk to begin treatment for diabetes. Clozapine use was not significantly associated with developing diabetes (adjusted odds ratio [OR], 0.98; 95% confidence interval [CI], 0.74-1.31). There was no suggestion of relationships between larger dosages or longer durations of clozapine use and increasing risks of diabetes. On the other hand, nonclozapine antipsychotic medication use was associated with a modest but significantly increased risk of developing diabetes (adjusted OR, 1.13; 95% CI, 1.05-1.22). Among individual nonclozapine antipsychotics, significantly elevated risks were observed for two phenothiazine agents: chlorpromazine (adjusted OR, 1.31; 95% CI, 1.09-1.56) and perphenazine (adjusted OR, 1.34; 95% CI, 1.11- 1.62). In contrast to earlier reports, these results provide some reassurance that clozapine does not increase the risk of developing diabetes. Additional data from pharmacoepidemiologic studies and randomized controlled trials are needed to exclude the possibility of residual confounding and ensure the appropriate use of this agent.


Interplay of interfacial noise and curvature-driven dynamics in two dimensions.
We explore the effect of interplay of interfacial noise and curvature-driven dynamics in a binary spin system. An appropriate model is the generalized two-dimensional voter model proposed earlier [M. J. de Oliveira, J. F. F. Mendes, and M. A. Santos, J. Phys. A: Math. Gen. 26, 2317 (1993)JPHAC50305-447010.1088/0305-4470/26/10/006], where the flipping probability of a spin depends on the state of its neighbors and is given in terms of two parameters, x and y. x=0.5andy=1 correspond to the conventional voter model which is purely interfacial noise driven, while x=1 and y=1 correspond to the Ising model, where coarsening is fully curvature driven. The coarsening phenomena for 0.5<x<1 keeping y=1 is studied in detail. The dynamical behavior of the relevant quantities show characteristic differences from both x=0.5 and 1. The most remarkable result is the existence of two time scales for x≥x_{c} where x_{c}≈0.7. On the other hand, we have studied the exit probability which shows Ising-like behavior with a universal exponent for any value of x>0.5; the effect of x appears in altering the value of the parameter occurring in the scaling function only.


Entanglement Induced Interactions in Binary Mixtures.
We establish a conceptual framework for the identification and the characterization of induced interactions in binary mixtures and reveal their intricate relation to entanglement between the components or species of the mixture. Exploiting an expansion in terms of the strength of the entanglement among the two species enables us to deduce an effective single-species description. In this way, we naturally incorporate the mutual feedback of the species and obtain induced interactions for both species which are effectively present among the particles of same type. Importantly, our approach incorporates few-body and inhomogeneous systems extending the scope of induced interactions where two particles interact via a bosonic bath-type environment. Employing the example of a one-dimensional ultracold Bose-Fermi mixture, we obtain induced Bose-Bose and Fermi-Fermi interactions with short-range attraction and long-range repulsion. With this, we show how beyond species mean-field physics visible in the two-body correlation functions can be understood via the induced interactions.


Synthesis and characterization of ultrathin metal coordination Prussian blue nanoribbons.
Ultrathin metal coordination Prussian blue (PB) nanoribbons with tunable width have been successfully synthesized. The morphology and microstructure of PB nanoribbons are characterized using UV-vis, FT-IR, AFM, TEM and XRD. PB nanoribbons synthesized possess an ultrathin thickness of approximately 1 nm and narrow width. The width of PB ribbons can be tuned by varying the chain length of polymeric precursors. The PB hybrid nanoribbons synthesized exhibit enhanced thermal stability and electrochemical activity. The merit of narrow and tunable width as well as ultrathin thickness of PB hybrid nanoribbons along with enhanced thermal stability and electrochemical activity makes them potentially useful in nano-devices, biosensors and so on.


Structure of an RNA polymerase II preinitiation complex.
The structure of a 33-protein, 1.5-MDa RNA polymerase II preinitiation complex (PIC) was determined by cryo-EM and image processing at a resolution of 6-11 Å. Atomic structures of over 50% of the mass were fitted into the electron density map in a manner consistent with protein-protein cross-links previously identified by mass spectrometry. The resulting model of the PIC confirmed the main conclusions from previous cryo-EM at lower resolution, including the association of promoter DNA only with general transcription factors and not with the polymerase. Electron density due to DNA was identifiable by the grooves of the double helix and exhibited sharp bends at points downstream of the TATA box, with an important consequence: The DNA at the downstream end coincides with the DNA in a transcribing polymerase. The structure of the PIC is therefore conducive to promoter melting, start-site scanning, and the initiation of transcription.


Estrogen Interactions With Lipid Rafts Related to Neuroprotection. Impact of Brain Ageing and Menopause.
Estrogens (E2) exert a plethora of neuroprotective actions against aged-associated brain diseases, including Alzheimer's disease (AD). Part of these actions takes place through binding to estrogen receptors (ER) embedded in signalosomes, where numerous signaling proteins are clustered. Signalosomes are preferentially located in lipid rafts which are dynamic membrane microstructures characterized by a peculiar lipid composition enriched in gangliosides, saturated fatty acids, cholesterol, and sphingolipids. Rapid E2 interactions with ER-related signalosomes appear to trigger intracellular signaling ultimately leading to the activation of molecular mechanisms against AD. We have previously observed that the reduction of E2 blood levels occurring during menopause induced disruption of ER-signalosomes at frontal cortical brain areas. These molecular changes may reduce neuronal protection activities, as similar ER signalosome derangements were observed in AD brains. The molecular impairments may be associated with changes in the lipid composition of lipid rafts observed in neurons during menopause and AD. These evidences indicate that the changes in lipid raft structure during aging may be at the basis of alterations in the activity of ER and other neuroprotective proteins integrated in these membrane microstructures. Moreover, E2 is a homeostatic modulator of lipid rafts. Recent work has pointed to this relevant aspect of E2 activity to preserve brain integrity, through mechanisms affecting lipid uptake and local biosynthesis in the brain. Some evidences have demonstrated that estrogens and the docosahexaenoic acid (DHA) exert synergistic effects to stabilize brain lipid matrix. DHA is essential to enhance molecular fluidity at the plasma membrane, promoting functional macromolecular interactions in signaling platforms. In support of this, DHA detriment in neuronal lipid rafts has been associated with the most common age-associated neuropathologies, namely AD and Parkinson disease. Altogether, these findings indicate that E2 may participate in brain preservation through a dual membrane-related mechanism. On the one hand, E2 interacting with ER related signalosomes may protect against neurotoxic insults. On the other hand, E2 may exert lipostatic actions to preserve lipid balance in neuronal membrane microdomains. The different aspects of the emerging multifunctional role of estrogens in membrane-related signalosomes will be discussed in this review.


Mediators of a coping and communication-enhancing intervention and a supportive counseling intervention among women diagnosed with gynecological cancers.
The authors evaluated mechanisms of change for a coping and communication-enhancing intervention (CCI) and supportive counseling (SC). They proposed that the effects of CCI on depressive symptoms would be mediated by psychological processes targeted by CCI, namely increases in the following: positive reappraisal, acceptance, planful problem solving, attempts to understand emotional reactions to cancer, emotional expression, seeking of emotional and instrumental support, and self-esteem. The authors hypothesized that the effects of SC on depressive symptoms would be mediated by the processes encouraged by SC, in this case increases in the following: expression of emotions, attempts to understand emotional reactions to cancer, and self-esteem. Three hundred fifty-three women were randomized to a CCI, SC, or usual care control group and completed measures at preintervention and 3, 6, and 9 months later. The effects of CCI were fully mediated by positive reappraisal, problem solving, and self-esteem and partially mediated by emotional expression. The effects of SC were partially mediated by positive reappraisal. These findings provide support for hypothesized mediators for CCI. The authors were less able to identify mediators for SC. Future research might benefit from identifying SC mediators.


A quaternary ammonium silane antimicrobial triggers bacterial membrane and biofilm destruction.
To study the antimicrobial effects of quaternary ammonium silane (QAS) exposure on Streptococcus mutans and Lactobacillus acidophilus bacterial biofilms at different concentrations. Streptococcus mutans and Lactobacillus acidophilus biofilms were cultured on dentine disks, and incubated for bacterial adhesion for 3-days. Disks were treated with disinfectant (experimental QAS or control) and returned to culture for four days. Small-molecule drug discovery-suite was used to analyze QAS/Sortase-A active site. Cleavage of a synthetic fluorescent peptide substrate, was used to analyze inhibition of Sortase-A. Raman spectroscopy was performed and biofilms stained for confocal laser scanning microscopy (CLSM). Dentine disks that contained treated dual-species biofilms were examined using scanning electron microscopy (SEM). Analysis of DAPI within biofilms was performed using CLSM. Fatty acids in bacterial membranes were assessed with succinic-dehydrogenase assay along with time-kill assay. Sortase-A protein underwent conformational change due to QAS molecule during simulation, showing fluctuating alpha and beta strands. Spectroscopy revealed low carbohydrate intensities in 1% and 2% QAS. SEM images demonstrated absence of bacterial colonies after treatment. DAPI staining decreased with 1% QAS (p < 0.05). Fatty acid compositions of dual specie biofilm increased in both 1% and 2% QAS specimens (p < 0.05). Quaternary ammonium silane demonstrated to be a potent antibacterial cavity disinfectant and a plaque inhibitor and can be of potential significance in eliminating caries-forming bacteria.


Identification and mechanism of Echinochloa crus-galli resistance to fenoxaprop-p-ethyl with respect to physiological and anatomical differences.
Identification and mechanism of Echinochloa crus-galli (L.) resistance to fenoxaprop-p-ethyl via physiological and anatomical differences between susceptible and resistant were investigated. The physiological and anatomical differences that were take into account were growth reduction, chlorophyll content reduction, lamina thickness, and xylem vessel diameter in both susceptible and resistant biotypes of E. crus-galli. The results showed that the growth reduction fifty (GR₅₀) of resistant biotype was 12.07-times higher than that of the susceptible biotype of E. crus-galli treated with fenoxaprop-p-ethyl. The chlorophyll content was highly reduced in the susceptible biotype relative to the resistant one of E. crus-galli treated with fenoxaprop-p-ethyl. An anatomical test showed significant differences in the cytology of susceptible and resistant biotypes of E. crus-galli treated with fenoxaprop-p-ethyl with respect to lamina thickness and xylem vessel diameter. The resistance of E. crus-galli to fenoxaprop-p-ethyl may be due to the faster metabolism of fenoxaprop-p-ethyl below the physiologically active concentration or the insensitivity of its target enzyme (Acetyl-CoA carboxylase).


Interventions for healthcare professionals, organizations and patients to enhance quality of life for people diagnosed with palliative esophagogastric cancer: a systematic review.
Esophagogastric (EG) cancer is the fifth most common malignancy, and its incidence is increasing. The disease is fast paced, and five-year survival rates are poor. Treatment with palliative intent is provided for the majority of patients but there remains a lack of empirical evidence into the most effective service models to support EG cancer patients. The overall objective of this quantitative systematic review was to establish best practice in relation to interventions targeted at healthcare professionals or the structures in which healthcare professionals deliver care (i.e. models of care and practice) and patients (diagnosed with palliative EG cancer) to enhance the quality of life for people diagnosed with palliative EG cancer. The current review considered studies that included patients diagnosed with palliative EG cancer and any health professionals involved in the delivery of palliative care to this patient group in a hospital, home or community setting. The current review considered studies that evaluated any intervention or combination of intervention strategies aimed at healthcare professionals, organizations or patients to improve quality of life for people diagnosed with palliative EG cancer. The current review considered both experimental and epidemiological study designs. Studies were excluded that evaluated: screening programs, pharmacology alone, palliative oncology and palliative endoscopy. The primary outcome measure was objectively measured quality of life. A three-step search strategy was utilized. Sixteen databases were searched for papers from the year 2000 onward and followed by hand searching of reference lists. Methodological quality was not assessed as no articles were found that met the inclusion criteria. Data extraction was not possible as no articles were found that met the inclusion criteria. It was not possible to complete data synthesis as no articles were found that met the inclusion criteria. Comprehensive searching and study selection process failed to identify any studies that were eligible for inclusion in the review. There is currently a lack of published evidence to establish which interventions and strategies are most effective in delivering services to patients diagnosed with palliative EG cancer in terms of service structure, process and delivery.


Emotional strategies and their relationship to complaints of psychosomatic and neurotic symptoms.
Examined the emotional strategies that people use and their psychological consequences. On the basis of a questionnaire answered by 270 adults, two questions were selected that would categorize people into "emotional strategy" groups; i.e., emotives and suppressed-emotives. A second sample of 329 psychotherapy group participants were classified according to their emotional strategy and also were scored on a Complaint Questionnaire (CQ) designed to measure psychological maladjustment and psychosomatic complaints. Suppressed-emotives had a significantly higher score on the CQ than the emotive and non-emotive groups. Because the CQ is similar to other questionnaires that have been shown to differentiate diagnosed "neurotics" from normals, we conclude that suppressed-emotives should be distinguished from non-emotives in that the former show neurotic tendencies, while the latter do not.


Biochemical Assessment of Bone Health in Working Obese Egyptian Females with Metabolic Syndrome; the Effect of Weight Loss by Natural Dietary Therapies.
To investigate the relation between bone parameters and the metabolic syndrome criteria, before and after the administration of two different natural dietary supplements in middle aged working obese Egyptian women suffering from metabolic syndrome (MetS). Fifty eight middle aged obese female volunteers suffering from metabolic syndrome were divided into two groups. During the first period, group (A) consumed a low caloric diet and nutritional supplement consisting of doum flour biscuits, while group (B) consumed whole meal wheat flour biscuit with the same instructions. During the second period, both supplements were omitted. Assessment of blood pressure, relevant anthropometric parameters, lipid accumulation product, fasting blood glucose, uric acid, 25 hydroxy vitamin D (25 (OH) D), parathyroid hormone (PTH) and bone-specific alkaline phosphatase were performed. Data showed that although both supplements improved the MetS criteria and the bone health parameters, the supplement containing the doum flour proved to be more effective. These results confirm the benefit of doum in improving bone health parameter [25 (OH) D/PTH axis] in the MetS patients, beside the MetS criteria. So, we can conclude that natural effective supplements lead towards the optimization of biochemical parameters in favor of a healthy outcome.


Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease.
Neutrophil gelatinase-associated lipocalin (Ngal) is a biomarker for acute and chronic renal injuries, including polycystic kidney disease (PKD). However, the effect of Ngal on PKD progression remains unexplored. To study this, we generated 3 strains of mice with different expression levels of Ngal within an established PKD model (Pkd1L3/L3): Pkd1L3/L3 (with endogenous Ngal), Pkd1L3/L3; NgalTg/Tg (with endogenous and overexpression of exogenous kidney-specific Ngal) and Pkd1L3/L3; Ngal-/- mice (with Ngal deficiency). Knockout of endogenous Ngal had no effect on phenotypes, cystic progression, or survival of the PKD mice. However, the transgenic mice had a significantly longer lifespan, smaller (but not fewer) renal cysts, and less interstitial fibrosis than the mice without or with endogenous Ngal. Western-blot analyses showed significant increases in Ngal and cleaved caspase-3 and decreases in α-smooth muscle actin, hypoxia-inducible factor 1-α, pro-caspase 3, proliferating cell nuclear antigen, Akt, mammalian target of rapamycin, and S6 Kinase in the transgenic mice as compared with the other 2 strains of PKD mice. Thus, overexpression of exogenous kidney-specific Ngal reduced cystic progression and prolonged the lifespan in PKD mice, was associated with reductions in interstitial fibrosis and proliferation, and augmented apoptosis.


The vibration-rotation emission spectra of gaseous CdH2 and CdD2.
The vibration-rotation emission spectra of CdH2 and CdD2 molecules have been recorded at high resolution using a Fourier-transform spectrometer. The molecules were generated in a furnace-discharge emission source by reaction of cadmium vapor with molecular hydrogen or deuterium. The fundamental bands for the antisymmetric stretching mode (upsilon3) of CdH2 and CdD2 were detected at about 1771.5 and 1278.3 cm(-1), respectively. In addition, the 002(sigma(g)+)-001(sigma(u)+) and 01 l(pi(g))-010(pi(u)) hot bands were observed for CdH2. Spectroscopic constants were determined for each of the 12 observed isotopologs: 110CdH2, 111CdH2, 112CdH2, 113CdH2, 114CdH2, 116CdH2, 1l0CdD2, 111CdD2, 112CdD2, 113CdD2, 114CdD2, and 116CdD2. The average Cd-H and Cd-D bond distances (r0) were determined to be 1.683028(10) and 1.679161(16) angstroms, respectively.


[Overview of drug therapy in elderly diabetic patients].
General treatment principles for elderly diabetic patient with type 2 diabetes are the same as those of adult care. However, hypoglycemia and other adverse effects of glucose-lowering treatment are more common in older patients. Understanding the advantages and disadvantages of each antihyperglycemic drug class helps clinicians individualize therapy for elderly patients. Especially, given the heterogeneity of the older adult population, the risk of hypoglycemia must be carefully considered before using sulfonylureas and insulin regimen. Less stringent goals for glycemic control are recommended for frail elderly diabetic patients with limited life expectancy, advanced diabetes complications, or extensive comorbid conditions. The aggressive management of cardiovascular risk factors, such as hypertension, dyslipidemia, obesity, inactivity or smoking, is likely to have even greater benefits.


Obese first-degree relatives of patients with type 2 diabetes with elevated triglyceride levels exhibit increased β-cell function.
Type 2 diabetes mellitus (T2DM) is characterized as a disease continuum that is marked by metabolic changes that are present for several years, sometimes well before frank diagnosis of T2DM. Genetic predisposition, ethnicity, geography, alterations in BMI, and lipid profile are considered important markers for the pathogenesis of T2DM through mechanisms that remain unresolved and controversial. The aim of this study was to investigate the relationship between triglycerides (TGs) and β-cell function, insulin resistance (IR), and insulin sensitivity (IS) in obese first-degree relatives of patients with T2DM (FDR-T2DM) among subjects from central Mexico with normal glucose tolerance (NGT). We studied 372 FDR-T2DM subjects (ages,18-65) and determined body mass index (BMI), fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), insulin, and TGs levels. Subjects were categorized based on glycemic control [NGT, prediabetes (PT2DM), or T2DM]. NGT subjects were further categorized by BMI [normal weight (Ob-) or obese (Ob+)] and TGs levels (TG-, <150 mg/dL, or TG+, ≥150 mg/dL). β-cell function, IR, and IS were determined by the homeostasis model assessment of β-cell function (HOMA2-β), homeostasis model assessment of insulin resistance (HOMA2-IR), and Quantitative Insulin Sensitivity Check Index (QUICKI) indices, respectively. The obese subjects with elevated TGs levels had 21%-60% increased β-cell function when compared to all groups (P<0.05). In addition, this group had insulin levels, IS, and IR similar to PT2DM. Furthermore, only in obese subjects did TGs correlate with β-cell function (ρ=0.502, P<0.001). We characterized FDR-T2DM subjects from central Mexico with NGT and revealed a class of obese subjects with elevated TGs and β-cell function, which may precede PT2DM.


The multiple dimensions of Platypnea-Orthodeoxia syndrome: A review.
Platypnea-Orthodeoxia syndrome (POS) is a rare clinical entity characterized by dyspnea and arterial desaturation while in the upright position. The various pathophysiologic mechanisms leading to POS has puzzled clinicians for years. The hypoxia in POS has been attributed to the mixing of the deoxygenated venous blood with the oxygenated arterial blood via a shunt. The primary mechanisms of POS in these patients can be broadly classified based on intracardiac abnormalities, extracardiac abnormalities and miscellaneous etiologies. A Patent Foramen Ovale (PFO) was the most common reported site of an intracardiac shunt. In addition to PFO, intracardiac shunt leading to POS has been reported from either an Atrial Septal Defect (ASD) or an Atrial Septal Aneurysm (ASA). Most patients with an intracardiac shunt also demonstrated a secondary anatomic or a functional defect. Extracardiac causes of POS included intra-pulmonary arteriovenous malformations and lung parenchymal diseases. A systematic evaluation is necessary to identify the underlying cause and institute an appropriate intervention. We conducted a review of literature and reviewed 239 cases of POS. In this article, we review the etiology and pathophysiology of POS and also summarize the diagnostic algorithms and treatment modalities available for early diagnosis and prompt treatment of patients presenting with symptoms of platypnea and/or orthodeoxia.


γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells.
γ-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain folylpolyglutamates are associated with functionally significant DNA methylation alterations in several important biological pathways.


The inherited epilepsies.
Our knowledge regarding the genetic bases of the human epilepsies is in a state of rapid flux. For some forms of epilepsy, epidemiologists are still trying to determine whether there is any familial (hereditary) predisposition. Other forms of epilepsy are known to run in families, but the mode of inheritance and degree of penetrance of the trait are still in doubt. Three forms of epilepsy have been tentatively localized to specific chromosomes, and several others are being analyzed with linkage analyses. In no case, has the gene responsible for any human epilepsy been isolated or characterized and we are not yet close to understanding how any specific genetically controlled biochemical or physiological parameter is responsible for the development of an epilepsy syndrome or of any specific epileptogenic increase in brain excitability. However, an extensive animal literature indicates that the mechanisms will be complex as a common phenotype can be the expression of multiple genes, and a single gene can be associated with several phenotypes (Buchhalter, 1993).


Endoscopy-Assisted Laparoscopic versus Laparoscopic Surgery for Gastrointestinal Stromal Tumor and the Impact on Patients' Coagulation, Surgical Condition, and Complications.
To assess the clinical efficiency of endoscopy-assisted laparoscopic versus laparoscopic surgery for gastrointestinal stromal tumors and the impact on patients' coagulation, surgical condition, and complications. Between November 2016 and May 2020, 126 eligible patients diagnosed with gastrointestinal stromal tumor (GIST) in our institution were recruited. They were concurrently randomly assigned at a ratio of 1 : 1 to receive either laparoscopic gastrectomy (reference group) or endoscopy-assisted laparoscopic gastrectomy (research group). The two groups were compared in terms of patients' coagulation function, surgical conditions, and complications. The two groups had similar preoperative coagulation indices and the postoperative levels of activated partial thromboplastin time (APTT) and thromboplastin time (TT) (P > 0.05). Compared with the reference group, the research group showed lower PT levels (10.48 ± 0.68 vs. 11.97 ± 0.46) and higher FIB levels (0.67 ± 0.11 vs. 0.29 ± 0.07) (P < 0.05). Compared with the reference group, the study group had shorter operative time (81.21 ± 10.24 min versus 98.98 ± 15.31 min), shorter surgical incision (3.63 ± 1.12 cm versus 5.01 ± 1.14 cm), and less intraoperative bleeding (18.74 ± 6.98 ml versus 58.69 ± 15.87 ml) (P < 0.05). A markedly shorter length of hospital stay, time to the first postoperative exhaustion, and duration of drainage tube and gastric tube dwelling were observed in the research group versus the reference group (P < 0.05). The study group presented higher nutritional levels of patients at 3 days after surgery and a lower incidence of complication. Endoscopy-assisted laparoscopic treatment shows significant improvements in the efficiency of minimally invasive surgery and ensures a better prognosis and quality of life of patients with a good safety profile, so it is worthy of clinical application.


Pioglitazone increases adiponectin levels in nondiabetic patients with coronary artery disease.
Hypoadiponectinemia is associated with coronary artery disease (CAD). Pioglitazone has been shown to increase levels of adiponectin in diabetic patients. We sought to assess whether administration of pioglitazone to patients with CAD and without diabetes would affect plasma adiponectin levels and endothelial function. Seventeen patients with stable CAD and without evidence of diabetes were treated for 12 weeks with pioglitazone hydrochloride 30 mg daily. Adiponectin levels and endothelium-dependent flow-mediated vasodilation (ED-FMD) measurements were obtained pretreatment, posttreatment, and after a 12-week washout period. Treatment with pioglitazone increased adiponectin levels from an average of 10.6 to 21.1 microg/ml (P=0.001) and improved ED-FMD from 4.45 to 8.43% (P=0.001). Treatment with pioglitazone increased plasma adiponectin levels and improved ED-FMD in patients with stable CAD and no evidence of diabetes or insulin resistance.


[Therapeutic effects of hTR-siRNA adenovirus on human cervical cancer xenografts in nude mice].
To study the anti-tumor effects and its mechanism of hTR-siRNA adenovirus on human cervical cancer in vivo. The in vivo model of human cervical cancer was established by the subcutaneous inoculation of HeLa cells at the right armpit of BALB/c nu/nu mice. After successful implantation, the mice were randomized into four groups, in which the mice were intratumorally injected with 0.1 mL of Ad-hTR-siRNA (10(13) pfu/L), or Ad-NT-siRNA (10(13) pfu/L), or Cisplatin (1.20 g/L), or serum-free DMEM alone respectively. These treatments were given once every 3 days for 6 times. After the last injection, the mice were observed for 7 days continuously and sacrificed at the end. The tumors were harvasted, weighed, and sectioned. The TUNEL assay was used to assess the apoptosis of these tumor cells. Tumors-implanted were established successfully by 100% with HeLa cells. As compared with Ad-NT-siRNA, Ad-hTR-siRNA could slow down tumor growth, decrease tumor volume (45.48%) and tumor weight (34.68%), as well as promote the apoptosis and necrosis of tumor cells. The TUNEL positive cells were about 11.8%. But the anti-tumor activity of Ad-hTR-siRNA didn't catch on Cisplatin's. This study indicated that the hTR-siRNA adenovirus could suppress cervical cancer-xenografted growth in vivo and induce tumor cell apoptosis or necrosis.


The effects of hydroxychloroquine on pregnancy outcomes in infertile women: a systematic review and meta-analysis.
A promising strategy for controlling repeated implantation failure (RIF) may be the use of hydroxychloroquine (HCQ). To the best of our knowledge, no systematic review has been conducted on the effects of hydroxychloroquine on pregnancy outcomes. A systematic research of the following electronic databases was conducted: Cochrane, EMBASE-Ovid, PubMed, Web of Science, and Scopus from inception to December 2021, using the following keywords [hydroxychloroquine] AND [infertility]. Fertilization and rate of live birth were significantly higher in the HCQ+ prednisone (PDN) group than in the PDN alone group. However, the abortion rate was not different between the two groups. The meta-analysis of two studies revealed no statistical significance between the PDN group and HCQ+PDN group regarding clinical pregnancy rate (OR=.14 [95%CI: 0.4-4.370]; heterogeneity; P=0.13; I2=54%; random effect model) and implantation rate (OR=1.99 [95%CI: 0.94-4.2]; heterogeneity; P=0.37; I2=0%; fixed-effect model). While HCQ may help improve fertilization and live birth rates, adding it to prednisone did not improve overall pregnancy outcomes. This systematic review should be used with caution due to the small size, study design, and difference in the studies' population.


The amount and timing of parent-adolescent sexual communication as predictors of late adolescent sexual risk-taking behaviors.
The present study examined the moderating role of timing of first discussion of sexual intercourse with mothers and fathers on the relationship between the amount of sexual communication and sexual risk-taking behaviors in late adolescence. Late adolescents (N = 214) completed questionnaire measures regarding the amount and timing of sexual communication with their mothers and fathers. In addition, the participants provided information about their various sexual risk-taking behaviors. In general, the results suggest that timing of first discussion of sexual intercourse contributes additional variance in several sexually risky behaviors beyond that contributed by the amount of communication with both fathers and mothers. The implications of these findings are discussed.


Specular UV reflectance measurements for cavity radiometer design.
Specular reflectance measurements were made on a black paint used in a solar constant monitoring cavity radiometer. Interference filters peaking at 180, 200, and 220 nm were used in conjunction with a deuterium lamp source and a silicon photodiode detector. Results showed that the black paint was specular for light incident 60 degrees from normal and it reflected ~8% of the light at these wavelengths. We conclude that the high absorptance of the radiometer calculated for visible wavelengths should remain valid down to ~190-nm UV wavelengths.


Reduced Sleep Acutely Influences Sedentary Behavior and Mood But Not Total Energy Intake in Normal-Weight and Obese Women.
Using a crossover design, 22 normal-weight and 22 obese women completed two free-living sleep conditions: (a) Normal Sleep: night of ~8 hr time in bed; and (b) Reduced Sleep: night of < 5 hr time in bed). Outcome measures were energy intake, physical activity and sedentary time, and mood. Sleep time was 7.7 ± 0.3 and 4.8 ± 0.2 hrs during the Normal Sleep and Reduced Sleep conditions, respectively (F = 1791.94; p < 0.0001). Energy intake did not differ between groups or as a function of sleep condition (F = 2.46; p = 0.1244). Sedentary time was ~ 30 min higher after the Reduced Sleep condition (F = 4.98; p = 0.0318); other physical activity outcomes were not different by condition (p > 0.05). Total mood score, depression, anger, vigor, fatigue, and confusion were worse after Reduced Sleep (p < 0.05). Reducing sleep acutely and negatively influenced sedentary time and mood in normal-weight and obese women.


[Expression of activins, follistatin mRNA in the development of hepatic fibrosis].
To examine the expression changes of activin beta A, beta C, beta E and follistatin mRNA in the development of rat hepatic fibrosis induced by carbon tetrachloride (CCl(4)). Hepatic fibrosis was induced in rats by subcutaneous injections of 40% carbon tetrachloride oily solution for a period of 1 to 7 weeks. After carbon tetrachloride injection of 1, 2, 3, 4, 5, 6, and 7 weeks, the 6-12 rats were killed every time. The kinetics of activin beta A, beta C, beta E and follistatin mRNA expression were assessed by the semi-quantity RT-PCR. Activin beta A, beta C, beta E and follistatin mRNA could be detected in normal rat livers. After CCl(4) injection for 2 or 3 weeks, beta A mRNA was transiently decreased and became undetectable, then increased gradually. After CCl injection for 6 and 7 weeks, beta A mRNA level was significantly higher than controls (P<0.01). beta C mRNA could be detected after CCl(4) injection for 1 to 4 weeks and was significantly increased after 5 weeks over controls (P<0.05). beta E mRNA could not be detected after CCl(4) injection for 1 to 5 weeks, but significantly increased after CCl(4) injection for 6 or 7 weeks compared with controls (P<0.01). Except for normal rat liver, no follistatin mRNA was detected in rats after CCl(4) injection. Activins and follistatin have different expression changes in the development of hepatic fibrosis and the imbalance of activins and follistatin expression may involve in the formation of hepatic fibrosis.


Comparison between Dual Arc VMAT and 7F-IMRT in the protection of hippocampus for patients during whole brain radiotherapy.
The purpose of this study was to compare the dosimetric characteristics for protection of the hippocampus between dual arc VMAT (volumetric modulated arc therapy) and 7 fields intensity-modulated radiation therapy (7F-IMRT) for patients with brain metastases from lung cancer under the whole brain radiotherapy. Based on ten cases with brain metastases from lung cancer, two types of radiotherapy plans were designed, namely, dual arc VMAT and 7F-IMRT. Provided that the clinical requirements were satisfied, the comparisons of target dose distribution, conformity index (CI), homogeneity index (HI), dose of organs at risk (OARs), monitor units (MU) and treatment time between dual arc VMAT and 7F-IMRT were investigated for their dosimetric difference. Both treatment plans met the requirements of clinical treatments. However, the PTV-HA conformity and homogeneity of dual arc VMAT were superior to those of 7F-IMRT (P < 0.05). As to OARs, the mean maximum doses (Dmax) of hippocampus, eyes and optic nerves in the dual arc VMAT plan were all lower than those in 7F-IMRT plan (P < 0.05), but the result had no statistical significance (P < 0.05) for the maximum dose of lens. Compared with 7F-IMRT, dual arc VMAT reduced the average number of MU by 67% and the average treatment time by 74%. Therefore, treatment time was shortened by dual arc VMAT. With regards to the patients with brain metastases from lung cancer under the whole brain radiotherapy, the PTV-HA conformity and homogeneity of dual arc VMAT were superior to those of 7F-IMRT under the precise of meeting the clinical requirements. In addition, dual arc VMAT remarkably reduced the irradiation dose to OARs (hippocampus, eyes and optic nerves), MU and treatment time, as well, guaranteed patients with better protection.


Increasing Reproducibility in Oral Microbiome Research.
Evidence on the role of the oral microbiome in health and disease is changing the way we understand, diagnose, and treat ailments. Numerous studies on diseases affecting the oral cavity have revealed a large amount of data that is invaluable for the advancements in diagnosing and treating these diseases. However, the clinical translation of most of these exploratory data is stalled by variable methodology between studies and non-uniform reporting of the data.Understanding the key areas that are gateways to bias in microbiome studies is imperative to overcome this challenge faced by oral microbiome research. Bias can be multifactorial and may be introduced in a microbiome research study during the formulation of the study design, sample collection and storage, or the sample processing protocols before sequencing. This chapter summarizes the recommendations from literature to eliminate bias in the microbiome research studies and to ensure the reproducibility of the microbiome research data.


Complex of N-phosphonacetyl-L-aspartate with aspartate carbamoyltransferase. X-ray refinement, analysis of conformational changes and catalytic and allosteric mechanisms.
The allosteric enzyme aspartate carbamoyltransferase of Escherichia coli consists of six regulatory chains (R) and six catalytic chains (C) in D3 symmetry. The less active T conformation, complexed to the allosteric inhibitor CTP has been refined to 2.6 A (R-factor of 0.155). We now report refinement of the more active R conformation, complexed to the bisubstrate analog N-phosphonacetyl-L-aspartate (PALA) to 2.4 A (R-factor of 0.165, root-mean-square deviations from ideal bond distances and angles of 0.013 A and 2.2 degrees, respectively). The antiparallel beta-sheet in the revised segment 8-65 of the regulatory chain of the T conformation is confirmed in the R conformation, as is also the interchange of alanine 1 with the side-chain of asparagine 2 in the catalytic chain. The crystallographic asymmetric unit containing one-third of the molecule (C2R2) includes 925 sites for water molecules, and seven side-chains in alternative conformations. The gross conformational changes of the T to R transition are confirmed, including the elongation of the molecule along its threefold axis by 12 A, the relative reorientation of the catalytic trimers C3 by 10 degrees, and the rotation of the regulatory dimers R2 about the molecular twofold axis by 15 degrees. No changes occur in secondary structure. Essentially rigid-body transformations account for the movement of the four domains of each catalytic-regulatory unit; these include the allosteric effector domain, the equatorial (aspartate) domain, and the combination of the polar (carbamyl phosphate) and zinc domain, which moves as a rigid unit. However, interfaces change, for example the interface between the zinc domain of the R chain and the equatorial domain of the C chain, is nearly absent in the T state, but becomes extensive in the R state of the enzyme; also one catalytic-regulatory interface (C1-R4) of the T state disappears in the more active R state of the enzyme. Segments 50-55, 77-86 and 231-246 of the catalytic chain and segments 51-55, 67-72 and 150-153 of the regulatory chain show conformational changes that go beyond the rigid-body movement of their corresponding domains. The localized conformational changes in the catalytic chain all derive from the interactions of the enzyme with the inhibitor PALA; these changes may be important for the catalytic mechanism. The conformation changes in segments 67-72 and 150-153 of the regulatory chain may be important for the allosteric control of substrate binding. On the basis of the conformational differences of the T and R states of the enzyme, we present a plausible scheme for catalysis that assumes the ordered binding of substrates and the ordered release o


Extreme Binge Drinking During Adolescence: Associations With Subsequent Substance Use Disorders in American Indian and Mexican American Young Adults.
This study collected retrospective data on adolescent binge drinking (ABD) (5 drinks for boys, 4 for girls per occasion at least once per month) and/or extreme adolescent binge drinking (EABD) (10 or more drinks per occasion at least once per month) and tested for associations with demographic and diagnostics variables including alcohol and other substance use disorders (AUD/SUD). Cross-sectional data were collected from young adult (age 18-30 yrs) American Indians (AI) (n = 534) and Mexican Americans (MA) (n = 704) using a semi-structured diagnostic instrument. Thirty percent (30%) of the sample reported ABD and 21% reported EABD. Those having had monthly ABD were more likely to be AI and have less education; those having had EABD were more likely to be AI, male, younger, have less education and lower economic status compared to participants without ABD. ABD/EABD was associated with higher impulsivity, a family history of AUD, and lower level of response to alcohol (ORs = 1.0-2.0), as well as with adult AUD (ORs = 3.7-48), other substance use disorders (ORs = 3.5-9), and conduct disorder/ antisocial personality disorder (ORs = 2.0-2.6), but not with anxiety/depression. Monthly EABD further increased the odds of AUD/SUD. Although binge drinking was more common in AI compared to MA, there were little effects of race in individual risk factor analyses. Monthly ABD and EABD were common among these AI/MA as adolescents, and, as with other ethnic groups, these drinking patterns resulted in highly significant increases in the odds of developing alcohol and other substance use disorders in young adulthood.


Improving Cardiometabolic Monitoring of Children on Antipsychotics.
This study evaluated changes in cardiometabolic monitoring for children and adolescents who were prescribed an antipsychotic medication in a state mental health system before and after a quality improvement intervention. The intervention included education for prescribers, auditing on metabolic monitoring, and feedback to mental health center leaders regarding their monitoring. Research staff extracted yearly data on cardiometabolic monitoring from randomly selected community mental health center records before and after the intervention. Pre- and postintervention changes in monitoring were assessed with chi-squared tests. Evidence of past year monitoring increased: for glucose 18.9%-42.1% (χ2 = 6.75, p < 0.001), for triglycerides 13.5%-31.0% (χ2 = 4.54, p = 0.033), for cholesterol 13.5%-33.1% (χ2 = 5.48, p = 0.019), and for weight 67.6%-84.1% (χ2 = 5.21, p = 0.022). Rates of monitoring for blood pressure and waist circumference increased but not significantly. In both years studied, weight was obtained most frequently and waist circumference was obtained least frequently. Monitoring rates significantly improved for four out of six parameters evaluated, but overall monitoring rates remained low at the end of the study period. Prescriber education with audit and feedback may improve cardiometabolic monitoring rates, but research is needed to evaluate barriers to monitoring in children.


Sulglycotide displays cytoprotective activity in rat gastric mucosa.
Sulglycotide, a well known antisecretory and antiulcer compound, has been further investigated for its ability to protect rat gastric mucosa against extensive necrosis induced by absolute ethanol, NaOH (0.2N) and NaCl (30%). Sulglycotide, which has been compared with cimetidine, displays a dose-dependent cytoprotective activity against the above necrotizing agents. The results obtained indicate that Sulglycotide requires a normal prostaglandin biosynthetic process in order to manifest its antiulcer activity. In fact gastric mucosa from animals treated with Sulglycotide releases in vitro a greater amount of PGl2-like activity; and furthermore no protection was observed against gastric lesions induced by indomethacin. As far as the mode of action of Sulglycotide is concerned it is tempting to speculate that the compound may interfere with prostaglandin degradation or it may trigger an adaptive cytoprotection which is important in maintaining the cellular integrity of rat gastric mucosa.


On-line coupling of sequential injection with liquid chromatography for the automated derivatization and determination of gamma-aminobutyric acid in human biological fluids.
The principle of sequential injection analysis (SIA) was exploited to develop a rapid fully automated and efficient pre-column derivatization procedure coupled on-line to liquid chromatography (HPLC). Using the SIA-HPLC derivatization protocol gamma-aminobutyric acid (GABA) was determined fluorimetrically in human biological fluids with o-phthaldialdehyde (OPA) as derivatization reagent and minimum sample pretreatment. A lab-built SIA system was used to handle samples, standard solutions and OPA reagent. Appropriate volumes of the reagents were introduced in the holding coil of the SIA system and were mixed on propulsion to the HPLC loop through a suitable reaction coil. The chemical (pH, c(OPA), c(mercaptoethanol)) and instrumental variables (volumes of sample and reagent, reaction time) of the reaction were studied and optimized in terms of maximum sensitivity. The chromatographic variables (gradient composition of the eluent and flow rate) were studied for optimum selectivity and peak characteristics. The developed experimental configuration facilitated fully-automated operation thus minimizing errors in handling. Additionally the method as a whole provided very satisfactory sensitivity, precision and accuracy. Direct determination of GABA in human urine and cerebrospinal fluid (CSF) at microg L(-1) (ppb) levels was accomplished, with minimum sample pretreatment.


The maze of the cerebrospinal fluid discovery.
The author analyzes a historical, long, and tortuous way to discover the cerebrospinal fluid. At least 35 physicians and anatomists described in the text have laid the fundamentals of recognition of this biological fluid's presence. On the basis of crucial anatomical, experimental, and clinical works there are four greatest physicians who should be considered as equal cerebrospinal fluid's discoverers: Egyptian Imhotep, Venetian Nicolo Massa, Italian Domenico Felice Cotugno, and French François Magendie.


Reconstruction of fingers after electrical injury using lateral tarsal artery flap.
Electrical injuries to the fingers account for the majority of total severe burns that occur each year. While several types of flaps have been used in covering finger defects, all have limitations or disadvantages. The purpose of this study was to introduce our clinical experiences of using the lateral tarsal artery (LTA) flap to successfully restore fingers after electrical injury. From 2005 to 2012, 10 patients with 14 severe electrical burns to their fingers, including six thumbs and four index and four middle fingers, were treated with LTA flap. The wound size ranged from 2.0×3.0 cm to 3.5×5.0 cm. The flap with free tendon graft was used to repair the tendon defect in four cases, free nerve graft was used to repair the feeling defect in two cases, and the flap with nerve was used to repair the feeling defect in two cases. All the patients were followed up for 3 months to 2 years. All skin flaps adhered successfully and there were no complications. All patients were satisfied with the esthetic appearance and functional outcome of the finger reconstruction. LTA flap is a reliable method to restore fingers after severe electrical injuries.


[Overprotectiveness as a coping reaction in intensive physical therapy].
25 mothers of children with cerebral palsy who were doing daily intensive physical therapy (Vojta) completed questionnaires concerning their child's temperament, parental attitudes and how they coped with everyday problems. Their responses were compared to those given by mothers who were not under the stress of conducting therapy. The results revealed compensatory coping processes: Mothers doing therapy try to compensate for their child's stress by being overprotective in ambiguous everyday situations.


Molecular Design of Phenanthrenequinone Derivatives as Organic Cathode Materials.
Conjugated carbonyl compounds have become the most promising type of organic electrode materials for rechargeable Li-ion batteries because only they can achieve simultaneously high energy density, high cycling stability, and high power density. In this work, we have performed first-principles density functional theory (DFT) calculations to explore the fundamental rules of how the electronic structure and redox properties of a typical conjugated carbonyl compound, phenanthrenequinone (PQ), are modified by adjusting the heteroaromatic building blocks. Such a molecular design strategy allows for the improvement in discharge potential while the specific capacity remains nearly unchanged. The correlation between the electronic structures and redox properties for the designed PQ derivatives is systematically discussed. It is demonstrated that the discharge potential of the PQ derivatives depends strongly on the frontier orbital levels, the electric potential, and the Li-bonding configurations. The electrostatic potential (ESP) maps show visible displays of molecular electric structures and can be applied to understand how the redox properties of the PQ derivatives are modified by the heteroaromatic building blocks.


Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3β inhibitors.
Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3β. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) μM and (14.67±0.78) μM for BACE-1 and GSK-3β, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.


Successful surgical treatment of prosthetic valve endocarditis and aortic root abscesses.
Repeated aortic prosthetic valve endocarditis and aortic root abscesses were successfully treated by implantation of a valved conduit into the ascending aorta and by placement of saphenous vein grafts to the aorta distal to the conduit and to the right and left anterior descending coronary arteries. This procedure provides several advantages, and six months after operation, the patient was in a satisfactory hemodynamic state and free from infection.


Jasmonate-inducible expression of a potato cathepsin D inhibitor-GUS gene fusion in tobacco cells.
A potato gene encoding cathepsin D inhibitor (CDI) is expressed constitutively in tubers and flower buds and it is inducible in leaves upon wounding of the tissue or by treatment with methyl jasmonate (MJA). A fusion gene (CDI:GUS) in which the 2.4 kb long promoter of the CDI gene was translationaly fused with the coding sequence for beta-glucuronidase (GUS) showed MJA-inducible expression in transformed tobacco cells in suspension. The maximum level of induction by MJA was obtained in the absence of auxin and repression of MJA-inducible expression of the fusion gene by auxin was released by aphidicolin, the results suggesting that MJA-inducible expression is repressed during active cell division. JA and MJA showed similar activities in inducing the expression of the fusion gene, while other JA-related compounds such as cucurbic acid, tuberonic acid and dihydrojasmonic acid neither induced expression of the fusion gene nor inhibited the MJA-inducible expression of the fusion gene. Methyl dihydrojasmonate specifically stimulated the MJA-inducible expression of the fusion gene. The MJA-inducible expression of the fusion gene was observed even with a 100 bp long promoter of the CDI gene albeit with significantly decreased level of expression compared to the 2.4 kb long promoter. The 100 bp long CDI promoter did not contain a G-box or hexamer motif that had been implicated in the MJA-responsive expression of several other plant genes. Further mutagenesis of the 100 bp long promoter by deletion or oligonucleotide insertion suggested that although a sequence between -100 and -82 is required for the MJA-responsive expression, the presence of this sequence alone does not confer the MJA-responsive expression.


Mucosal Healing in Ulcerative Colitis--When Zero is Better.
Extensive evidence has underlined the importance of mucosal healing as a treatment aim for ulcerative colitis (UC). We aimed to assess differences in the incidence of clinical relapse at 12 months between UC patients with Mayo endoscopic scores (MES) 0 and 1. This retrospective study included consecutive patients in corticosteroid-free remission between 2008 and 2013 and with follow-up of at least 1 year, with MES 0 or 1 in complete colonoscopy. Clinical relapse was defined as need for induction treatment, treatment escalation, hospitalization or surgery. A p value <0.05 was considered statistically significant. The study included 138 patients, 72 (52.2%) female, with mean age of 49 (±14) years. Inflammatory activity was classified as MES 0 in 61 (44.2%) patients and MES 1 in 77 (55.8%) patients. Clinical relapse during follow-up was significantly more frequent in patients with MES 1 than MES 0 (27.3 vs 11.5%, p = 0.022), and in the multivariate analysis MES 1 was the only factor significantly associated with an increased risk of relapse (odds ratio 2.89, 95% confidence interval 1.14-7.36, p = 0.026). This association was encountered in the subgroup of patients with left-sided/extensive colitis (29.7 vs 11.1%, p = 0.049), but not proctitis (25.0 vs 12.0%, p = 0.202). In patients with UC in corticosteroid-free remission, particularly those with left-sided colitis or extensive colitis, MES 1 was significantly associated with a 3-fold increased risk of relapse compared with endoscopic MES 0. Our results support the use of endoscopic MES 0 as the most suitable treatment endpoint to define mucosal healing in patients with UC.


The Association Between Socioeconomic Status and Adult Mortality in a Developing Country: Evidence From a Nationally Representative Longitudinal Survey of Indonesian Adults.
To estimate the association between socioeconomic status (SES) and adult mortality in Indonesia and determine the contribution of adult behavioral risk factors to SES differences in mortality. Discrete failure-time regression models and period life tables were used to estimate life expectancy at age 30 (e30) across wealth and consumption groups by sex and urban/rural residence. For urban men, e30 increases by an average of 1.10 years per wealth quartile (p = .014) from 38.7 years (95% confidence interval (CI): 37.4-40.5) in the bottom wealth quartile to 42.1 years (95% CI: 40.3-44.1) in the top quartile; for rural men, e30 increases by an average of 1.35 years per quartile (p = .007) from 40.6 years (95% CI: 39.2-42.5) in the bottom wealth quartile to 44.3 years (95% CI: 42.4-46.6) in the top quartile. SES differences are smaller for women. Behavioral risk factors are inconsistently patterned across SES and do not explain SES differences in mortality. The associations between SES and adult life expectancy in Indonesia are moderate when compared with developed countries and are not explained by traditional behavioral risk factors. In a context where behavioral risk factors are inconsistent across SES groups, mortality inequality may be driven by inequalities in health care access or other social factors.


Sexual abuse and psychopathology.
With the recognition that sexual exploitation of children is far more common than previously thought, a substantial research effort has aimed to describe its acute and long-term effects (Kluft 1990). Most studies have been quantitative and have pursued one of two strategies: Children identified by referral from child protective services as physically victimized are concurrently assessed for psychiatric sequelae; alternatively, adults with or without various psychiatric syndromes are retrospectively asked to recall the presence or absence of traumatic childhood experiences. Descriptive in focus, the results of these research efforts have broadened our understanding of the typical constellation of symptoms experienced by childhood incest victims and have delineated the adult psychiatric diagnostic categories most associated with a history of childhood trauma.


Silencing of disease-related genes by small interfering RNAs.
In recent years a new mechanism of posttranscriptional gene silencing has been discovered and named RNA interference. The interference is based on mRNA degradation mediated by small double-stranded RNA molecules approximately 21 nucleotides in length, the so-called short interfering or siRNAs. These molecules are produced from long dsRNAs by Dicer, a dsRNA-specific endonuclease, and cause specific degradation of their mRNA-targets by Watson-Crick base-pairing within a 300 kD multi-enzyme complex named RISC. RNAi is highly conserved between plants and animals of various phyla including mammals. The high sequence-specificity of RNAi makes it a new, promising tool in gene-function analysis as well as in potential therapeutics. In this review the discovery and molecular background of RNAi are summarized and possible fields of application pointed out.


Investigating relationship between water production and interfacial activity of γ-oryzanol, ethyl ferulate, and ferulic acid during peroxidation of bulk oil.
In this study, lecithin (as a surfactant) was added to promote the inhibitory-mechanism of γ-oryzanol, ethyl-ferulate and ferulic acid (based on the interfacial phenomena) so as to inhibit the oxidation of stripped sunflower oil. Monitoring the amount of water production as a byproduct of oxidation showed that the water content of the lipid system increased remarkably through the oxidation progress. Lecithin enhanced the critical concentration of hydroperoxides in reverse micelles, compared to the basic state (14.8 vs. 9.2 mM), thereby improving the hydrogen-donating mechanism of antioxidants. The size of reverse micelles increased progressively during the oxidation, while two breakpoints were pointed out in the micelles growth, i.e. at the end of the initiation and the propagation phases. Based on the kinetic data, ferulic acid showed the highest antioxidant activity (23.4), compared to ethyl-ferulate (15.5) and γ-oryzanol (13.7). Generally, lecithin enhanced antioxidant activity (~ 65%) by improving the interfacial performance of antioxidants.


Elevation of voice volume in young developmentally delayed children via an operant shaping procedure.
Unusually low voice volume was identified by teachers as a significant impediment to the academic and social progress of two preschool students. A simple operant shaping procedure was conducted by teachers to increase voice volume using a voice-activated apparatus with attractive visual display. Setting generalization of volume increases to the classroom was achieved and maintained at one- and four-month follow-ups.


The process of recovery from alcoholism: III. Comparing functioning in families of alcoholics and matched control families.
Families of recovered (N = 54) and relapsed (N = 51) alcoholic patients were studied 2 yr after the patients completed residential treatment and were compared with sociodemographically matched families of community controls (N = 105) on three sets of family-functioning indices--role functioning, family environment and husband-wife congruence. Families of recovered patients were functioning as well as families of controls. Families of relapsed patients showed less cohesion, expressiveness and recreational orientation, and lower agreement about their family environment than matched families of recovered patients and of community controls, and reported more family arguments than families of recovered patients. They also showed altered role functioning, the nonalcoholic spouse performing more household tasks and the alcoholic partner performing fewer. Family functioning was affected by the adequacy of the alcoholic partner's adaptation, and by life events, stressors and spouse's level of dysfunction.


Long-term leaching from MSWI air-pollution-control residues: leaching characterization and modeling.
Long-term leaching of Ca, Fe, Mg, K, Na, S, Al, As, Ba, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Zn, Mo, Sb, Si, Sn, Sr, Ti, V, P, Cl, and dissolved organic carbon from two different municipal solid waste incineration (MSWI) air-pollution-control residues was monitored during 24 months of column percolation experiments; liquid-to-solid (L/S) ratios of 200-250L/kg corresponding to more than 10,000 years in a conventional landfill were reached. Less than 2% of the initially present As, Cu, Pb, Zn, Cr, and Sb had leached during the course of the experiments. Concentrations of Cd, Fe, Mg, Hg, Mn, Ni, Co, Sn, Ti, and P were generally bellow 1microg/L; overall less than 1% of their mass leached. Column leaching data were further used in a two-step geochemical modeling in PHREEQC in order to (i) identify solubility controlling minerals and (ii) evaluate their interactions in a water-percolated column system over L/S of 250L/kg. Adequate predictions of pH, alkalinity, and the leaching of Ca, S, Al, Si, Ba, and Zn were obtained in a simultaneous calculation. Also, it was suggested that removal of Ca and S together with depletion of several minerals apparently caused dissolution of ettringite-like phases. In turn, significant increase in leaching of oxyanions (especially Sb and Cr) was observed at late stage of leaching experiments.


Single amino acids in the carboxyl terminal domain of aquaporin-1 contribute to cGMP-dependent ion channel activation.
Aquaporin-1 (AQP1) functions as an osmotic water channel and a gated cation channel. Activation of the AQP1 ion conductance by intracellular cGMP was hypothesized to involve the carboxyl (C-) terminus, based on amino acid sequence alignments with cyclic-nucleotide-gated channels and cGMP-selective phosphodiesterases. Voltage clamp analyses of human AQP1 channels expressed in Xenopus oocytes demonstrated that the nitric oxide donor, sodium nitroprusside (SNP; 3-14 mM) activated the ionic conductance response in a dose-dependent manner. Block of soluble guanylate cyclase prevented the response. Enzyme immunoassays confirmed a linear dose-dependent relationship between SNP and the resulting intracellular cGMP levels (up to 1700 fmol cGMP /oocyte at 14 mM SNP). Results here are the first to show that the efficacy of ion channel activation is decreased by mutations of AQP1 at conserved residues in the C-terminal domain (aspartate D237 and lysine K243). These data support the idea that the limited amino acid sequence similarities found between three diverse classes of cGMP-binding proteins are significant to the function of AQP1 as a cGMP-gated ion channel, and provide direct evidence for the involvement of the AQP1 C-terminal domain in cGMP-mediated ion channel activation.


Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.
The aim of this study was to compare the efficacy of single-agent weekly docetaxel with the combination of docetaxel and gemcitabine in elderly and/or poor performance status patients with advanced nonsmall cell lung cancer (NSCLC). Previously untreated patients with stage IIIB/IV NSCLC who were either >65 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status 2 were eligible. Patients were randomized to receive weekly docetaxel (36 mg/m(2)) Days 1, 8, and 15 or docetaxel (30 mg/m(2))/gemcitabine (800 mg/m(2)) Days 1, 8, and 15. Both regimens were repeated on 28-day cycles for 6 cycles or until disease progression. Three hundred fifty patients were randomized, and 345 received treatment. The median age of patients was 74 years; 38% were >75 years old, and 35% had ECOG performance status 2. Intent-to-treat analysis showed median survivals of 5.5 months versus 5.1 months in the groups receiving docetaxel/gemcitabine versus weekly docetaxel, respectively (P = .65). There were no survival differences detected with docetaxel/gemcitabine versus weekly docetaxel in the 223 patients with good performance status (7.2 months vs 8.0 months, respectively) or in the 122 poor performance status patients (3.8 months vs 2.9 months, respectively). Median time-to-progression was longer in patients who received docetaxel/gemcitabine (4.8 months vs 2.9 months; P = .004). Both regimens were generally well tolerated. Treatment with docetaxel/gemcitabine produced a modest improvement in time-to-progression but had no impact on survival when compared with single-agent weekly docetaxel in this group of patients. Results with both regimens were disappointing, particularly in patients with poor performance status. Improved treatment for these patients will require the introduction of novel, well-tolerated, targeted agents.


Production of chicken chimeras from injection of frozen-thawed blastodermal cells.
To execute a strategy for reconstituting genetic resources from cryopreserved blastodermal cells, experiments were conducted to optimize conditions for producing chimeric chickens from frozen-thawed blastodermal cells. Stage X blastodermal cells were collected from Barred Plymouth Rock embryos and dispersed. Cells were resuspended in 10% dimethyl sulfoxide in Dulbecco's modified Eagle's medium (DMEM) containing 20% fetal bovine serum, and distributed into plastic ampules. Cell suspensions were seeded to induce ice formation at -7 C, cooled from -7 to -35 C at 1 C/min and then ampules were plunged into liquid nitrogen. Thawing was done by plunging the ampules into warm water (37 C) for 3 min. After centrifugation, the supernatant was replaced with DMEM, and dead or broken cells were removed by density gradient centrifugation. Approximately 500 cells were injected into irradiated Stage X White Leghorn recipient embryos. Following incubation, several somatic chimeras were produced. The frequency of somatic chimerism when fresh (unfrozen) cells, or cells that were frozen and selected by density gradient centrifugation on Percoll or Nycoprep were injected into recipient embryos was 84, 79, and 85%, respectively. The percentage of donor-derived pigmentation in the down of these chimeric chickens was 79, 50, and 58%, respectively. Germline chimerism was determined by mating the chimeras that survived to sexual maturity to Barred Plymouth Rocks. Nine of 16 birds (56.2%) injected with fresh cells, 2 of 26 birds (7.7%) injected with cells that were frozen and selected by density gradient centrifugation on a Percoll gradient, and 3 of 26 birds (11.5%) injected with cells that were frozen and selected on a Nycoprep gradient showed germline transmission; the percentage of donor-derived progeny in these chimeras were 29.5, 5.2, and 6.8%, respectively. The Barred Plymouth Rock donor stock was "reconstituted" by inter se mating of germline male and female chimeras. These data demonstrate that the strategy described here for reconstituting genetic resources from cryopreserved blastodermal cells via chimeric intermediates can be performed successfully.


N-heterocyclization of naphthylamines with 1,2- and 1,3-diols catalyzed by an iridium chloride/BINAP system.
Benzoquinoline derivatives were successfully synthesized by iridium-catalyzed N-heterocyclization of naphthylamines with diols. For instance, the reaction of 1-naphthylamine with 1,3-propanediol catalyzed by IrCl(3) combined with BINAP as a ligand produced 7,8-benzoquinoline in quantitative yield. The N-heterocyclization reaction was found to be markedly influenced by the ligands employed. Benzoindoles were also synthesized by the same strategy from napthylamines with 1,2-diols. A reaction mechanism for the N-heterocyclization of naphthylamines with 1,3-diols by IrCl(3) was proposed.


Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases.
It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE-/- animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE-/- mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE-/- animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.


Potential role of rilotumumab in the treatment of gastric cancer.
In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET-targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in 'MET-positive' gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date.


Individual-Based Modeling Approach to Assessment of the Impacts of Landscape Complexity and Climate on Dispersion, Detectability and Fate of Incipient Medfly Populations.
The objective of the presented study was to demonstrate the potential of a bottom-up "ethological" approach and individual-based model of Markov-like stochastic processes, employed to gain insights into the factors driving behavior and fate of the invasive propagule, which determine the initial stages of pest invasion and "cryptic" existence of the localized, ultra-low density incipient pest populations. The applied model, PESTonFARM, is driven by the parameters derived directly from the behavior and biology of the target insect species, and spatiotemporal traits of the local terrain and climate. The model projections are actively generated by behavior of the primary causative actors of the invasion processes-individual "virtual" insects-members of the initial propagules or incipient populations. Algorithms of the model were adjusted to reflect behavior and ecology of the Mediterranean fruit fly, Ceratitis capitata, used as a case-example in the presented study. The model was parametrized based on compiled published experimental information about C. capitata behavior and development, and validated using published data from dispersion and trapping studies. The model reliably simulated behavior, development and dispersion of individual members of an invasive cohort, and allowed to quantify pest establishment and detection chances in landscapes of varying spatiotemporal complexity, host availability and climates. The results support the common view that, under optimal conditions (farmland with continuous fruit availability and suitable climate), even a single propagule of medium size (100 females) usually results in pest establishment and detection within the first year post-invasion. The results demonstrate, however, that under specific sub-optimal conditions determined by the local climate, weather fluctuations and landscape topography (e.g., sub-urban), the incipient cryptic populations may occasionally continue for several generations, and remain undetected by typical pest surveillance grids for the periods extending beyond 2-years post-invasion.


[Multiple "granulomas" of unknown origin; a clinical case].
A case of multiple mandibular periapical radiolucencies (granuloma) with unknown etiology is presented. A connection with herpes zoster, which formerly had occurred in the same area could not be found. Several theories are discussed, however none of them seem to fit the case inspite of thorough examination.


Hematopoietic progenitor cells residing in muscle engraft into bone marrow following transplantation.
Hematopoietic and mesenchymal stem cells can potentially be the same cell type or adhere simultaneously in both bone marrow (BM) and muscle. In this study, we asked whether murine BM-derived cells could be tracked in muscle tissue after BM transplantation and whether muscle-derived cells have hematopoietic potential. To answer the first question, we transplanted BM from male BALB/c mice into irradiated female recipients and analyzed for engraftment. We used quantitative polymerase chain reaction (PCR) and fluorescent in situ hybridization techniques for Y chromosome-specific gene probes. A high number of BM-derived cells were located in both the intravascular and extravascular spaces in muscle tissue after BM transplantation. To answer the second question, we analyzed colony-forming potential in vitro with soft-agar assays and the competitive engraftment potential in vivo of muscle-derived cells. Engraftment levels of male cell populations were tested by quantitative PCR. The long-term engraftment potential of muscle-derived cells was low compared with that of BM. We conclude that there is intensive cellular trafficking between BM and muscle tissue. The engraftment potential of muscle-derived stem cells into BM is low and corresponds to the low amounts of hematopoietic colony-forming cells found in muscle tissue.


Socio-medicinal aspects of vibration-induced white finger disease.
The influence of vibration-induced white finger disease on the quality of life and possible social consequences is the subject of the study presented herein. The data acquisition was carried out by means of a standardized questionnaire. Parameters such as quality of life, professional practice, prevention and social security were assessed among other things. Nearly three quarters of the interviewees (n = 115) did not consult a physician with the occurrence of the first complaints. Physicians frequently made the correct diagnosis only with delay. From the first occurrence of symptoms to the acknowledgment as an occupational disease 0.5-34.5 years had usually elapsed. The quality of life affected the patients and their families. Change of profession and unemployment were frequently associated with substantial problems. There is clear need for information regarding the clinical picture, protective possibilities in the workplace, recognition as an occupational disease and financial problems. The introduction of industrial safety measures was not substantially affected by the occurrence of the disease. A quick diagnosis and the recognition of this occupational disease are important in view of its potential reversibility upon discontinuation of the exposition to vibration. As a consequence, intensified preventive measures need to be called for.


Incidence of pulmonary tuberculosis by occupation of hospital employees in the National Health Service in England and Wales 1980-84.
Examination of occupational health records for National Health Service employees in hospitals in England and Wales for 1980-84 has shown that the incidence of pulmonary tuberculosis has fallen for all occupations. Levels for all occupational groups, except mortuary attendants, are now comparable to or lower than that for the general population. An average of 3 cases of pulmonary tuberculosis would be expected to occur annually amongst the 20,790 staff (including mortuary attendants) classified as being at higher risk and offered annual X-rays. Routine annual X-rays failed to identify 60 per cent of the cases found within this group in this study, the diagnosis being made after individuals presented with clinical symptoms. The falling incidence and low yield from chest X-rays found in this study suggest that the current policy of annual chest X-rays for NHS staff in the higher risk category no longer seems justified.


Integration of Phosphotungstic Acid into Zeolitic Imidazole Framework-67 for Efficient Methylene Blue Adsorption.
To enhance the dye adsorption capacity of zeolitic imidazolate framework-67 (ZIF-67), phosphotungstic acid (HPW) was integrated into ZIF-67 to prepare composite adsorbents. Characterization results demonstrated that the electronegative HPW was uniformly and tightly deposited on the electropositive ZIF-67. Methylene blue (MB) was selected as a model contaminant to evaluate the adsorption performance of hybrid adsorbents. Results showed that HPW@ZIF-67 had excellent adsorption capacity toward cationic MB. The optimal ZIF-67-0.2 HPW sample with a HPW dosage of 9.9 wt % presented an adsorption capacity of 446.4 mg g-1. ZIF-67-0.2 HPW displayed good reusability, and the adsorption data can be well described by pseudo-second order and Langmuir isotherm models. The adsorption mechanism was ascribed to the preferred electrostatic attraction and π-π stacking between MB and composite adsorbents. This work provides a route to enhance organic dye removal efficiency of ZIF materials through regulation of surface charge property and sheds light on the development of ZIF-based adsorbents.


Cost-effectiveness of vinorelbine alone or vinorelbine plus cisplatin for stage IV NSCLC.
Le Chevalier and colleagues have reported results of a randomized controlled clinical trial comparing vinorelbine alone, versus vinorelbine combined with cisplatin, versus standard treatment consisting of vindesine and cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Data on survival in the three study arms and estimates of the resources used to treat these patients were extracted from the publication and inserted into Statistics Canada's POpulation HEalth Model (POHEM). This model includes data on diagnostic methods, treatment, and outcomes appropriate for stage at presentation, health care utilization, and direct care costs ($ Canadian) for best supportive care and for several "standard" chemotherapy regimens used to treat advanced NSCLC. POHEM was then used to model the cost of care per patient and the total burden of cost on the Canadian health care system for each of the chemotherapy treatment strategies and for best supportive care. Based on the published survival curves for each of the vinorelbine regimens, it was possible to estimate the survival gain relative to the standard chemotherapy regimens and to best supportive care, and to estimate their cost-effectiveness as cost per life year gained. Based on this analysis, the most cost-effective standard regimen relative to best supportive care was vinblastine/cisplatin, as it increased average survival while reducing costs by $2,846 per case. Vinorelbine/cisplatin increased survival to a greater degree, but inpatient administration costs associated with the delivery of cisplatin increased treatment costs by $2,983 per case and resulted in a cost-effectiveness ratio of $6,386 per life year gained. As high-dose cisplatin is not routinely administered in the inpatient setting in Canadian institutions, estimates were made of the cost of outpatient administration. The cost of outpatient care was $55 less per case demonstrating that this is the most cost-effective way to administer the regimen. Relative to etoposide/cisplatin and vinblastine/cisplatin, outpatient vinorelbine/cisplatin proved to be cost-effective. Various chemotherapy regimens used in the management of advanced NSCLC all fall within the boundaries of cost-effectiveness generally accepted for health care interventions in Canada. Therefore, cost and cost-effectiveness should not be barriers to the utilization of vinorelbine/cisplatin in Canada.


The impact of preload alteration on the myocardial performance index through implementing positive end expiratory pressure.
Load independent methods should be used for the assessment of ventricular function. Debate still exists regarding whether tissue Doppler imaging (TDI) indices are influenced by preload. Here, we evaluated the effect of positive end expiratory pressure (PEEP) related preload reduction on both conventional pulsed Doppler (PD) and TDI myocardial performance index (MPI). Thirty-eight mechanically ventilated patients of 3 months to 12 years old (mean ± SD age of 30 ± 11 months) without overt heart disease were enrolled. Doppler mitral inflow velocities, isovolumetric contraction and relaxation times and aortic ejection time in addition to TDI peak systolic, early and late diastolic velocities from the basal segment of left ventricular lateral wall were determined for each patient before and after applying high PEEP (10 cmH(2) O).PD-MPI was load dependent (0.61 ± 0.22 vs. 0.78 ± 0.25, P = 0.002). However, TDI-MPI did not significantly change after the use of high PEEP declining the left ventricular volume loading (0.78 ± 0.21 vs. 0.84 ± 0.22, P = 0.23). Hence, regarding various interfering pathophysiologic factors particularly preload reduction, it seems that TDI-MPI would be a more reliable index for the assessment of ventricular function.


Change of tumor vascular reactivity during tumor growth and postchemotherapy observed by near-infrared spectroscopy.
Breast cancer is one of the most common cancers in females. To monitor chemotherapeutic efficacy for breast cancer, medical imaging systems such as x-ray mammography, computed tomography, magnetic resonance imaging, and ultrasound imaging have been used. Currently, it can take up to 3 to 6 weeks to see the tumor response from chemotherapy by monitoring tumor volume changes. We used near-infrared spectroscopy (NIRS) to predict breast cancer treatment efficacy earlier than tumor volume changes by monitoring tumor vascular reactivity during inhalational gas interventions. The results show that the amplitude of oxy-hemoglobin changes (vascular reactivity) during hyperoxic gas inhalation is well correlated with tumor growth and responded one day earlier than tumor volume changes after chemotherapy. These results may imply that NIRS with respiratory challenges can be useful in early detection of tumor and in the prediction of tumor response to chemotherapy.


The development of modal intuitions: A test of two accounts.
Young children, unlike adults, deny that improbable events can happen. We test two accounts explaining this developmental shift. The development = reflection account posits that this shift is driven by an emerging ability to reflect on modal intuitions. In contrast, the development = intuition account posits that this shift is driven by changes in modal intuitions themselves, due to age-related changes in what people know and how they sample their knowledge and memories. These accounts make competing predictions about how long children and adults should take to make possibility judgments. In Experiment 1, we asked 123 children (39 5-year-olds, 42 7-year-olds, 42 9-year-olds; 49.60% White) and 40 adults (50% White) to judge the possibility of 78 ordinary, improbable, and impossible events and recorded their response times. In Experiment 2, we tested an additional 52 adults (42.32% White) who were under speeded conditions and thus less able to reflect before responding. Our results favor the development = intuition account. At all ages, people judged improbable events more slowly than ordinary or impossible events, and slow responding did not consistently predict affirmation over denial. Further, adults' possibility judgments did not change under speeded conditions. We also fit a drift-diffusion model to our data, which suggested that adults and children may sample different kinds of knowledge when generating intuitions. Our findings suggest that possibility judgments are often driven by modal intuitions with little reflection, and that a developmental shift in what children know and how knowledge is retrieved can explain why these intuitions change over time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Functional Assessment of Calcium-Sensing Receptor Variants Confirms Familial Hypocalciuric Hypercalcemia.
In the clinic it is important to differentiate primary hyperparathyroidism (PHPT) from the more benign, inherited disorder, familial hypocalciuric hypercalcemia (FHH). Since the conditions may sometimes overlap biochemically, identification of calcium-sensing receptor (CASR) gene variants causative of FHH (but not PHPT) is the most decisive diagnostic aid. When novel variants are identified, bioinformatics and functional assessment are required to establish pathogenicity. We identified 3 novel CASR transmembrane domain missense variants, Thr699Asn, Arg701Gly, and Thr808Pro, in 3 probands provisionally diagnosed with FHH and examined the variants using bioinformatics and functional analysis. Bioinformatics assessment utilized wANNOVAR software. For functional characterization, each variant was cloned into a mammalian expression vector; wild-type and variant receptors were transfected into HEK293 cells, and their expression and cellular localization were assessed by Western blotting and confocal immunofluorescence, respectively. Receptor activation in HEK293 cells was determined using an IP-One ELISA assay following stimulation with Ca++ ions. Bioinformatics analysis of the variants was unable to definitively assign pathogenicity. Compared with wild-type receptor, all variants demonstrated impaired expression of mature receptor reaching the cell surface and diminished activation at physiologically relevant Ca++ concentrations. Three CASR missense variants identified in probands provisionally diagnosed with FHH result in receptor inactivation and are therefore likely causative of FHH. Inactivation may be due to inadequate processing/trafficking of mature receptor and/or conformational changes induced by the variants affecting receptor signaling. This study demonstrates the value of functional studies in assessing genetic variants identified in hypercalcemic patients.