Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects.
Cervical cancer is one of the most common cancers that affects middle-aged women and the discovery of new drugs to aid clinical management is needed. As an important member of the protein arginine methyltransferases (PRMTs) family, PRMT1 catalyzes the methylation of protein arginine, which can influence multiple biological processes of cancer cells, such as activating epithelial-mesenchymal transformation (EMT) and acquiring resistance to apoptosis. Therefore, PRMT1 can be considered as a potential drug target for cervical cancer. In the current study, a new sub-binding pocket was discovered by molecular modeling, and by introducing a third substitute on the thiazole group to occupy this pocket, a series of compounds were designed and synthesized as potential PRMT1 inhibitors. Of these, two compounds (ZJG51 and ZJG58) exhibited significant inhibitory activities against PRMT1 without significantly inhibiting PRMT5. Both ZJG51 and ZJG58 displayed potent inhibitory effects on the proliferation of four cancer-derived cell lines and ZJG51 exerted relative selectivity against the cervical cancer cell line, HeLa. Further studies showed that ZJG51 inhibited migration and induce the apoptosis of HeLa cells. Mechanistically, ZJG51 significantly regulated PRMT1 related proteins, and indicated that the induction of apoptosis and inhibition of migration by ZJG51 may involve the activation of Caspase 9 and the inhibition of EMT, respectively. Molecular dynamic simulation and free energy calculation showed that ZJG51 can bind to PRMT1 stably and the binding mode was predicted. These data indicated that introducing the third substitute on the five-membered ring could be a future direction for structure-based optimization of PRMT1 inhibitors, and ZJG51 could be an important lead compound to inform the design of more potent inhibitors.


No differences in knee joint loading between individuals who had a medial or lateral meniscectomy: An ancillary study.
Arthroscopic partial meniscectomy is a frequently undertaken procedure for traumatic meniscal injuries. The location of knee joint degeneration and long-term prognosis differs between knees who have had a medial or lateral meniscectomy. However, there is no evidence comparing knee loading following a medial or lateral meniscectomy during sporting tasks. This study compared knee loading during walking and running between individuals who either had a medial or lateral meniscectomy. Knee kinematic and kinetic data were collected during walking and running in individuals three to twelve months post-surgery. Participants were grouped according to the location of surgery (medial, n = 12, and lateral, n = 16). An independent t-test compared knee biomechanics between the groups and Hedge's g effects sizes were also conducted. External knee adduction and knee flexion moments were similar between groups for walking and running with negligible to small effect sizes (effect size, 0.08-0.30). Kinematic (effect size, 0.03-0.22) and spatiotemporal (effect size, 0.02-0.59) outcomes were also similar between the groups. The lack of differences in surrogate knee loading variables between medial and lateral meniscectomy groups was unexpected. These findings suggest that combining groups in the short-term period following surgery is applicable. However, the data presented in this study cannot explain the differences in long-term prognosis between medial and lateral meniscectomies.


Non-surgical correction of cryptotia and the analysis of treatment time and other influence factors.
To explore correlations between post-treatment outcomes of non-surgical correction for cryptotia and treatment time and other influence factors. Forty-seven consecutive patients with 64 cryptotias were treated with the adjusted external stretching device and followed up over 12 months. A subjective evaluation scale was designed for patients to collect clinical data. Pretreatment and posttreatment evaluation were conducted by two blinded investigators. The correlations between influence factors and outcomes were explored through fractional polynomial method, multiple logistic regression, and robust linear regression methods. Thirty-five patients with 49 cryptotias were included. Twenty-nine cryptotias (23 patients) have been successfully managed. Two of 17 unilateral cryptotias achieved nearly complete symmetry. The final optimal cutoff value for initiating treatment time is 6 months and for the duration of treatment per day is 5 h per day. Positive relationships between initiating treatment time >6 months and onset time, type II and onset time, initiating treatment time >6 months and effect stabilization time were observed. Initiating treatment time <6 months and duration of treatment per day >5 h benefit for the posttreatment outcomes. Patients wearing the device under 6 months old would have earlier onset time and effect stabilization time. It is hard to achieve complete bilateral symmetry in unilateral patients. The adjustable devices can used for the auricles with different sizes and removed and equipped conveniently.


Architecture of the SARS coronavirus prefusion spike.
The emergence in 2003 of a new coronavirus (CoV) responsible for the atypical pneumonia termed severe acute respiratory syndrome (SARS) was a stark reminder that hitherto unknown viruses have the potential to cross species barriers to become new human pathogens. Here we describe the SARS-CoV 'spike' structure determined by single-particle cryo-EM, along with the docked atomic structures of the receptor-binding domain and prefusion core.


Exercise prescription and strategies to promote the cross-education of strength: a scoping review.
The cross-education of strength is moderated by exercise design and prescription in clinical and non-clinical populations. This review synthesizes the available evidence regarding exercise design strategies for unilateral resistance training and provides evidence-based recommendations for the prescription of unilateral training to maximize the cross-education of strength. Greater insights regarding the timing and effectiveness of cross-education interventions in clinical scenarios will strengthen the use of unilateral resistance training for individuals who may benefit from its use.


Evaluating the Use of 18F-FDG PET CT for External Beam Radiotherapy Planning in Gynaecological Malignancies.
To evaluate the evidence for the use of fluorine-18-fluorodeoyglucose (18F-FDG) PET CT in external beam radiotherapy planning for treatment of gynaecological malignancies. Our review confirms that the incorporation of 18F-FDG PET CT during radiotherapy planning may decrease inter-observer variability during target delineation. It can also provide useful functional information regarding the tumour, which may facilitate the development of techniques for dose escalation and 'dose painting' not only for primary disease, especially in cervical cancer, but also nodal metastasis. The utilisation of this functional modality in external beam radiotherapy planning, particularly in locally advanced cervical malignancy, is an exciting topic that warrants further prospective research. Perhaps the most valuable role may be the potential to deliver dose escalation to 18F-FDG PET CT avid targets previously limited by organ at risk constraints, now that we have significantly more advanced radiotherapy planning tools at our disposal.


A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation.
Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrials.gov identifier: NCT00326287].


NUF2 is correlated with a poor prognosis and immune infiltration in clear cell renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, immunotherapy has been considered a promising treatment for metastatic ccRCC. NUF2 is a crucial component of the Ndc80 complex. NUF2 can stabilize microtubule attachment and is closely related to cell apoptosis and proliferation. This research is dedicated to investigating the role of NUF2 in ccRCC and the possible mechanisms. First, analysis of NUF2 mRNA expression levels in ccRCC and normal tissues by The Cancer Genome Atlas (TCGA) database and further verified by analysis of independent multiple microarray data sets in the Gene Expression Omnibus (GEO) database. Moreover, we evaluated and identified correlations between NUF2 expression, clinicopathologic variable, and overall survival (OS) in ccRCC by various methods. We investigated the relationship between NUF2 and tumor immune infiltration and the expression of corresponding immune cell markers via the Gene Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER) databases. Then, we performed functional enrichment analysis of NUF2 co-expressed genes using R software and protein-protein interactions (PPIs) using the search tool used to retrieve interacting genes/proteins (STRING) databases. We discovered that NUF2 mRNA expression was upregulated in ccRCC tissues and was associated with sex, grade, pathological stage, lymph node metastasis, and worse prognosis. In addition, NUF2 was positively linked to tumor immune cells in ccRCC. Moreover, NUF2 was closely related to genetic markers of different immune cells. Finally, functional enrichment and protein-protein interaction (PPI) analysis suggested that NUF2 and its closely related genes may be involved in the regulation of the cell cycle and mitosis. Our results suggested that NUF2 is correlated with a poor prognosis and immune infiltration in ccRCC.


A case of persistent atrial fibrillation cured by focal ablation in a young patient.
We present a case of a 25-year-old man who had persistent atrial fibrillation (AF) lasting for three months. The persistent AF was terminated by a 20-mg bolus infusion of adenosine triphosphate. Frequent and repetitive episodes of ectopic atrial tachycardia (EAT) emerged from the mid-portion of the saddle between the left superior and inferior pulmonary veins. The successful ablation was achieved by a focal ablation at the site with the earliest activation preceding the P-wave onset by 42 ms, and exhibited a QS pattern in the unipolar recording. This is rare case in which focal ablation could cure persistent AF.


Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats.
Membrane phospholipids like phosphatidylcholine (PC) are required for cellular growth and repair, and specifically for synaptic function. PC synthesis is controlled by cellular levels of its precursor, cytidine-5'-diphosphate choline (CDP-choline), which is produced from cytidine triphosphate (CTP) and phosphocholine. In rat PC12 cells exogenous uridine was shown to elevate intracellular CDP-choline levels, by promoting the synthesis of uridine triphosphate (UTP), which was partly converted to CTP. In such cells uridine also enhanced the neurite outgrowth produced by nerve growth factor (NGF). The present study assessed the effect of dietary supplementation with uridine-5'-monophosphate disodium (UMP-2Na+, an additive in infant milk formulas) on striatal dopamine (DA) release in aged rats. Male Fischer 344 rats consumed either a control diet or one fortified with 2.5% UMP for 6 wk, ad libitum. In vivo microdialysis was then used to measure spontaneous and potassium (K+)-evoked DA release in the right striatum. Potassium (K+)-evoked DA release was significantly greater among UMP-treated rats, i.e., 341+/-21% of basal levels vs. 283+/-9% of basal levels in control rats (p<0.05); basal DA release was unchanged. In general, each animal's K+-evoked DA release correlated with its striatal DA content, measured postmortem. The levels of neurofilament-70 and neurofilament-M proteins, biomarkers of neurite outgrowth, increased to 182+/-25% (p<0.05) and 221+/-34% (p<0.01) of control values, respectively, with UMP consumption. Hence, UMP treatment not only enhances membrane phosphatide production but also can modulate two membrane-dependent processes, neurotransmitter release and neurite outgrowth, in vivo.


Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in guinea-pig vessels, but not in rat and mouse aorta.
Cannabinoids exert complex effects on blood pressure related to their interference with cardiovascular centres in the central nervous system and to their direct influence on vascular muscle, vascular endothelium and heart. In view of the relative lack of information on the occurrence of CB1 receptors on the vascular postganglionic sympathetic nerve fibres, the aim of the present study was to examine whether cannabinoid receptor ligands affect the electrically evoked tritium overflow in superfused vessels (tissue pieces) from the guinea-pig, the rat and the mouse preincubated with 3H-noradrenaline. The cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3-de]1,4-benzoxazinyl](1-naphthalenyl) methanone) inhibited the evoked tritium overflow in the guinea-pig aorta, but not in that of the rat or mouse. The concentration-response curve of WIN 55,212-2 was shifted to the right by the CB1 receptor antagonist rimonabant, yielding an apparent pA2 value of 7.9. The most pronounced (near-maximum) inhibition obtained at the highest WIN 55,212-2 concentration applied (3.2 microM) amounted to 40%. WIN 55,212-2 also inhibited the evoked overflow in guinea-pig pulmonary artery, basilar artery and portal vein, again in a manner sensitive to antagonism by rimonabant. The latter did not affect the evoked overflow by itself in the four vessels, but did increase the electrically evoked tritium overflow from superfused guinea-pig hippocampal slices preincubated with 3H-choline and from superfused guinea-pig retina discs preincubated with 3H-noradrenaline (labelling dopaminergic cells in this tissue). The inhibitory effect of 3.2 microM WIN 55,212-2 on the evoked overflow from the guinea-pig aorta was comparable in size to that obtained with agonists at the histamine H3, kappa opioid (KOP) and ORL1 (NOP) receptor (1 or 10 microM, producing the respective near-maximum effects) whereas prostaglandin E2 1 microM caused a higher near-maximum inhibition of 70%. Prostaglandin E2 also induced an inhibition by 65 and 80% in the rat and mouse aorta respectively, indicating that the present conditions are basically suitable for detecting presynaptic receptor-mediated inhibition of noradrenaline release. The results show that the postganglionic sympathetic nerve fibres in the guinea-pig aorta, but not in the rat or mouse aorta, are endowed with presynaptic inhibitory cannabinoid CB1 receptors; such receptors also occur in guinea-pig pulmonary artery, basilar artery and portal vein. These CB1 receptors are not subject to an endogenous tone and the extent of inhibition obtainable via these receptors is within the same range as that of several other presynaptic heteroreceptors, but markedly lower than that obtainable via receptors for prostaglandin E2.


Relationship of soccer heading to computerized neurocognitive performance and symptoms among female and male youth soccer players.
The purpose of this study was to investigate the relationship between soccer heading and computerized neurocognitive performance and symptoms in female and male youth soccer players. Cross-sectional and prospective design. A total of 63 (27 females, 36 males) youth soccer players aged 13-18 years (M = 15.89, SD = 1.17) participated in the study. Participants completed the Immediate Post-concussion Assessment and Cognitive Test (ImPACT) and symptom report. Computerized neurocognitive performance (e.g., verbal and visual memory, motor processing, and reaction time) and symptoms. There were no differences in neurocognitive performance or symptoms among low-, moderate-, and high-exposure header groups. The current sample outperformed the 10th percentile norms for neurocognitive and symptom scores. Males headed the ball more frequently and reported lower verbal and visual memory and motor processing speed scores than females. The current findings did not support a relationship between soccer heading and computerized neurocognitive performance and symptoms. The researchers suggest that any purported effects of soccer heading in youth are subtle and may affect only a small number of athletes. The reported sex differences in heading exposure warrant further attention.


Identification of Subclinical Myocardial Dysfunction and Association with Survival after Transcatheter Mitral Valve Repair.
Transcatheter mitral valve repair (TMVr) using edge-to-edge mitral valve clip is effective for patients with mitral regurgitation (MR) and high or prohibitive surgical risk. Global longitudinal strain (GLS) allows evaluation of subclinical myocardial dysfunction, but its incremental clinical utility into risk stratification, beyond traditional clinical parameters, is unknown in patients treated with TMVr. We sought to evaluate the association of baseline GLS with 1-year all-cause mortality in patients treated with TMVr using edge-to-edge mitral valve clip. We analyzed 155 patients who underwent transcatheter edge-to-edge mitral valve clip implantation (mean age, 83 ± 7 years; 48% were women; mean left ventricular ejection fraction, 56% ± 10%, Society of Thoracic Surgeons Predicted Risk of Mortality score for repair, 6.62% ± 5.22%). Baseline left ventricular GLS was obtained by two-dimensional speckle-tracking echocardiography, averaging 18 segments from three apical views. Receiver operating characteristic analyses were used to assess the GLS cut point associated with all-cause mortality. Multivariable models with Cox regression tested its relationship after adjustment for baseline comorbidities. During a median follow-up of 316 days, all-cause deaths occurred in 30 patients at a median of 156 days after TMVr. The area under the curve of preoperative GLS associated with the outcome was 0.60, with a cutoff point of -14.5%. Baseline GLS > -14.5% was associated with 1-year mortality (hazard ratio = 2.50; 95% CI, 1.20-5.21; P = .02) before and after adjustment for baseline characteristics. After accounting for baseline characteristics, patients with GLS > -14.5% had worse 1-year mortality than those with GLS ≤ -14.5% (χ2P < .001). In nested Cox proportional hazards models, the addition of baseline GLS to Society of Thoracic Surgeons Predicted Risk of Mortality score, left ventricular ejection fraction, and the etiology of MR significantly increased the model χ2 value (χ2 = 12.32). Baseline GLS is independently associated with 1-year all-cause mortality in patients who undergo TMVr, and its assessment improves risk stratification in these patients.


Bacterial staphylokinase as a promising third-generation drug in the treatment for vascular occlusion.
Vascular occlusion is one of the major causes of mortality and morbidity. Blood vessel blockage can lead to thrombotic complications such as myocardial infarction, stroke, deep venous thrombosis, peripheral occlusive disease, and pulmonary embolism. Thrombolytic therapy currently aims to rectify this through the administration of recombinant tissue plasminogen activator. Research is underway to design an ideal thrombolytic drug with the lowest risk. Despite the potent clot lysis achievable using approved thrombolytic drugs such as alteplase, reteplase, streptokinase, tenecteplase, and some other fibrinolytic agents, there are some drawbacks, such as high production cost, systemic bleeding, intracranial hemorrhage, vessel re-occlusion by platelet-rich and retracted secondary clots, and non-fibrin specificity. In comparison, bacterial staphylokinase, is a new, small-size plasminogen activator, unlike bacterial streptokinase, it hinders the systemic degradation of fibrinogen and reduces the risk of severe hemorrhage. A fibrin-bound plasmin-staphylokinase complex shows high resistance to a2-antiplasmin-related inhibition. Staphylokinase has the potential to be considered as a promising thrombolytic agent with properties of cost-effective production and the least side effects.


Determination of the palatal masticatory mucosa thickness by dental MRI: a prospective study analysing age and gender effects.
The aim of this prospective study was to evaluate age and gender effects on the palatal masticatory mucosa thickness by using non-invasive and non-ionizing MRI. 40 periodontally healthy participants of five gender-balanced age groups (20-29, 30-39, 40-49, 50-59 and 60-69 years, respectively) underwent dental MRI at 3 Tesla using a contrast-enhanced, high-resolution 3D-sequence. The palatal masticatory mucosa was measured at 40 standard measurement points by two independent observers. Statistical analysis was performed by using intraclass correlation coefficient (ICC), Shapiro-Wilk test, two-way analysis of variance and post-hoc Tukey HSD test. Measurements of the palatal masticatory mucosa thickness were highly reliable with a mean intraobserver ICC of 0.989 and a mean interobserver ICC of 0.987. Mean palatal masticatory mucosa thickness increased with the distance from the gingival margin in all tooth regions. Molars showed a considerably lower average palatal masticatory mucosa thickness at intermediate heights in comparison to canines and premolars. Average palatal masticatory mucosa thickness continuously increased with age and significantly differed between age groups (p < 0.01). A significant increase was observed between the age groups of 30-39 years and 40-49 years (p = 0.04). Gender had no significant effect on average palatal mucosa thickness (p = 0.19). However, there was a tendency towards thicker mucosa in males (mean ± SD, 3.36 mm ± 0.47) compared to females (3.23 mm ± 0.44). In the present study, dental MRI allowed for a highly reliable determination of the palatal masticatory mucosa thickness. Considerable intra- and interindividual variations in palatal masticatory mucosa thickness were observed. Average palatal masticatory mucosa thickness was dependent on age but not on gender.


Patterns of health lifestyle behaviours: findings from a representative sample of Israel.
Researchers are increasingly acknowledging the importance of understanding patterns of engagement in multiple, as opposed to isolated, health behaviours. Accordingly, several studies, targeting various geographical regions, have begun to identify and characterize unique classes of individuals in terms of their engagement in health behaviours, towards gaining insights that might guide tailored health interventions. Our study extends this stream of research to the Israeli context, as well as examines whether certain sociodemographic characteristics tend to be associated with affiliation to a specific group of individuals, i.e., class membership. Two large representative samples were obtained from the 2010 and 2017 National Social Surveys of the Israel Central Bureau of Statistics. Latent Class Analysis was used to identify different classes, based on levels of engagement in five health behaviours: fruit-and-vegetable consumption, physical activity, smoking avoidance, sleep, and influenza vaccination. Multinomial logistic regression was applied to test the associations between sociodemographic characteristics (age, gender, religion, education level) and class membership. We identified three distinct classes (denoted "healthy", "unhealthy", and "mixed"). Overall, the "healthy" class was characterized by healthy levels of fruit-and-vegetable consumption and physical activity, a low rate of currently-smoking individuals, and a high proportion of influenza vaccination. The "mixed" class was characterized by healthy levels of fruit-and-vegetable consumption and sleep duration, moderate levels of physical exercise, a high proportion of currently light smokers, and a low rate of vaccination. The "unhealthy" class was marked by relatively low levels of engagement in health behaviours. Generally, older, Jewish, and more-educated individuals were more likely to belong to the "healthy" class, while young, non-Jewish, and less-educated individuals were more likely to belong to the "unhealthy" class. We further identified differences between the 2010 and 2017 samples (e.g., differences in men's likelihood of being in the "unhealthy" class), suggesting that some behavioural patterns might have changed over time. This research identified three classes of engagement in health behaviours across two large and representative samples. Moreover, the classes were associated with unique sociodemographic characteristics. Consequently, our findings can highlight health-behavioural patterns relevant to different sub-populations that should be considered in public health interventions.


Long-term results of conventional surgical treatment for epilepsy. Delayed recurrence after a period of 10 years.
The results of the surgical treatment of epilepsy were studied in 44 patients 10 or more years after operation. Thirty-seven patients underwent operation only once; these patients were observed 11-26 years postoperatively. Seven patients had a recurrence within 5 years after operation and required a second operation; these patients were observed 11-17 years after the second operation. Recovery persisted for 15-27 years in 32 patients. There was a recurrence in 12 cases 11-19 years after operation. With one exception, these recurrences were satisfactorily treated medically.


Hypertension in adolescents and young adults referred to a tertiary hypertension clinic in Cape Town, South Africa.
To audit the young patients referred to the Hypertension Clinic at Groote Schuur Hospital that predominately serves the underprivileged communities of Cape Town.Folders of patients between the ages of 15 and 30 years over a 2 year period were reviewed. The data collected included demographic, clinical and laboratory data, investigations, causes of hypertension, and presence of hypertensive organ damage.Of the 110 patients reviewed, 61 (55.5%) were females, 22 (20%) Black African, and 88 (80%) of Mixed Ancestry. Eight (7.3%) were found to be normotensive, 16 (14.5%) had a secondary cause and 86 (78.2%) had essential hypertension. Thirty five (31.8%) were current or previous smokers, and 11 (10%) admitted to current or prior use of metamphetamines. A family history of hypertension in a first degree relative was present in 80 (72.7%) patients. Comorbidities present were diabetes in 7 (6.4%) patients, metabolic syndrome in 13 (11.8%), and obesity in 26 (23.6%), but 42.6% had a body mass index (BMI) <25 kg/m. Chronic kidney disease (CKD) was present in 29 (26.4%) patients and ECG left ventricular hypertrophy in 56 (50.9%). Overall organ damage was present in 72 (65.5%) patients.In this cohort of young hypertensives most patients had essential hypertension with a strong family history. Significant organ damage was identified. High risk behavior, including smoking and illicit drug use, and obesity were identified as contributing factors. Secondary causes were identified in 14.2%. These results suggest a targeted approach to the investigation of young hypertensives for secondary causes, and significant opportunities for lifestyle intervention.


Huffing-induced cardiomyopathy: a case report.
The intentional inhalation of fumes from gasoline or solvents for recreational purposes is commonly known as Huffing, Sniffing or Dusting (Anderson and Loomis in Am Fam Physician 68(5):869-874, 2003). Inhalant abuse is known to be "Cardio-toxic", causing sudden death and chronic myocardial damage (Meadows and Verghese in South Med J 89(5):455-462, 1996; Anderson and Loomis in Am Fam Physician 68(5):869-874, 2003). We report a 20-year-old white man who presented with altered mental status following ingestion of multiple alprazolam and oxycodone tablets. He was found to have diffused ST-T changes on his EKG. Cardiac enzymes were found to be elevated-CK: 599 U/L, CK-MB: 16.8 ng/mL and Troponin: 0.78 ng/mL. A transthoracic echocardiogram (TTE) revealed global left ventricular (LV) dysfunction with an ejection fraction (EF) of 10-15%. During hospitalization, the cardiac enzymes started trending downward and this was followed by spontaneous resolution of the LV dysfunction. The patient also admitted to inhaling "Dust-Off" spray 2-3 days prior to admission. Inhalant abuse can cause cardiomyopathy and should be considered a probable cause in patients presenting with cardiac dysfunction of unknown etiology, particularly in teenagers and young adults.


DNA synthesis in the pituitary gland of the rat: effect of sulpiride and clomiphene.
Sulpiride administration to rats releases prolactin and increases DNA replication in the anterior pituitary gland. Clomiphene prevents the stimulation of DNA synthesis produced by sulpiride, but does not affect prolactin release from the gland. These findings suggest that the intracellular prolactin content of the anterior pituitary gland plays a role in the regulation of DNA synthesis through a mechanism mediated by oestrogens.


Effects of an adolescent sexual and reproductive health intervention on health service usage by young people in northern Ghana: a community-randomised trial.
While many Ghanaian adolescents encounter sexual and reproductive health problems, their usage of services remains low. A social learning intervention, incorporating environment, motivation, education, and self-efficacy to change behaviour, was implemented in a low-income district of northern Ghana to increase adolescent services usage. This study aimed to assess the impact of this intervention on usage of sexual and reproductive health services by young people. Twenty-six communities were randomly allocated to (i) an intervention consisting of school-based curriculum, out-of-school outreach, community mobilisation, and health-worker training in youth-friendly health services, or (ii) comparison consisting of community mobilisation and youth-friendly health services training only. Outcome measures were usage of sexually-transmitted infections (STIs) management, HIV counselling and testing, antenatal care or perinatal services in the past year and reported service satisfaction. Data was collected, at baseline and three years after, from a cohort of 2,664 adolescents aged 15-17 at baseline. Exposure was associated with over twice the odds of using STI services (AOR 2.47; 95%CI 1.78-3.42), 89% greater odds of using perinatal services (AOR 1.89; 95%CI 1.37-2.60) and 56% greater odds of using antenatal services (AOR 1.56; 95%CI 1.10-2.20) among participants in intervention versus comparison communities, after adjustment for baseline differences. The addition of targeted school-based and outreach activities increased service usage by young people more than community mobilisation and training providers in youth-friendly services provision alone.


Survival in patients with postnecrotic cirrhosis and Laennec's cirrhosis undergoing therapeutic portacaval shunt.
Survival rates were compared in 82 patients who underwent therapeutic portacaval shunt. All patients were followed for at least 5 years after shunt or until death. Survival rates were calculated by Life Table methods. Based on a combination of currently accepted histological and clinical criteria, there were 45 patients with Laennec's cirrhosis, 29 patients with postnecrotic cirrhosis, 11 of whom had histological evidence of chronic active hepatitis, and 8 patients with primary biliary cirrhosis. Survival rates were similar in all three groups, alcoholic cirrhosis, postnecrotic cirrhosis, and primary biliary cirrhosis. Hepatic reserve, as defined by Child's classification, provided the best criteria for predicting survival. The type of shunt, end-to-side, side-to-side, or splenorenal, did not influence survival. Histological evidence of chronic active hepatitis adversely affected survival in patients with postnecrotic cirrhosis. However, histological evidence of ongoing alcoholic hepatitis in patients with Laennec's cirrhosis did not influence survival adversely. The data indicate that once a patient with cirrhosis has bled from esophageal varices, the etiology of the cirrhosis is not a major factor in determining survival after a therapeutic portacaval shunt.


[Natural infection of Equus asinus by Leishmania braziliensis braziliensis-Bahia, Brazil].
In Corte de Pedra, Valença, state of Bahia, a donkey, Equus asinus, was found naturally infected with Leishmania braziliensis braziliensis. The parasite was isolated from a lesion located on a castration scar, and identified by means of monoclonal antibodies.


Ouabain Modulates the Lipid Composition of Hippocampal Plasma Membranes from Rats with LPS-induced Neuroinflammation.
The effects of ouabain (OUA) and lipopolysaccharide (LPS) in vivo on hippocampal membranes (RHM) of Wistar male rats aged 3 months were analyzed. After intraperitoneal (i.p.) injection of OUA only, LPS only, OUA plus LPS, or saline, the content of proteins, phospholipids, cholesterol and gangliosides from RHM was analyzed. The total protein and cholesterol contents of RHM were not significantly affected by OUA or LPS for the experimentally paired groups. In contrast, total phospholipids and gangliosides were strongly modulated by either OUA or LPS treatments. LPS reduced the total phospholipids (roughly 23 %) and increased the total gangliosides (approximately 40 %). OUA alone increased the total phospholipids (around 23 %) and also the total gangliosides (nearly 34 %). OUA pretreatment compensated the LPS-induced changes, preserving the total phospholipids and gangliosides around the same levels of the control. Thus, an acute treatment with OUA not only modulated the composition of hippocampal membranes from 3-month-old rats, but also was apparently able to counteract membrane alterations resulting from LPS-induced neuroinflammation. This study demonstrates for the first time that the OUA capacity modulates the lipid composition of hippocampal plasma membranes from rats with LPS-induced neuroinflammation.


Impact of the Higgins Nutrition Intervention Program on birth weight: a within-mother analysis.
A study was conducted to evaluate the impact of the Higgins Nutrition Intervention Program of individual nutritional assessment and rehabilitation on pregnancy outcome in a group of urban low-income women. Developed as an adjunct to routine prenatal care, the Higgins program utilizes an individualized approach to dietary treatment that combines an assessment of the risk profile for the presenting pregnancy with the application of specific nutritional rehabilitation allowances to compensate for the negative impact of diagnosed risks. This report presents results of analyses evaluating differences in birth outcomes between 552 sibling pairs; each mother had participated in the Higgins program during the pregnancy of the second-born, but not of the first-born, member of her pair. After adjustment for parity and sex, the intervention infants weighed an average of 107 gm more than their matched siblings at birth (p less than .01). The rate of low birth weight was 50% lower among the intervention infants than among their siblings (p less than .01); rates of intra-uterine growth retardation and perinatal mortality were also lower in the intervention group. The high risk of poor pregnancy outcome in this group of urban low-income women was reduced by the Higgins program.


"I was afraid my baby would be upset with me" - women living with HIV's accounts going through non-breastfeeding in São Paulo, Brazil.
In Brazil prevention of mother to child HIV transmission guidelines recommend formula feeding. This qualitative study, carried out in a public clinic (CEADIPE/UNIFESP), aimed at exploring experiences of breastfeeding avoidance of women living with HIV living in São Paulo. Individual interviews were carried out with the support of a semi-structured questionnaire. Data was analyzed in a thematic approach with the support of AtlasTi®. During the months of January-February 2010, 25 women were interviewed, including women with (n = 12) and without previous breastfeeding experience (n = 13). Major themes identified were: Non-breastfeeding as a trigger for stigmatization, Non-breastfeeding, guilt and coping, Attitudes around non-breastfeeding for women with and without previous breastfeeding experience, and Women's support through non-breastfeeding. In conclusion women interviewed faced challenges related to HIV diagnosis, which got entangled with difficulties with breastfeeding avoidance. Different patterns of reaction and coping could be identified, regardless of mothers' previous breastfeeding experiences. Health systems were key in providing women living with HIV with tailored services and the necessary support.


Mammalian-like differentiation of gastric cells in the shark Hexanchus griseus.
Gastric glands of submammalian vertebrates are formed by one single cell type known as the oxyntopeptic cell. This cell secretes both hydrochloric acid and pepsinogen. In mammals, this cell differentiates into an acid secreting cell and a pepsinogen secreting one. In the elasmobranch fish Hexanchus griseus we observed, by means of histological studies at the light- and electron-microscopic levels, two different cell types for the secretion of acid and zymogen. This organization represents an evolutionary divergence in a primitive animal, i.e., the appearance of a feature that is acquired much later in evolution, in mammals.


Feather's Composition of South Polar Skua (Stercorarius maccormicki) Using WDXRF.
This study investigated the feathers' composition of South polar skua (Stercorarius maccormicki) using WDXRF, evaluating the concentration of essential and non-essential elements in the feathers, and dividing it into rachis and barb parts. We collected South polar skuas feathers from Hennequin Point, King George Island, South Shetland, Antarctic Peninsula in January of 2013. Our results show that 18 elements were observed in the composition of the feathers, with a different concentration between the rachis and barbs, qualitatively and quantitatively. Only 3 elements observed were classified as non-essentials but still mostly elements do not have a function described in the literature to the feathers. According to our knowledge, this is the first study that uses this technique to evaluate the concentration of different elements in the feathers. The findings of this study highlight the use of alternative techniques to biomonitoring elements in the ecosystem and bring baseline information for future studies.


Pyoderma gangrenosum as a manifestation of leukemia in childhood.
Pyoderma gangrenosum is an uncommon skin lesion often associated with autoimmune diseases. A clear association between leukemia and pyoderma gangrenosum in adults has been established. Two cases of pyoderma gangrenosum in children with leukemia in whom it may be an initial finding are presented.


HIF-1α increases the osteogenic capacity of ADSCs by coupling angiogenesis and osteogenesis via the HIF-1α/VEGF/AKT/mTOR signaling pathway.
Stabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) can directly increase cancellous bone formation and play an essential role in bone modeling and remodeling. However, whether an increased HIF-1α expression in adipose-derived stem cells (ADSCs) increases osteogenic capacity and promotes bone regeneration is not known. In this study, ADSCs transfected with small interfering RNA and HIF-1α overexpression plasmid were established to investigate the proliferation, migration, adhesion, and osteogenic capacity of ADSCs and the angiogenic ability of human umbilical vein endothelial cells (HUVECs). Overexpression of HIF-1α could promote the biological functions of ADSCs, and the angiogenic ability of HUVECs. Western blotting showed that the protein levels of osteogenesis-related factors were increased when HIF-1α was overexpressed. Furthermore, the influence of upregulation of HIF-1α in ADSC sheets on osseointegration was evaluated using a Sprague-Dawley (SD) rats implant model, in which the bone mass and osteoid mineralization speed were evaluated by radiological and histological analysis. The overexpression of HIF-1α in ADSCs enhanced bone remodeling and osseointegration around titanium implants. However, transfecting the small interfering RNA (siRNA) of HIF-1α in ADSCs attenuated their osteogenic and angiogenic capacity. Finally, it was confirmed in vitro that HIF-1α promotes osteogenic differentiation and the biological functions in ADSCs via the VEGF/AKT/mTOR pathway. This study demonstrates that HIF-1α has a critical ability to promote osteogenic differentiation in ADSCs by coupling osteogenesis and angiogenesis via the VEGF/AKT/mTOR signaling pathway, which in turn increases osteointegration and bone formation around titanium implants.


Quantification of the nonlinear susceptibility of the hydrogen and deuterium stretch vibration for biomolecules in coherent Raman micro-spectroscopy.
Deuterium labelling is increasingly used in coherent Raman imaging of complex systems, such as biological cells and tissues, to improve chemical specificity. Nevertheless, quantitative coherent Raman susceptibility spectra for deuterated compounds have not been previously reported. Interestingly, it is expected theoretically that -D stretch vibrations have a Raman susceptibility lower than -H stretch vibrations, with the area of their imaginary part scaling with their wavenumber, which is shifted from around 2900 cm-1 for C-H into the silent region around 2100 cm-1 for C-D. Here, we report quantitative measurements of the nonlinear susceptibility of water, succinic acid, oleic acid, linoleic acid and deuterated isoforms. We show that the -D stretch vibration has indeed a lower area, consistent with the frequency reduction due to the doubling of atomic mass from hydrogen to deuterium. This finding elucidates an important trade-off between chemical specificity and signal strength in the adoption of deuterium labelling as an imaging strategy for coherent Raman microscopy.


The uricosuric effect of oxaprozin in humans.
The effects of oxaprozin, a new investigational propionic acid analogue, and indomethacin on uric acid metabolism were compared in 12 healthy volunteers receiving either agent, first as a single dose and then daily for seven days. While indomethacin did not alter either serum or urinary uric acid values, oxaprozin caused a fall in serum uric acid levels from 5.8 +/- 0.2 mg/dL to 4.8 +/- 0.4 mg/dL (P less than 0.01). Urinary uric acid excretion rose from a baseline of 673 +/- 47 mg to 825 +/- 66 mg/24 h by day 7 of treatment (P less than 0.01). Since oxaprozin was associated with no change in glomerular filtration rate in these studies, the hypouricemic effect of oxaprozin is most likely a result of its direct uricosuric action. Because indomethacin and oxaprozin both are inhibitors of urinary prostaglandin E2 excretion, the data suggest that prostaglandin inhibition per se is not associated with changes in uric acid excretion.


Mechanical stimuli activate gene expression via a cell envelope stress sensing pathway.
Mechanosensitive mechanisms are often used to sense damage to tissue structure, stimulating matrix synthesis and repair. While this kind of mechanoregulatory process is well recognized in eukaryotic systems, it is not known whether such a process occurs in bacteria. In Vibrio cholerae, antibiotic-induced damage to the load-bearing cell wall promotes increased signaling by the two-component system VxrAB, which stimulates cell wall synthesis. Here we show that changes in mechanical stress within the cell envelope are sufficient to stimulate VxrAB signaling in the absence of antibiotics. We applied mechanical forces to individual bacteria using three distinct loading modalities: extrusion loading within a microfluidic device, direct compression and hydrostatic pressure. In all cases, VxrAB signaling, as indicated by a fluorescent protein reporter, was increased in cells submitted to greater magnitudes of mechanical loading, hence diverse forms of mechanical stimuli activate VxrAB signaling. Reduction in cell envelope stiffness following removal of the endopeptidase ShyA led to large increases in cell envelope deformation and substantially increased VxrAB response, further supporting the responsiveness of VxrAB. Our findings demonstrate a mechanosensitive gene regulatory system in bacteria and suggest that mechanical signals may contribute to the regulation of cell wall homeostasis.


An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity.
Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p < 0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p < 0.001) compared with rat liver microsomes. MPA UGT activities were reduced >80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.


Check in the Mail or More in the Paycheck: Does the Effectiveness of Fiscal Stimulus Depend on How It Is Delivered?
Recent fiscal policies, including the 2008 stimulus payments and the 2009 Making Work Pay Tax Credit, aimed to increase household spending. This paper quantifies the spending response to these policies and examines differences in spending by whether the stimulus was delivered as a one-time payment or as a flow of payments from reduced withholding. Based on responses from a representative sample of households in the Thomson Reuters University of Michigan Surveys of Consumers, the paper finds that the reduction in withholding in 2009 boosted spending at roughly half the rate (13 percent) as the one-time payments (25 percent) in 2008.


Clinical validation and applications for CT-based atlas for contouring the lower cranial nerves for head and neck cancer radiation therapy.
Radiation induced cranial nerve palsy (RICNP) involving the lower cranial nerves (CNs) is a serious complication of head and neck radiotherapy (RT). Recommendations for delineating the lower CNs on RT planning studies do not exist. The aim of the current study is to develop a standardized methodology for contouring CNs IX-XII, which would help in establishing RT limiting doses for organs at risk (OAR). Using anatomic texts, radiologic data, and guidance from experts in head and neck anatomy, we developed step-by-step instructions for delineating CNs IX-XII on computed tomography (CT) imaging. These structures were then contoured on five consecutive patients who underwent definitive RT for locally-advanced head and neck cancer (LAHNC). RT doses delivered to the lower CNs were calculated. We successfully developed a contouring atlas for CNs IX-XII. The median total dose to the planning target volume (PTV) was 70Gy (range: 66-70Gy). The median CN (IX-XI) and (XII) volumes were 10c.c (range: 8-12c.c) and 8c.c (range: 7-10c.c), respectively. The median V50, V60, V66, and V70 of the CN (IX-XI) and (XII) volumes were (85, 77, 71, 65) and (88, 80, 74, 64) respectively. The median maximal dose to the CN (IX-XI) and (XII) were 72Gy (range: 66-77) and 71Gy (range: 64-78), respectively. We have generated simple instructions for delineating the lower CNs on RT planning imaging. Further analyses to explore the relationship between lower CN dosing and the risk of RICNP are recommended in order to establish limiting doses for these OARs.


Obscure gastrointestinal bleeding: role of videocapsule and double-balloon enteroscopy.
Capsule endoscopy (CE), which allows the non-invasive visualisation of mucosa throughout the entire small bowel, has revolutionised the exploration of small-bowel diseases, and particularly the evaluation of obscure gastrointestinal bleeding (OGIB) after a negative initial evaluation, including gastroscopy and colonoscopy. CE has a high negative predictive value and a higher diagnostic yield than all other modalities, such as radiology (small-bowel X-rays or computed tomography scan) or push enteroscopy. CE may be the preferred initial diagnostic choice in OGIB because of its non-invasive quality and better tolerance. Double-balloon enteroscopy, also known as push-and-pull enteroscopy, has recently been developed. It has made it possible not only to explore the small bowel but also to carry out therapeutic interventions deep in the small bowel without the need for surgical laparotomy. This exploration should be considered as a second-line exploration for OGIB in patients with a positive finding on CE requiring endoscopic follow-up for histology or intervention, and in patients in whom suspicion of a small-bowel lesion is high despite a negative CE.


Serum IL8 and mRNA level of CD11b in circulating neutrophils are increased in clinically amyopathic dermatomyositis with active interstitial lung disease.
The objective of this study is to assess serum IL8 and the potential activity of circulating neutrophils on relative messenger RNA (mRNA) levels and their relationship with disease activity in clinically amyopathic dermatomyositis (CADM) associated with interstitial lung disease (ILD). We studied 18 CADM patients and compared them with 18 classic dermatomyositis (DM) patients and 18 healthy control subjects. Serum IL8 level and mRNA expressions of neutrophils (chemokine (C-X-C motif) receptor 1 (CXCR1), cluster of differentiation molecule 11b (CD11b), cluster of differentiation 64 (CD64), myeloid cell leukemia 1 (MCL1), interleukin-18 (IL18)) were detected. The overproduction of serum IL8 level was most significant in the CADM group with active period. The mRNA expressions of CD11b, IL18, and MCL1 were greatly increased in the neutrophils in patients with CADM compared with DM or healthy controls. Up-expressions of CD11b, IL18, and MCL1 were detected in the neutrophils in CADM patients of active period compared with remission period. A positive correlation was found between CD11b mRNA level and high-resolution computed tomography (HRCT) score, in CADM associated with ILD. Serum IL8 level and mRNA levels of CD11b, MCL1, and IL18 in circulating neutrophils are related with the disease activity of CADM-ILD. The mRNA level of CD11b is positively correlated with HRCT score in CADM-ILD.


Multimodal integrated strategy for the discovery and identification of quality markers in traditional Chinese medicine.
With the modernization and internationalization of traditional Chinese medicine (TCM), the requirement for quality control has increased. The quality marker (Q-marker) is an important standard in this field and has been implemented with remarkable success in recent years. However, the establishment of Q-markers remains fragmented and the process lacks systematicity, resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM. This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Q-markers, thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM. These include the whole-process quality control strategy, chemical-activity-based screening method, efficacy, safety, and consistent combination strategy, and TCM theory-guided approach. Furthermore, methodologies and representative examples of these strategies are described, and important future directions and questions in this field are also proposed.


The influence of recycling non-condensable gases in the fractional catalytic pyrolysis of biomass.
In this study, the effect of recycling the non-condensable gases (NCG) in the catalytic pyrolysis of hybrid poplar using FCC catalyst was investigated. A 50mm bench scale fluidized bed reactor at 475°C with a weight hourly space velocity (WHSV) of 2h(-1) and a gas recycling capability was used for the studies. Model fluidizing gas mixtures of CO/N(2), CO(2)/N(2), CO/CO(2)/N(2) and H(2)/N(2) were used to determine their independent effects. Recycling of the NCG in the process was found to potentially increase the liquid yield and decrease char/coke yield. The model fluidizing gases increased the liquid yield and the CO(2)/N(2) fluidizing gas had the lowest char/coke yield. The (13)C-NMR analysis showed that recycling of NCG increases the aromatic fractions and decreases the methoxy, carboxylic and sugar fractions. Recycling of NCG increased the higher heating value and the pH of the bio-oil as well as decreased the viscosity and density.


[Heptral potentialities in the treatment of hepatic damage in children with malignant blood disease].
To assess benefit for children with malignant blood disease (MBD) of the hepatoprotector heptral. 67 children with blood malignancy aged 3-14 years were examined (53 of them had acute lymphoblastic leukemia). 39 patients were in the study group (25 of them had hepatitis B or C), 28 were controls. Initially, heptral was injected intravenously (14 days) then orally (16-30 days). Activity of transaminases and number of violations of polychemotherapy protocols because of hepatic toxicity were registered. Heptral administration led to inhibited activity of AlAT and AsAT especially in non-infected patients. Protocol deviations became less frequent. Heptral is a potent hepatoprotector in hepatic lesions of toxic, viral and mixed origin.


Sample size re-estimation for pivotal clinical trials.
It is well known that if the hypothesis test is left unchanged, the Type I error rate may be inflated for sample size re-estimation (SSR) designs. To address this issue, three main approaches have been proposed in the literature: combination test, conditional error and conventional test with sample size increase in the allowable region (AR) only. These three seemingly different approaches are in fact connected. For each combination test, there is a corresponding conditional error function and AR. Designing adaptation rules in this AR with conventional test guarantees the Type I error rate control but at the same time always leads to smaller power comparing to the corresponding combination test (or conditional error) approach. In cases where conventional test is still preferable, step-wise type adaptation rules that do not fully reside in the AR can be alternatively considered. We believe controversies in the statistical community on the efficiency comparisons between group sequential (GS) and SSR design stem partially from the misalignment of performance metrics and conditional versus unconditional evaluations. We advocate summary metrics, such as median, variance or tail probabilities of the sample size in addition to expectation and personalizing efficiency definition for each trial sponsor. Conditional metrics by favorable, promising and unfavorable zones of the interim results provide additional insights and should always be incorporated into the decision-making process.


Estimation of BTEX in groundwater by using gas chromatography-mass spectrometry.
Advanced analytical modern technology such as coupling a gas chromatography to a mass spectrometric technique provides sufficient information to the environmental and analytical chemists to identify the presence of a variety of components of the specific volatile organic product, determine the degree of the product weathering and in some instances estimate the age of the product as well in the testing sample. In this study, we estimated BTEX in groundwater sample by using gas chromatography-mass spectrometry (GC-MS) after standardization of this technique for advancement towards purification check of water samples in the petro-polluted regions of the soil.


Relational Quantum Mechanics and the PBR Theorem: A Peaceful Coexistence.
According to Relational Quantum Mechanics (RQM) the wave function ψ is considered neither a concrete physical item evolving in spacetime, nor an object representing the absolute state of a certain quantum system. In this interpretative framework, ψ is defined as a computational device encoding observers' information; hence, RQM offers a somewhat epistemic view of the wave function. This perspective seems to be at odds with the PBR theorem, a formal result excluding that wave functions represent knowledge of an underlying reality described by some ontic state. In this paper we argue that RQM is not affected by the conclusions of PBR's argument; consequently, the alleged inconsistency can be dissolved. To do that, we will thoroughly discuss the very foundations of the PBR theorem, i.e. Harrigan and Spekkens' categorization of ontological models, showing that their implicit assumptions about the nature of the ontic state are incompatible with the main tenets of RQM. Then, we will ask whether it is possible to derive a relational PBR-type result, answering in the negative. This conclusion shows some limitations of this theorem not yet discussed in the literature.


Responsiveness to glucagon by isolated rat hepatocytes controlled by the redox state of the cytosolic nicotinamide--adenine dinucleotide couple acting on adenosine 3':5'-cyclic monophosphate phosphodiesterase.
1. The effects of changes in the cytoplasmic [NADH]/[NAD+] ratio on the efficacy of glucagon to alter rates of metabolism in isolated rat hepatocytes were examined. 2. Under reduced conditions (with 10mM-lactate), 10nM-glucagon stimulated both gluconeogenesis and urea synthesis in isolated hepatocytes from 48h-starved rats; under oxidized conditions (with 10mM-pyruvate), 10nM-glucagon had no effect on either of these rates. 3. The ability of glucagon to alter the concentration of 3':5'-cyclic AMP and the rates of glucose output, glycogen breakdown and glycolysis in cells from fed rats were each affected by a change in the extracellular [lactate]/[pyruvate] ratio; minimal effects of glucagon occurred at low [lactate]/[pyruvate] ratios. 4. Dose-response curves for glucagon-mediated changes in cyclic AMP concentration and glucose output indicated that under oxidized conditions the ability of glucagon to alter each parameter was decreased without affecting the concentration of hormone at which half-maximal effects occurred. 5. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.05 mM) significantly reversed the inhibitory effects of pyruvate on glucagon-stimulated glucose output. 6. For exogenously added cyclic [3H]AMP(0.1 mM), oxidized conditions decreased the stimulatory effect on glucose output as well as the intracellular concentration of cyclic AMP attained, but did not alter the amount of cyclic [3H]AMP taken up. 7. The effects of lactate, pyruvate, NAD+ and NADH on cyclic AMP phosphodiesterase activities of rat hepatocytes were examined. 8. NADH (0.01--1 MM) inhibited the low-Km enzyme, particularly that which was associated with the plasma membrane. 9. The inhibition of membrane-bound cyclic AMP phosphodiesterase by NADH was specific, reversible and resulted in a decrease in the maximal velocity of the enzyme. 10. It is proposed that regulation of the membrane-bound low-Km cyclic AMP phosphodiesterase by nicotinamide nucleotides provides the molecular basis for the effect of redox state on the hormonal control of hepatocyte metabolism by glucagon.


Levorotatory carbohydrates and xylitol subdue Streptococcus mutans and Candida albicans adhesion and biofilm formation.
Dietary carbohydrates and polyols affect the microbial colonization of oral surfaces by modulating adhesion and biofilm formation. The aim of this study was to evaluate the influence of a select group of l-carbohydrates and polyols on either Streptococcus mutans or Candida albicans adhesion and biofilm formation in vitro. S. mutans or C. albicans suspensions were inoculated on polystyrene substrata in the presence of Tryptic soy broth containing 5% of the following compounds: d-glucose, d-mannose, l-glucose, l-mannose, d- and l-glucose (raceme), d- and l-mannose (raceme), l-glucose and l-mannose, sorbitol, mannitol, and xylitol. Microbial adhesion (2 h) and biofilm formation (24 h) were evaluated using MTT-test and Scanning Electron Microscopy (SEM). Xylitol and l-carbohydrates induced the lowest adhesion and biofilm formation in both the tested species, while sorbitol and mannitol did not promote C. albicans biofilm formation. Higher adhesion and biofilm formation was noted in both organisms in the presence of d-carbohydrates relative to their l-carbohydrate counterparts. These results elucidate, hitherto undescribed, interactions of the individually tested strains with l- and d-carbohydrates, and how they impact fungal and bacterial colonization. In translational terms, our data raise the possibility of using l-form of carbohydrates and xylitol for dietary control of oral plaque biofilms.


Influence of Area-Level Characteristics on the Suicide Rate in Korean Adolescents.
We aimed to investigate the influence of area-level factors on adolescent suicide and to determine which variables differ according to age and sex. We selected variables that were available for collection through an online database from 2005 to 2015 in the Korean Statistical Information Service and the Korea Labor Institute. We used administrative districts of Korea in 2017 for geographical classification. We examined the relationships between regional suicide rates and area-level variables in male and female subjects aged 10-14 years and 15-19 years. In addition, we analyzed area-level variables in adolescents aged 15-19 years according to sex. Our findings indicated that several area-level variables affected adolescent suicide rates, varying according to age and sex. Economic problems were shown to be more associated with suicide in male adolescents than in female adolescents. On the other hand, social fragmentation and health services were shown to be more associated with suicide in females. Suicide in adolescents was attributable to area-level factors such as economic status, social fragmentation, and community health services. By identifying area-level variables affecting adolescent suicide rates, we will be able to contribute to implement mental health policies related to adolescent suicide.


Protective effect of plasmin in marginal donor lungs in an ex vivo lung perfusion model.
Donor lung thrombi are considered an important etiology for primary graft dysfunction in lung transplantation. We hypothesized that thrombolysis before lung transplantation could alleviate ischemia-reperfusion injury. This study was designed to evaluate the effect of the fibrinolytic agent plasmin on lungs damaged by thrombi in an ex vivo lung perfusion (EVLP) system. Rats were divided into control, non-plasmin, and plasmin groups (n = 7 each). In the control and plasmin groups, cardiac arrest was induced by withdrawal of mechanical ventilation without heparinization. Ventilation was restarted 150 minutes after cardiac arrest. The lungs were flushed, and the heart and lungs were excised en bloc. The lungs were perfused in the EVLP system for 60 minutes, and plasmin or placebo was administered upon EVLP initiation. Fibrin/fibrinogen degradation products in the perfusate were significantly higher in the plasmin group than in the control and non-control groups (p < 0.001 for both). Plasmin administration significantly decreased pulmonary vascular resistance (plasmin vs non-plasmin, p = 0.011) and inhibited the exacerbation of dynamic compliance (plasmin vs non-plasmin, p = 0.003). Lung weight gain was less in the plasmin group than in the non-plasmin group (p = 0.04). Our results confirmed that plasmin administration in an EVLP model dissolved thrombi in the lungs, resulting in reconditioning of the lungs as assessed by various physiologic parameters.


Lower Urinary Tract Symptoms in Croatian Obese Patients.
Patients with obesity may experience lower urinary tract symptoms (LUTS). Little is known about these symptoms in obese patients in Croatia. The aim of this study was to asses LUTS in this group of patients. This cross-sectional study was carried out in a tertiary healthcare centre. 111 participants were included (81 women and 30 men, age 23-78 years), with BMI>30 kg/m2. LUTS were evaluated using International consultation on incontinence questionnaires (ICIQ) investigating symptoms of overactive bladder (OAB) and urinary incontinence (UI): ICIQ-OAB and ICIQ-UI Short Form (SF). We evaluated also some of the questions on the EQ-5D-5L questionnaire. On ICIQ-OAB patients most often reported:UI (46.85% (N=52)), nocturia (42.34% (N=47)) and increased frequency of urination (34.23% (N=38)), and on ICIQ-UI SF: UI when coughing and sneezing (44.44% (N=32)), urgency UI (43.06% (N=31)) and UI during exercise/physical activity (22.22% (N=16)). Women were found to be more significantly affected by OAB symptoms (p<0.05). Significant correlations were found between the overall results on ICIQ-OAB and hypertension (r=0.32). The results of this study confirm that obese patients in Croatia experience LUTS as well. A higher incidence of LUTS was found among women and gender-independent among hypertensive obese patients.


Getting to the Core of It All: Nanocapsules to Mitigate Infusion Reactions Can Promote Hemostasis and Be a Platform for Intravenous Therapies.
One of the significant challenges to translation of intravenously administered nanomaterials has been complement-mediated infusion reactions which can be lethal. Slow infusions can reduce infusion reactions, but slow infusions are not always possible in applications like controlling bleeding following trauma. Thus, avoiding complement activation and infusion responses is essential to manage bleeding. We identified nanocapsules based on polyurethane as candidates that did not activate C5a and explored their PEGylation and functionalization with the GRGDS peptide to create a new class of hemostatic nanomaterials. Using the clinically relevant rotational thromboelastography (ROTEM), we determined that nanocapsules promote faster clotting than controls and maintain the maximum clot firmness, which is critical for reducing bleeding. Excitingly, these polyurethane-based nanocapsules did not activate complement or the major pro-inflammatory cytokines. This work provides critical evidence for the role of modulating the core material in developing safer nanomedicines for intravenous applications.


Impact of socioeconomic deprivation on outcome after surgery for colorectal cancer.
Previous studies have demonstrated that socioeconomic deprivation is associated with poorer survival in patients with colorectal cancer. These differences have been attributed to more advanced disease at presentation. A total of 2269 patients undergoing resection for colorectal cancer in hospitals in central Scotland between 1991 and 1994 were studied. Socioeconomic status was defined using the Carstairs deprivation index. The impact of deprivation on case mix, treatment and outcome was analysed. There were no significant differences in mode of presentation, extent of disease at presentation, type of resection and postoperative mortality rate among the socioeconomic groups. Following curative resection, the overall survival rate at 5 years was 47.0 per cent in deprived patients, compared with 55.4 per cent in affluent patients (P = 0.05); the cancer-specific survival rate was 62.6 per cent in the deprived and 68.1 per cent in the affluent (P = 0.05). Compared with the affluent, the adjusted hazard ratios for the deprived were 1.36 (95 per cent confidence interval (c.i.) 1.09 to 1.69) for overall mortality and 1.26 (95 per cent c.i. 0.95 to 1.67) for cancer-specific mortality. Following palliative resection, there was no difference in survival between the affluent and deprived for either overall (P = 0.27) or cancer-specific (P = 0.89) mortality. These findings confirm that the cancer-specific survival rate following surgery for colorectal cancer is lower in deprived patients. Stage of disease at presentation and type of operation did not account for this difference. The excess mortality was confined to patients undergoing apparently curative resection.


Activation of Rac-1 and Cdc42 stabilizes the microvascular endothelial barrier.
We have demonstrated previously that the Rho family GTPase Rac-1 is required for maintenance of endothelial barrier functions in mouse microvascular myocardial endothelial (MyEnd) cells in vitro as well as in rat mesenteric microvessels in vivo. In this study, we tested the hypothesis that specific activation of Rac-1 would stabilize microvascular endothelial barrier functions. For this purpose we used Escherichia coli Cytotoxic necrotizing factor (CNF-1) under conditions (300 ng/ml, 120 min) where it strongly activated Rac-1 and Cdc42 but not Rho A in MyEnd cells. Under these conditions, CNF-1 induced translocation of the actin-binding proteins cortactin and vasodilator-stimulated phosphoprotein (VASP) to cell junctions, increased the junction-associated actin filament belt, and reduced monolayer permeability. We also tested the effect of CNF-1 on endothelial barrier properties in vivo using single-perfused mesenteric microvessels. In contrast to cultured microvascular monolayers, CNF-1 did not reduce baseline barrier functions assayed as hydraulic conductivity (Lp). However, following 120 min pretreatment, CNF-1 significantly attenuated the peak Lp increase in response to platelet-activating factor (PAF, 10 nM) to 12.6+/-4 x 10(-7) cm/(s cmH(2)O) compared to 46.2+/-10 x 10(-7) cm/(s cmH(2)O) in experiments using PAF alone. These experiments indicate that activation of Rac-1 and Cdc42 stabilizes microvascular endothelial barrier functions in vitro and in vivo, likely by increasing the junction-associated actin cytoskeleton.


A transcriptional inhibitor targeted by the atypical orphan nuclear receptor SHP.
SHP (short heterodimer partner, NROB2) is an atypical orphan member of the mammalian nuclear receptor family that consists only of a putative ligand-binding domain and thus cannot bind DNA. Instead, SHP acts as a transcriptional coregulator by inhibiting the activity of various nuclear receptors (downstream targets) via occupation of the coactivator-binding surface and active repression. However, repression mechanisms have remained elusive and may involve coinhibitory factors (upstream targets) distinct from known nuclear receptor corepressors. Here, we describe the isolation of mouse E1A-like inhibitor of differentiation 1 (EID1) as a candidate coinhibitor for SHP. We characterize the interactions between SHP and EID1 and identify two repression-defective SHP mutations that have lost the ability to bind EID1. We suggest histone acetyltransferases and histones as targets for EID1 action and propose that SHP inhibition of transcription involves EID1 antagonism of CBP/p300-dependent coactivator functions.


Decorating an anisotropic Au13 core with dendron thiolates: enhancement of optical absorption and photoluminescence.
We successfully introduced up to 12 poly(benzyl ether)dendron-thiols of the second generation (D2SH) into the Au13 core of [Au23(ScC6H11)16]- while retaining the geometric structure. The decoration with D2SH enhanced the optical absorbance in the >2.5 eV region and the quantum yield of photoluminescence at ∼1.6 eV by ∼15 times.


Factors determining renal impairment in unilateral ureteral colic secondary to calcular disease: a prospective study.
To evaluate all possible risk factors that can cause impairment of overall renal function in patients with unilateral ureteral calculus and a normal contralateral kidney. This is a prospective study of 90 patients who presented to our institute complaining of renal colic secondary to unilateral ureteral calculus. All patients were evaluated with a thorough history, physical examination, and laboratory and radiological investigations including renal function testing, urine analysis, non-contrast computed topography, and radionucleotide scan. Patients were divided into two groups according to their calculated creatinine clearance using the Modification of Diet in Renal Disease (MDRD) formula. Group I (favorable group) had a creatinine clearance >60 ml/min, while group II (unfavorable group) had a creatinine clearance <60 ml/min. The patients' mean age ± SD was 38.8 ± 11.4 years. Group I included 54 patients (60 %), while group II included 36 patients (40 %). On univariate analysis, factors that were associated with overall renal function impairment were patients' age, urea-to-creatinine ratio (UCR), use of nonsteroidal anti-inflammatory drugs, stone location, and presence of obstruction. However, using binary logistic regression analysis, only patients' age, UCR, and presence of obstruction sustained statistical significance in association with renal function impairment. The study of factors that help explain the presence of renal impairment in patients with unilateral ureteral calculus is important in the clinical setting. Patients' age, urea-to-creatinine ratio, and degree of obstruction seem to be significantly associated with overall renal function impairment.


Hemispherectomy for the treatment of intractable seizures in childhood.
This article discusses the role of hemispherectomy in the treatment of children with intractable seizures associated with hemiplegia. The postnatal development and plasticity of the brain are discussed, leading to a justification for early surgery in appropriate candidates. Methods of investigation, the process of selection, and the various surgical techniques are outlined.


The influence of ultrasound on the release of gentamicin from antibiotic-loaded acrylic beads and bone cements.
Gentamicin-loaded acrylic beads are loosely placed in infected bone cavities, whereas gentamicin-loaded acrylic bone cement is used as a mechanical filler in bone to anchor prosthetic components. Both drug delivery systems are used to decrease infection rates by gentamicin release. The objective of this study is to investigate the effects of pulsed ultrasound on gentamicin release from both materials. Gentamicin release from gentamicin-loaded beads (Septopal) and from three commercially-available brands of gentamicin-loaded bone cement (CMW 1, Palacos R-G, and Palamed G) was measured after 18 h of exposure in PBS to an ultrasonic field of 46.5 kHz in a 1:3 duty cycle with an average acoustic intensity of 167 mW/cm(2). Samples not exposed to ultrasound were used as controls. Pulsed ultrasound significantly enhanced gentamicin release from gentamicin-loaded beads, whereas gentamicin release from the gentamicin-loaded bone cements was not significantly enhanced. Mercury intrusion porosimetry revealed an increased distribution of pores between 0.1 and 0.01 microm in beads after gentamicin release, while in bone cements no increase in the number of pores was found. Increased gentamicin release in beads due to ultrasound may be explained by micro-streaming in a porous structure, whereas the absence of changes in pore structure after gentamicin release in bone cement is concurrent with the lack of an enhanced release of the antibiotic by ultrasound. As an effective treatment of infections requires high local concentrations of antibiotic, increased gentamicin release due to ultrasound may be of clinical significance, especially since ultrasound has been demonstrated to increase bacterial killing by antibiotics.


[Assessment of epidemic manifestations of the West Nile fever in the Volgograd region depending on the climatic conditions].
Results of the analysis of the increase in the incidence of epidemic of the West Nile fever and climate conditions in the Volgograd region were presented. Certain seasonal periods and threshold values of temperature and humidity statistically associated with the epidemic rise were identified. The discussion of the probable mechanisms of indirect effects of atmospheric heat on the elements of the epidemic process was carried out.


Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes.
Using emicizumab in lieu of immune tolerance induction (ITI) for patients with hemophilia A (HA) and factor (F)VIII inhibitors has been well described. However, decisions regarding ITI initiation, regimen, and preservation of tolerance remain to be elucidated. To study the course of FVIII inhibitors in patients with HA and a history of FVIII inhibitors receiving emicizumab prophylaxis. Patients with HA, with and without FVIII inhibitors, initiating emicizumab prophylaxis were prospectively followed up in our center. All patients with current or previous inhibitors were included in this analysis. Plasma samples for FVIII inhibitor assays were obtained every 3 to 6 months or following FVIII exposure. Patients documented annual bleeding rate and any FVIII exposure days (EDs). Of 162 emicizumab-treated participants, 51 met the inclusion criteria. A decrease in annual bleeding rate was observed in all 51 participants followed up for a median of 3.3 years, with 31 breakthrough bleeding episodes reported in 22 of 51 participants. FVIII inhibitor level transiently increased following FVIII exposures in 5 of 15 failed ITI participants. Eight of 21 participants who did not undergo ITI were exposed to FVIII (1-2 EDs)), and 1 of these 8 participants demonstrated increased FVIII inhibitor levels after head trauma (following 1 ED). Among participants who underwent successful ITI, 8 of 15 patients were exposed to FVIII over a total of 13 EDs (1-2 ED(s) each) for traumatic breakthrough bleeds. In all these participants, inhibitor levels remained zero, indicating successful tolerance maintenance. Our longitudinal follow-up of emicizumab-treated patients with HA and FVIII inhibitors shows that occasional exposure to FVIII may induce a transient anamnestic response. Nonetheless, no FVIII inhibitor recurrence was noted following FVIII exposures in patients who underwent successful ITI.


Insulin Signaling in Bone Marrow Adipocytes.
The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.


Uterine preservation with Alcides-Pereira's compressive sutures for postpartum uterine atony.
Postpartum hemorrhage (PPH) is mostly caused by uterine atony and is the leading cause of maternal death. Hysterectomy may be necessary in severe cases, but uterine compressive sutures are an uterine-sparing alternative. In 2005, Alcides Pereira proposed a technique with serial superficial stiches around the uterus. To date, there were no further reports on its clinical use. To evaluate a tertiary center's experience with Alcides-Pereira's compressive uterine sutures for severe PPH due to uterine atony, reviewing its efficacy, morbidity, and impact on reproductive outcomes. An 11-year retrospective cohort study of Alcides-Pereira's sutures for PPH at a single tertiary hospital. Demographic and obstetric data were collected. Details of subsequent pregnancies and fertility plans were collected through a telephonic interview. Comparison between women in which the sutures were effective and ineffective to prevent hysterectomy was made. Alcides-Pereira's sutures were applied in 23 patients with PPH due to uterine atony. The technique was successful in controlling the hemorrhage and avoiding hysterectomy in 20 patients (87%). When successful, the sutures avoided the need for any blood therapy in 55% (RR 0.45, 95% CI 0.28-0.73) of patients, intensive care unit admission in 80% (RR 0.2, 95% CI 0.08-0.48) and significantly shortened the length of hospital stay. All patients with preserved uterus resumed their usual menstrual pattern. One had a subsequent term vaginal delivery; one had three first trimester miscarriages. All other patients did not try to conceive. Alcides-Pereira's sutures are a feasible, uterine-sparing technique, providing an effective and safe option for PPH.


Life history of female preferences for male faces: a comparison of pubescent girls, nonpregnant and pregnant young women, and middle-aged women.
Although scientific interest in facial attractiveness has developed substantially in recent years, few studies have contributed to our understanding of the ontogeny of facial preferences. In this study, attractiveness of 30 male faces was evaluated by four female groups: girls at puberty, nonpregnant and pregnant young women, and middle-aged women. The main findings are as follows: (1) Preference for sexy-looking faces was strongest in young, nonpregnant women. (2) Biologically more mature girls displayed more adultlike preferences. (3) The intragroup consistency for postmenopausal women was relatively low. (4) In terms of the preference pattern, pregnant women were more similar to perimenopausal women than they were to their nonpregnant peers. (5) Preference for youthful appearance decreased with the age of the women. I argue that the life history of female preferences for male faces is, to a large extent, hormone-driven and underpinned by a set of evolutionary adaptations.


Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex.
The long-term effects of stress during development have been well characterized. However, the effects of developmental stress on the underlying neurological mechanisms related to the reward system are not well understood. The present report studied the long term effects of stress during development on the structural plasticity in the cortical and subcortical regions. Rats exposed to stress during embryonic development (prenatal stress; PS) or soon after birth (maternal separation; MS) were studied for structural alteration at the neuronal level in the nucleus accumbens (NAc), orbital frontal cortex (OFC), and medial prefrontal cortex (mPFC). The findings show that stress during development increased dendritic branching, length, and spine density in the NAc, and subregions of the PFC. PS experience increased dendritic branching and length in the mPFC apical and basilar dendrites. In contrast, a PS-associated decrease in dendritic branching and length was observed in the basilar branches of the OFC. MS resulted in an increase in dendritic growth and spine density in the subregions of the PFC. The effect of PS on neuroanatomy was more robust than MS despite the shorter duration and intensity. The altered dendritic growth and spine density associated with stress during development could have potential impact on NAc and PFC related behaviors.


A simple and robust nanosystem for photoacoustic imaging of bladder cancer based on α5β1-targeted gold nanorods.
Early detection and removal of bladder cancer in patients is crucial to prevent tumor recurrence and progression. Because current imaging techniques may fail to detect small lesions of in situ carcinomas, patients with bladder cancer often relapse after initial diagnosis, thereby requiring frequent follow-up and treatments. In an attempt to obtain a sensitive and high-resolution imaging modality for bladder cancer, we have developed a photoacoustic imaging approach based on the use of PEGylated gold nanorods (GNRs) as a contrast agent, functionalized with the peptide cyclic [CphgisoDGRG] (Iso4), a selective ligand of α5β1 integrin expressed by bladder cancer cells. This product (called GNRs@PEG-Iso4) was produced by a simple two-step procedure based on GNRs activation with lipoic acid-polyethyleneglycol(PEG-5KDa)-maleimide and functionalization with peptide Iso4. Biochemical and biological studies showed that GNRs@PEG-Iso4 can efficiently recognize purified integrin α5β1 and α5β1-positive bladder cancer cells. GNRs@PEG-Iso4 was stable and did not aggregate in urine or in 5% sodium chloride, or after freeze/thaw cycles or prolonged exposure to 55 °C, and, even more importantly, do not settle after instillation into the bladder. Intravesical instillation of GNRs@PEG-Iso4 into mice bearing orthotopic MB49-Luc bladder tumors, followed by photoacoustic imaging, efficiently detected small cancer lesions. The binding to tumor lesions was competed by a neutralizing anti-α5β1 integrin antibody; furthermore, no binding was observed to healthy bladders (α5β1-negative), pointing to a specific targeting mechanism. GNRs@PEG-Iso4 represents a simple and robust contrast agent for photoacoustic imaging and diagnosis of small bladder cancer lesions.


Evaluation of the colorimetric malachite green loop-mediated isothermal amplification (MG-LAMP) assay for the detection of malaria species at two different health facilities in a malaria endemic area of western Kenya.
Prompt diagnosis and effective malaria treatment is a key strategy in malaria control. However, the recommended diagnostic methods, microscopy and rapid diagnostic tests (RDTs), are not supported by robust quality assurance systems in endemic areas. This study compared the performance of routine RDTs and smear microscopy with a simple molecular-based colorimetric loop-mediated isothermal amplification (LAMP) at two different levels of the health care system in a malaria-endemic area of western Kenya. Patients presenting with clinical symptoms of malaria at Rota Dispensary (level 2) and Siaya County Referral Hospital (level 4) were enrolled into the study after obtaining written informed consent. Capillary blood was collected to test for malaria by RDT and microscopy at the dispensary and county hospital, and for preparation of blood smears and dried blood spots (DBS) for expert microscopy and real-time polymerase chain reaction (RT-PCR). Results of the routine diagnostic tests were compared with those of malachite green loop-mediated isothermal amplification (MG-LAMP) performed at the two facilities. A total of 264 participants were enrolled into the study. At the dispensary level, the positivity rate by RDT, expert microscopy, MG-LAMP and RT-PCR was 37%, 30%, 44% and 42%, respectively, and 42%, 43%, 57% and 43% at the county hospital. Using RT-PCR as the reference test, the sensitivity of RDT and MG-LAMP was 78.1% (CI 67.5-86.4) and 82.9% (CI 73.0-90.3) at Rota dispensary. At Siaya hospital the sensitivity of routine microscopy and MG-LAMP was 83.3% (CI 65.3-94.4) and 93.3% (CI 77.9-99.2), respectively. Compared to MG-LAMP, there were 14 false positives and 29 false negatives by RDT at Rota dispensary and 3 false positives and 13 false negatives by routine microscopy at Siaya Hospital. MG-LAMP is more sensitive than RDTs and microscopy in the detection of malaria parasites at public health facilities and might be a useful quality control tool in resource-limited settings.


Slow-paced inspiration regularizes alpha phase dynamics in the human brain.
The phase of low-frequency, rhythmic cortical activity is essential for organizing brain processes because it provides a recurrent temporal frame for information coding. However, the low-frequency cortical phase exhibits great flexibility in response to external influences. Given that brain rhythms have been found to track respiratory inputs, we hypothesized that slow breathing, commonly associated with mental regulation, could reorganize the relationship between these two rhythmic systems through the adjustment of the cortical phase to such a slow train of inputs. Based on simultaneous magnetoencephalography and respiratory measurements, we report that while participants performed paced breathing, slow relative to normal breathing modulated cortical phase activity in the alpha range across widespread brain areas. Such modulation effects were specifically locked to the middle of the inspiration stage and exhibited a well-structured pattern. At the single-subject level, the phase angles underlying the effects became more likely to be diametrically opposed across breaths, indicating unique and consistent phase adjustment to slow inspiratory inputs. Neither cardiac fluctuations nor breathing-unrelated task effects could account for the findings. We suggest that slow-paced inspiration could organize the cortical phase in a regularized phase pattern, revealing a rhythmic but dynamic neural network integrated with different neurophysiological systems through volitional control.NEW & NOTEWORTHY Breathing is more complicated than a simple gas exchange, as it is integrated with numerous cognitive and emotional functions. Controlled slow breathing has often been used to regulate mental processes. This magnetoencephalography study demonstrates that slow-paced relative to normal-paced inspiration could organize the timing of alpha rhythmic activities across breathing cycles in a structured manner over widespread brain areas. Our results reveal how a volitionally controlled change in respiratory behavior could systematically modulate cortical activity.


Redistribution of hydrophobic hypericin from nanoporous particles of SBA-15 silica in vitro, in cells and in vivo.
Nanoporous silica is nowadays used in various fields of nano- and micro-materials research. The advantage of nanoporous material is that it can be filled with various hydrophilic and hydrophobic molecules, which are then delivered to the target cells and tissues. In the present study, we have studied the interaction of nanoporous silica with hydrophobic and photodynamically active molecule - hypericin. Hypericin was adsorbed on/in SBA-15 silica, which led to the disappearance of its fluorescence due to hypericin aggregate formation. However, it was observed here that hypericin can be easily redistributed from these particles towards proteins and lipids in serum and cells in vitro and in vivo. Moreover, the charged surface character of SBA-15 pores forced the creation of protein/lipid corona on particles. Such complex enabled monomerization of hypericin on the surface of particles presented by fluorescence in the corona and singlet oxygen production suitable for photodynamic therapy (PDT). The PDT efficacy achieved by introducing the new construct into the PDT protocol was comparable to the efficacy of hypericin PDT. In conclusion, this study demonstrates a promising approach for the delivery of hydrophobic photosensitizers to cancer cells by nanoporous silica using fluorescence techniques.


[Hyperthermic intraoperative intraperitoneal chemotherapy in combined treatment of patients with tumors of the abdominal organs].
Based on a comparative analysis of the results of treatment of 142 patients the author has shown expediency of the proposed method of intraperitoneal chemotherapy. It allows to prolong the patients' life and to increase the number of cases of one-year survival.


The Sleep Blanket.
The sleep blanket is a visualization of my son's sleep pattern from birth to his first birthday. It has a crochet border surrounding a double-knit body. Each row represents a single day. Each stitch represents 6 min of time spent awake or asleep. The blanket itself is just another way I get to tell my son I love him.


Biogeometallurgical pre-mining characterization of ore deposits: an approach to increase sustainability in the mining process.
Based on the knowledge obtained from acid mine drainage formation in mine waste environments (tailings impoundments and waste rock dumps), a new methodology is applied to characterize new ore deposits before exploitation starts. This gives the opportunity to design optimized processes for metal recovery of the different mineral assemblages in an ore deposit and at the same time to minimize the environmental impact and costs downstream for mine waste management. Additionally, the whole economic potential is evaluated including strategic elements. The methodology integrates high-resolution geochemistry by sequential extractions and quantitative mineralogy in combination with kinetic bioleach tests. The produced data set allows to define biogeometallurgical units in the ore deposit and to predict the behavior of each element, economically or environmentally relevant, along the mining process.


Dental development of the permanent lateral incisor in patients with incomplete and complete unilateral cleft lip.
This study aimed to evaluate a possible delay in root development of the permanent lateral incisor on the cleft side compared with its contralateral tooth in patients with incomplete and complete unilateral cleft lip. Retrospective. Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRAC/USP), Bauru, São Paulo, Brazil. A sample of 95 panoramic radiographs of patients with incomplete and complete unilateral cleft was obtained from the files of HRAC/USP. The patients were both boys and girls of various races, aged 5 to 11 years, and did not have any syndrome or associated congenital malformation. The sample was divided into three groups according to the severity of the cleft lip. Radiographs were analyzed to compare root development stage of the lateral incisor on the cleft side with the noncleft side according to the classification of Nolla. The mean delay in root development of the permanent lateral incisor on the cleft side ranged from 0.5 to 1.6 scores for all three groups investigated. Root development of the permanent lateral incisor on the cleft side was delayed compared with the noncleft side.