A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.
Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent ("FGF1 decoy").


Competitive learning with floating-gate circuits.
Competitive learning is a general technique for training clustering and classification networks. We have developed an 11-transistor silicon circuit, that we term an automaximizing bump circuit, that uses silicon physics to naturally implement a similarity computation, local adaptation, simultaneous adaptation and computation and nonvolatile storage. This circuit is an ideal building block for constructing competitive-learning networks. We illustrate the adaptive nature of the automaximizing bump in two ways. First, we demonstrate a silicon competitive-learning circuit that clusters one-dimensional (1-D) data. We then illustrate a general architecture based on the automaximizing bump circuit; we show the effectiveness of this architecture, via software simulation, on a general clustering task. We corroborate our analysis with experimental data from circuits fabricated in a 0.35-mum CMOS process.


Costimulatory signals through B7.1/CD28 prevent T cell apoptosis during target cell lysis.
Expression of B7 on tumor cells can circumvent T cell tolerance and lead to the generation of tumor cell-specific T cell immunity. The effect of B7 expression on the generation of protective antitumor immunity has been attributed primarily to 1) more efficient T cell activation and 2) better generation of tumor-specific killer T cells. We have investigated the role of costimulation through B7.1 and its receptor, the CD28 molecule, in the generation of allogeneic human CTLs against MCF-7 breast cancer cells. In this setting, we describe how activated CTLs undergo activation-induced cell death upon killing the target cell. Instead of proliferation and clonal expansion, the majority of the CTLs underwent apoptotic cell death. CTL apoptosis could be blocked by 50% when binding of the Fas ligand to its receptor, the CD95 (APO-1/Fas) molecule, was prevented. Fas ligand was detected in the activated T cells, but not in MCF-7 or a panel of other breast cancer cell lines. This excludes an active role for MCF-7 during CTL death and indicates that the CTL apoptosis is due to an autocrine production of the Fas ligand by CTLs. Costimulation of CTLs by retrovirally B7.1-transfected MCF-7 drastically reduced the sensitivity of the CTLs to apoptosis during target contact. Thus, in tumor cell vaccination, B7.1 might play a major role in preventing T cell death by altering T cell susceptibility for apoptosis.


Peripheral arterial disease: meta-analysis of the diagnostic performance of MR angiography.
To summarize the overall diagnostic performance of magnetic resonance (MR) angiography in the evaluation of peripheral arteriosclerotic occlusive disease and to identify the most important sources of variation in diagnostic accuracy between studies. A search strategy in MEDLINE and citation tracking were used to identify relevant English-language articles published since 1991. Each article was critically appraised for examination, patient, and study design characteristics. The accuracy data from different studies were analyzed by constructing summary receiver operating characteristic curves; multiple linear regression was used to examine the variation between study results. Twenty-three studies were included. There was much heterogeneity in the study results, which could not be explained as differences in the threshold for a positive result. About half of the variation was due to the type of MR angiographic examination and the extent of image evaluation. The relative diagnostic odds ratio (DOR) for three-dimensional (3D) gadolinium-enhanced MR angiography compared with two-dimensional (2D) time-of-flight MR angiography was 7.46 (95% CI: 2.48, 22.20). The relative DOR for review of transverse source images or multiplanar reformations in addition to maximum intensity projections (MIPs) compared with the use of only MIPs for image evaluation was 4.53 (95% CI: 1.46, 13.87). The diagnostic accuracy of 3D gadolinium-enhanced MR angiography is superior to that of 2D time-of-flight MR angiography. Also, the review of transverse source images or use of additional postprocessing techniques, such as multiplanar reformation, results in significantly better diagnostic performance.


Thapsigargin induces phosphorylation of the 27-kDa heat shock protein in human keratinocytes.
In the human keratinocyte line HaCaT, the nonphosphorylated 27-kDa heat shock protein (HSP27) isoform A (pI 6.5) is constitutively expressed. Application of thapsigargin, which inhibits Ca2+-ATPase in the endoplasmic reticulum, results in the rapid formation of the phosphorylated HSP27 isoform B (pI 6.0) and reduction of HSP27 A without affecting the synthesis of HSP27. The thapsigargin-dependent HSP27 isoform change is similar to that induced by 43 degrees C heat shock, but different from that induced by arsenite, where the biphosphorylated isoform HSP27 C (pI 5.7) is observed. The receptor agonist bradykinin, which increases intracellular Ca2+ (Ca(i)) level, shows no effect on the distribution of HSP27 isoforms. The responses of HSP27 isoforms to thapsigargin are independent of Ca(i) concentration in HaCaT cells. These observations suggest that the thapsigargin-induced change in HSP27 isoforms is dependent on the depletion of internal Ca2+ stores rather than on the increase in Ca(i) concentration. The thapsigargin-induced change in HSP27 isoforms is reduced by the tyrosine kinase inhibitor, genistein, but not the protein kinase C inhibitor, H-7. We propose that the modulation of HSP27 phosphorylation status by Ca(i) homeostasis may be mechanistically linked to control of keratinocyte growth and differentiation and responses of keratinocytes to extracellular stresses.


Are threatened species special? An assessment of Dutch bees in relation to land use and climate.
Red Lists are widely used as an indicator of the status and trends of biodiversity and are often used in directing conservation efforts. However, it is unclear whether species with a Least Concern status share a common relationship to environmental correlates compared to species that are on the Red List. To assess this, we focus here on the contribution and correlates of land use, climate, and soil to the occurrence of wild bees in the Netherlands. We used observation data and species distribution models to explain the relation between wild bees and the environment. Non-threatened bees had a relatively higher variable importance of the land use variables to their models, as opposed to the climate variables for the threatened bees. The threatened bees had a smaller extent of occurrence and occupied areas with more extreme climatic conditions. Bees with a Least Concern status showed more positive responses to urban green spaces and Red List species showed a different response to climatic variables, such as temperature and precipitation. Even though Red List bees were found in areas with a higher cover of natural areas, they showed a more selective response to natural land use types. Pastures and crops were the main contributing land use variables and showed almost exclusively a negative correlation with the distribution of all wild bees. This knowledge supports the implementation of appropriate, species-specific conservation measures, including the preservation of natural areas, and the improvement of land use practices in agricultural and urban areas, which may help mitigate the negative impacts of future global change on species' distributions.


Parathyroid hormone--a drug for orthopedic surgery?
Whereas continuous exposure to PTH results in bone resorption, administration at intermittent doses results in bone formation by increasing osteoblast number and activity. The anabolic action of PTH has also been demonstrated in clinical trials, in which PTH increased the bone mass and reduced fracture rate in patients with osteoporosis. In animal models of fracture healing and fixation of orthopedic implants, PTH increases the bone density in a dose-dependent manner, leading to faster repair and better fixation. The effect appears to be stronger on the new forming bone than on pre-existing bone. Based on these preclinical studies, we suggest that intermittent PTH treatment may also benefit fracture healing and implant fixation in patients.


[Protein interaction with macroporous silicas].
Potentiometric titration curves were obtained for macroporous silicas (MPS). The effect of the MPS structure on adsorption of various protein was studied. The maximal experimental and theoretical values of the adsorption capacity of a macroporous silica are presented.


Sarco/endoplasmic reticulum Ca2+ (SERCA)-pumps: link to heart beats and calcium waves.
Mobilization of endoplasmic reticulum Ca2+ is pivotal to the ability of a cell to send or respond to stimuli. Ca(2+)-Mg(2+)-ATPases, termed SERCA pumps, sequester Ca2+ into the sarco/endoplasmic reticulum. There are several SERCA protein isoforms encoded by three genes. This paper summarizes the structure, function, tissue and subcellular distribution, and regulation of various SERCA isoforms. Then it attempts to link divergence in the signal transduction processes of cells to the types and levels of SERCA proteins they express and to how the cells regulate their SERCA pump activity. The paper examines possible linkages between SERCA pumps and receptor-activated Ca2+ entry, SERCA isoform localization and Ca(2+)-waves, and the role of SERCA pumps in nuclear Ca2+ in cell proliferation and apoptosis. Then it uses available information on cardiac function and chronic stimulation of the fast-twitch muscle to answer a series of basic questions on the regulation of SERCA activity and expression and their linkage to signal transduction. Finally, it discusses the possibility that neurons exhibit complex Ca(2+)-waves whose interactions have the potential to explain the operational basis of neural networks. A series of unanswered questions emerge based on this synthesis, including the unsettling issue of whether all the isoforms are needed to achieve the divergence in signal transduction or if there is a degree of redundancy in the system.


Physiological oxygen concentration alters glioma cell malignancy and responsiveness to photodynamic therapy in vitro.
The partial pressure of oxygen (pO2) in brain tumors ranges from 5 to 15%. Nevertheless, the majority of in vitro experiments with glioblastoma multiforme (GBM) cell lines are carried out under an atmospheric pO2 of 19 to 21%. Recently, 5-aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), has been introduced to neurosurgery to allow for photodynamic diagnosis and photodynamic therapy (PDT) in high-grade gliomas. Here, we investigate whether low pO2 affects GBM cell physiology, PpIX accumulation, or PDT efficacy. GBM cell lines (U-87 MG and U-251 MG) were cultured under atmospheric (pO2 = 19%) and physiological (pO2 = 9%) oxygen concentrations. PpIX accumulation and localization were investigated, and cell survival and cell death were observed following in vitro PDT. A physiological pO2 of 9% stimulated GBM cell migration, increased hypoxia-inducible factor (HIF)-1 alpha levels, and elevated resistance to camptothecin in U-87 MG cells compared to cultivation at a pO2 of 19%. This oxygen reduction did not alter 5-ALA-induced intracellular PpIX accumulation. However, physiological pO2 changed the responsiveness of U-87 MG but not of U-251 MG cells to in vitro PDT. Around 20% more irradiation light was required to kill U-87 MG cells at physiological pO2, resulting in reduced lactate dehydrogenase (LDH) release (one- to two-fold) and inhibition of caspase 3 activation. Reduction of oxygen concentration from atmospheric to a more physiological level can influence the malignant behavior and survival of GBM cell lines after in vitro PDT. Therefore, precise oxygen concentration control should be considered when designing and performing experiments with GBM cells.


[Effect of phenamine and sydnocarb on bioelectrical activity in the ventrolateral columns of the spinal cord].
It was shown in experiments on spinal rats that amphetamine (1-5 mg/kg) and sydnocarb (3.4-30 mg/kg) have an effect on bioelectrical activity in ventrolateral columns and posterior cornua of the spinal cord induced by stimulation of the sciatic nerve and intraarterial administration of bradykinin. Amphetamine (1-2 mg/kg) enhances spontaneous and evoked activities in the posterior cornua but does not change these in the ventrolateral columns. Amphetamine in a dose of 5 mg/kg reduces spontaneous and evoked activities in the formations in question. Sydnocarb (3.4-30 mg/kg) increases spontaneous and evoked activities in the posterior cornua and ventrolateral columns. Phenoxybenzamine (5 mg/kg) reduces the inhibitory action of amphetamine on the bradykinin-induced activity in the ventrolateral columns.


Effect of High-Intensity Interval Training and Moderate-Intensity Continuous Training in People With Poststroke Gait Dysfunction: A Randomized Clinical Trial.
Background The exercise strategy that yields the greatest improvement in both cardiorespiratory fitness (V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$) and walking capacity poststroke has not been determined. This study aimed to determine whether conventional moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) have different effects on V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6-minute walk distance (6MWD). Methods and Results In this 24-week superiority trial, people with poststroke gait dysfunction were randomized to MICT (5 days/week) or HIIT (3 days/week with 2 days/week of MICT). MICT trained to target intensity at the ventilatory anaerobic threshold. HIIT trained at the maximal tolerable treadmill speed/grade using a novel program of 2 work-to-recovery protocols: 30:60 and 120:180 seconds. V̇O2 and heart rate was measured during performance of the exercise that was prescribed at 8 and 24 weeks for treatment fidelity. Main outcomes were change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6MWD. Assessors were blinded to the treatment group for V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ but not 6MWD. Secondary outcomes were change in ventilatory anaerobic threshold, cognition, gait-economy, 10-meter gait-velocity, balance, stair-climb performance, strength, and quality-of-life. Among 47 participants randomized to either MICT (n=23) or HIIT (n=24) (mean age, 62±11 years; 81% men), 96% completed training. In intention-to-treat analysis, change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ for MICT versus HIIT was 2.4±2.7 versus 5.7±3.1 mL·kg-1·min-1 (mean difference, 3.2 [95% CI, 1.5-4.8]; P<0.001), and change in 6MWD was 70.9±44.3 versus 83.4±53.6 m (mean difference, 12.5 [95% CI, -17 to 42]; P=0.401). HIIT had greater improvement in ventilatory anaerobic threshold (mean difference, 2.07 mL·kg-1·min-1 [95% CI, 0.59-3.6]; P=0.008). No other between-group differences were observed. During V̇O2 monitoring at 8 and 24 weeks, MICT reached 84±14% to 87±18% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ while HIIT reached 101±22% to 112±14% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ (during peak bouts). Conclusions HIIT resulted in more than a 2-fold greater and clinically important change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ than MICT. Training to target (ventilatory anaerobic threshold) during MICT resulted in ~3 times the minimal clinically important difference in 6MWD, which was similar to HIIT. These findings show proof of concept that HIIT yields greater improvements in cardiorespiratory fitness than conventional MICT in appropriately screened individuals. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03006731.


Transcription Factor YY1 Modulates Lung Cancer Progression by Activating lncRNA-PVT1.
Lung cancer is the leading cause of cancer-related death worldwide. Despite the advancement in surgery and chemotherapy, the prognosis of patients with advanced lung cancer is still poor. Yin Yang-1 (YY1) is a multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes. In this study, we showed that the expression of YY1 is upregulated in lung cancer tissues as compared to adjacent normal tissues. Patients with higher expression of YY1 had larger tumor size, poor differentiation, higher TNM stage, and lymph node metastasis. Ectopic expression of YY1 in lung cancer cells promoted cell proliferation and invasion. Inversely, siRNA-mediated silencing of YY1 inhibited cell proliferation and induced apoptosis. These results suggested that YY1 may function as an oncogene in lung cancer. Moreover, through luciferase reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay, we showed that YY1 could directly bind to the promoter region of (long noncoding RNA-plasmacytoma variant translocation 1 [lncRNA-PVT1]) and activated its transcription through the consensus YY1 motif. Knockdown of the expression of YY1 reduced cell proliferation in vivo, consistent with the results obtained from silencing the expression of YY1 in lung cancer cells. Collectively, our study showed a critical role of YY1 in the regulation of tumorigenesis, partly through its downstream target PVT1.


Health-related quality of life variations by sociodemographic factors and chronic conditions in three metropolitan cities of South Asia: the CARRS study.
Health-related quality of life (HRQOL) is a key indicator of health. However, HRQOL data from representative populations in South Asia are lacking. This study aims to describe HRQOL overall, by age, gender and socioeconomic status, and examine the associations between selected chronic conditions and HRQOL in adults from three urban cities in South Asia. We used data from 16 287 adults aged ≥20 years from the baseline survey of the Centre for Cardiometabolic Risk Reduction in South Asia cohort (2010-2011). HRQOL was measured using the European Quality of Life Five Dimension-Visual Analogue Scale (EQ5D-VAS), which measures health status on a scale of 0 (worst health status) to 100 (best possible health status). 16 284 participants completed the EQ5D-VAS. Mean age was 42.4 (±13.3) years and 52.4% were women. 14% of the respondents reported problems in mobility and pain/discomfort domains. Mean VAS score was 74 (95% CI 73.7 to 74.2). Significantly lower health status was found in elderly (64.1), women (71.6), unemployed (68.4), less educated (71.2) and low-income group (73.4). Individuals with chronic conditions reported worse health status than those without (67.4 vs 76.2): prevalence ratio, 1.8 (95% CI 1.61 to 2.04). Our data demonstrate significantly lower HRQOL in key demographic groups and those with chronic conditions, which is consistent with previous studies. These data provide insights on inequalities in population health status, and potentially reveal unmet needs in the community to guide health policies.


Patient supply charges: still a revenue source?
Patient supply charges, billed to patients for the consumption of medical/surgical supplies, have been in use since the first medical insurance programs were established. But, as healthcare costs have escalated, so have supply charges. In turn, initiatives to limit supply charges have been promulgated, and healthcare financial managers should be sensitive to the fact that the cost of a patient supply charge program can exceed the real contribution generated by such a program.


Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain.
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [¹¹C]AZ10419369 is a novel 5-HT(1B) receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [¹¹C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect.


Anatomic location is a risk factor for atypical and malignant meningiomas.
Grade II and III meningiomas have higher rates of tumor recurrence than grade I meningiomas after surgery and/or external irradiation. As the utility of noninvasive treatments for brain tumors increases, it is becoming increasingly important to assess the likelihood that a tumor is not benign before treatment initiation. Hence, the authors have reviewed a large series of their patients to determine risk factors for higher-grade pathology, with particular interest paid to tumor location. The authors reviewed 378 patients presenting at their institution from 2000 to 2007 with histologically confirmed meningioma, central pathology grading according to the World Health Organization 2000 guidelines, and tumor location confirmed with preoperative imaging. They performed univariate and multivariate logistic regression on potential risk factors for high-grade pathology. Risk factors for grade II/III pathology included nonskull base location (2-fold) and male sex (2-fold). Patients with prior surgery had a 3-fold increased incidence of higher-grade meningiomas at presentation at the authors' center. The authors controlled for this referral bias by performing a multivariate regression, and analysis without patients receiving prior treatment. Ninety-seven percent of operations were performed for tumor size and clinical symptoms, whereas <3% were performed for interval growth or features concerning higher-grade pathology. Nonskull-base meningiomas, male sex, and prior surgery impart increased risk for grade II or III pathology. This increased risk translates to probable poorer prognosis and increased likelihood of recurrence after treatment. Thus, it is prudent to take these specific variables into consideration in conjunction with the complete clinical presentation when advising patients regarding their prognosis.


Failure of endoscopic therapy in upper gastrointestinal hemorrhage due to duodenal ulcers.
to evaluate the efficacy of endoscopic treatment in patients with upper gastrointestinal (UGIH) due to duodenal ulcer with high risk of persistent or recurrent bleeding and to determine the associated failure factors of this procedure. three hundred and thirty-six patients with UGIH due to duodenal ulcer requiring endoscopic treatment were analyzed between January 1992 and December 2001. The patients were classified according to the endoscopic findings: a) patients with limited bleeding; and b) patients with persistent and/or recurrent bleeding due to therapeutic failure. The clinical guidelines followed in patients with endoscopic treatment failure were previously established in the internal protocol. The variables that obtained statistical significance in the univariate analysis were included in the logistic regression model to identify those with an independent predictive value for failure of the endoscopic treatment. mean age of the patients was 60 +/- 17 years, 271 (81%) were male. Bleeding with severe hemodynamic affectation was detected in 82 patients (24%). The most common location of the duodenal ulcer was on the anterosuperior part of the duodenal bulb (227 patients, 68%). In 43 patients (13%) the ulcer was larger than 2 cm. The bleeding stigmata were classified as: Forrest I in 125 (38%) and Forrest II in 211 (62%). It was initially reached in 297 patients (88%). Twenty-two patients required emergency surgery (6,5%) and the global mortality rate was 3%. Severe hemodynamic affectation at admission (OR 11.8, p>0.001), ulcers exceeding 2 cm (OR 6.95, p = 0.019) and the presence of active bleeding during endoscopy (Forrest I) (OR 3.55, p = 0.08) were the variables included in the multivariate analysis independently associated to endoscopic therapy failure. endoscopic therapy is an efficient treatment of upper gastrointestinal bleeding due to duodenal ulcer. By means of a clinical variable, the hemodynamic status and two endoscopies, bleeding stigmata and the size of the ulcer, a group of patients with high risk of endoscopic treatment failure can be selected.


Mother-to-child transmission of human immunodeficiency virus type 1 and type 2 and dual infection: a cohort study in Banfora, Burkina Faso.
A prospective cohort study on the mother-to-child transmission of human immunodeficiency virus type 1 (HIV1), type 2 (HIV2) and dual positivity (HIV1 + HIV2) was carried out in Banfora, West Burkina Faso. The study samples consist of 117 newborns of HIV-seropositive women matched to 234 newborns of HIV-seronegative women. Among cases, 91 were born of HIV1-seropositive mothers, 15 were born of HIV2-seropositive mothers and 11 were born of HIV1 and HIV2 dual-seropositive mothers and were included in an 18-month follow-up. Calculation of the mother-to-child transmission rate was according to the recommendations of the European Economic Community working group. The HIV1 mother-to-child transmission rate was estimated to be 27.8% (95% confidence interval (CI) 24.5 to 32.4) with one method and 25.5% (95% CI 13.5 to 37.5) with a second method. For HIV2, this rate was estimated to be 29.5% (95% CI 26.0 to 39.8) and was not statistically different from the HIV1 mother-to-child transmission rate. No case of transmission was observed in children born of dual seropositive mothers. Survival rate at month 18 was significantly lower for children born of HIV1 mothers: 83.7% (95% CI 78.2 to 92.2). Survival rates were similar between children born of HIV2-seropositive (86.7), dual HIV1 + 2-positive (100) and seronegative mothers (92.0%). Findings suggest a higher mother-to-child transmission rate of HIV2 in children born in Burkina Faso than in Europe and a low clinical expression of HIV2 in children.


Characteristics of suicidal behavior in a Turkish sample.
Suicidal behavior is one of the most important problems in psychiatric clinics. Several sociodemographic and clinical characteristics may have different effects on suicidal behavior. To examine the sociodemographic and clinical characteristics of a sample of 144 suicide attempters admitted to a Turkish emergency clinic for a suicide attempt. All subjects were interviewed by a consultant psychiatrist. For all individuals, data on DSM-IV psychiatric diagnoses, sociodemographic data, Beck's Hopelessness Scale (BHS), Becks's Suicidal Ideation Scale (SIS), and Beck's Suicidal Intention Scale (BSIS) were collected. The majority of suicide attempters were females characterized by low educational status and low religious orientation. Drug overdose was the most common method of suicide attempt and conflict within the family was the most frequent psychological stress factor. Three-quarters of attempters (74.6%) met DSM-IV criteria for at least one psychiatric diagnosis. Of these, 28.5% met criteria for major depressive disorder. Suicide attempters with depression tended to be immigrant, urban dwellers with high scores on the suicide intent scale. In the present study, the findings are useful in showing the risk factors related to suicidal behavior.


Placebo Intervention Enhances Reward Learning in Healthy Individuals.
According to the placebo-reward hypothesis, placebo is a reward-anticipation process that increases midbrain dopamine (DA) levels. Reward-based learning processes, such as reinforcement learning, involves a large part of the DA-ergic network that is also activated by the placebo intervention. Given the neurochemical overlap between placebo and reward learning, we investigated whether verbal instructions in conjunction with a placebo intervention are capable of enhancing reward learning in healthy individuals by using a monetary reward-based reinforcement-learning task. Placebo intervention was performed with non-invasive brain stimulation techniques. In a randomized, triple-blind, cross-over study we investigated this cognitive placebo effect in healthy individuals by manipulating the participants' perceived uncertainty about the intervention's efficacy. Volunteers in the purportedly low- and high-uncertainty conditions earned more money, responded more quickly and had a higher learning rate from monetary rewards relative to baseline. Participants in the purportedly high-uncertainty conditions showed enhanced reward learning, and a model-free computational analysis revealed a higher learning rate from monetary rewards compared to the purportedly low-uncertainty and baseline conditions. Our results indicate that the placebo response is able to enhance reward learning in healthy individuals, opening up exciting avenues for future research in placebo effects on other cognitive functions.


Reproductive tactics, birth timing and the risk-resource trade-off in an income breeder.
In variable environments, habitats that are rich in resources often carry a higher risk of predation. As a result, natural selection should favour individuals that balance allocation of time to foraging versus avoiding predation through an optimal decision-making process that maximizes fitness. The behavioural trade-off between resource acquisition and risk avoidance is expected to be particularly acute during gestation and lactation, when the energetic demands of reproduction peak. Here, we investigated how reproductive female roe deer adjust their foraging activity and habitat use during the birth period to manage this trade-off compared with non-reproductive juveniles, and how parturition date constrains individual tactics of risk-resource management. Activity of reproductive females more than doubled immediately following parturition, when energy demand is highest. Furthermore, compared with non-reproductive juveniles, they increased their exposure to risk by using open habitat more during daytime and ranging closer to roads. However, these post-partum modifications in behaviour were particularly pronounced in late-parturient females who adopted a more risk-prone tactic, presumably to compensate for the growth handicap of their late-born offspring. In income breeders, individuals that give birth late may be constrained to trade risk avoidance for foraging during peak allocation to reproduction, with probable consequences for individual fitness.


The Nerves of the Adductor Canal and the Innervation of the Knee: An Anatomic Study.
Adductor canal block contributes to analgesia after total knee arthroplasty. However, controversy exists regarding the target nerves and the ideal site of local anesthetic administration. The aim of this cadaveric study was to identify the trajectory of all nerves that course in the adductor canal from their origin to their termination and describe their relative contributions to the innervation of the knee joint. After research ethics board approval, 20 cadaveric lower limbs were examined using standard dissection technique. Branches of both the femoral and obturator nerves were explored along the adductor canal and all branches followed to their termination. Both the saphenous nerve (SN) and the nerve to vastus medialis (NVM) were consistently identified, whereas branches of the anterior obturator nerve were inconsistently present. The NVM contributed significantly to the innervation of the knee capsule, through intramuscular, extramuscular, and deep genicular nerves. The SN had a relatively more modest contribution through superficial infrapatellar and posterior branches as well as contributing to the origin of the deep genicular nerves. The results suggest that both the SN and NVM contribute to the innervation of the anteromedial knee joint and are therefore important targets of adductor canal block. Given the site of exit of both nerves in the distal third of the adductor canal, the midportion of the adductor canal is suggested as an optimal site of local anesthetic administration to block both target nerves while minimizing the possibility of proximal spread to the femoral triangle.


EEG findings in dementia with Lewy bodies and Alzheimer's disease.
To evaluate the role of the EEG in the diagnosis of dementia with Lewy bodies (DLB). Standard EEG recordings from 14 patients with DLB confirmed at postmortem were examined and were compared with the records from 11 patients with Alzheimer's disease confirmed at postmortem Seventeen of the total of 19 records from the patients with DLB were abnormal. Thirteen showed loss of alpha activity as the dominant rhythm and half had slow wave transient activity in the temporal lobe areas. This slow wave transient activity correlated with a clinical history of loss of consciousness. The patients with Alzheimer's disease were less likely to show transient slow waves and tended to have less marked slowing of dominant rhythm. The greater slowing of the EEG in DLB than in Alzheimer's disease may be related to a greater loss of choline acetyltransferase found in DLB. Temporal slow wave transients may be a useful diagnostic feature in DLB and may help to explain the transient disturbance of consciousness which is characteristic of the disorder.


The genome sequence of the model ascomycete fungus Podospora anserina.
The dung-inhabiting ascomycete fungus Podospora anserina is a model used to study various aspects of eukaryotic and fungal biology, such as ageing, prions and sexual development. We present a 10X draft sequence of P. anserina genome, linked to the sequences of a large expressed sequence tag collection. Similar to higher eukaryotes, the P. anserina transcription/splicing machinery generates numerous non-conventional transcripts. Comparison of the P. anserina genome and orthologous gene set with the one of its close relatives, Neurospora crassa, shows that synteny is poorly conserved, the main result of evolution being gene shuffling in the same chromosome. The P. anserina genome contains fewer repeated sequences and has evolved new genes by duplication since its separation from N. crassa, despite the presence of the repeat induced point mutation mechanism that mutates duplicated sequences. We also provide evidence that frequent gene loss took place in the lineages leading to P. anserina and N. crassa. P. anserina contains a large and highly specialized set of genes involved in utilization of natural carbon sources commonly found in its natural biotope. It includes genes potentially involved in lignin degradation and efficient cellulose breakdown. The features of the P. anserina genome indicate a highly dynamic evolution since the divergence of P. anserina and N. crassa, leading to the ability of the former to use specific complex carbon sources that match its needs in its natural biotope.


Metabolite collision cross section prediction without energy-minimized structures.
Matching experimental ion mobility-mass spectrometry data to computationally-generated collision cross section (CCS) values enables more confident metabolite identifications. Here, we show for the first time that accurately predicting CCS values with simple models for the largest library of metabolite cross sections is indeed possible, achieving a root mean square error of 7.0 Å2 (median error of ∼2%) using linear methods accesible to most researchers. A comparison on the performance of 2D vs. 3D molecular descriptors for the purposes of CCS prediction is also presented for the first time, enabling CCS prediction without a priori knowledge of the metabolite's energy-minimized structure.


Design, engineering and structural integrity of electro-responsive carbon nanotube- based hydrogels for pulsatile drug release.
Triggerable drug delivery from polymeric implants offers the possibility to generate remote-controlled drug release profiles that may overcome the deficiencies of conventional administration routes (intravenous injections and oral administration) including the toxicity due to overdose and systemic administration. An electro-responsive delivery system was engineered to deliver drug molecules in a pulsatile manner, controlled by the on/off application of electric voltage. Pristine multi-walled carbon nanotubes (pMWNTs) were incorporated into a polymethacrylic acid (PMAA)-based hydrogel matrix by in situ radical polymerisation. The effect of pMWNTs and cross-linker concentration on the electrical and mechanical properties of the hydrogel hybrids was thoroughly investigated. The incorporation of pMWNTs into the polymeric network improved the electrical properties of the hydrogel hybrids and drug release from the gels was significantly enhanced at high pMWNT concentrations, reaching 70% of the loaded dose after two short electrical stimulations. The presence of pMWNTs within the hydrogel matrix affected however the mechanical properties of the hydrogel by decreasing the pore size and therefore the swelling/de-swelling of the gels. The damage to the hybrid gel surfaces after electrical stimulation and the loss of the pulsatile release profile at high cross-linker concentrations suggested that the mechanism of drug release involved a compressing effect and intensified the stress on the polymeric network as a result of the electrical properties of pMWNTs.


The next frontier in clinical pathways. The journey to outcomes management.
The Children's Memorial Hospital, a 265-bed pediatric hospital in Chicago, Illinois, is a leader in pediatric clinical pathway development. Significant improvements in care coordination and cost savings have been realized from the 14 pathways implemented to date. Use of a project management methodology and adaptation of continuous quality improvement tools for pathway development have proven effective to streamline and standardize this process. Despite its success in pathway development, Children's Memorial Hospital has realized the need to go further. It is necessary to measure outcomes--real clinical, patient outcomes--not just financial or utilization outcomes. Solid comparative data from which practice changes can be made are needed. Additional ways must be found to facilitate movement along the care continuum. Pathways must be used consistently. This article will outline the process Children's Memorial Hospital used and share the development tools that have been implemented. Children's Memorial Hospital's vision for the future and the technology designed to realize that vision are delineated.


Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant.
Treatment with an all-oral interferon-free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non-liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3-F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV-based regimens) received treatment and were followed for a median of 30 weeks (range 12-53 weeks). The median time from LT to treatment was 32 months (range 2-317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84%-96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3-F4 (71%) compared to those with F0-F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug-induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. An all-oral interferon-free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection.


Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism.
The cardiac and hematopoietic progenitors (CPs and HPs, respectively) in the mesoderm ultimately form a well-organized circulation system, but mechanisms that reconcile their development remain elusive. We found that activating transcription factor 3 (atf3) was highly expressed in the CPs, HPs, and mesoderm, in zebrafish. The atf3 -/- mutants exhibited atrial dilated cardiomyopathy and a high ratio of immature myeloid cells. These manifestations were primarily caused by the blockade of differentiation of both CPs and HPs within the anterior lateral plate mesoderm. Mechanistically, Atf3 targets cebpγ to repress slc2a1a-mediated glucose utilization. The high rate of glucose metabolism in atf3 -/- mutants inhibited the differentiation of progenitors by changing the redox state. Therefore, atf3 could provide CPs and HPs with metabolic adaptive capacity to changes in glucose levels. Our study provides new insights into the role of atf3 in the coordination of differentiation of CPs and HPs by regulating glucose metabolism.


NF1-cAMP signaling dissociates cell type-specific contributions of striatal medium spiny neurons to reward valuation and motor control.
The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- and D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways are parsed out to regulate distinct behavioral outcomes in a neuron-specific manner is poorly understood. Here, we reveal that distinct contributions of D1R-MSNs and D2R-MSNs towards reward and motor behaviors are delineated by the multifaceted signaling protein neurofibromin 1 (NF1). Using genetic mouse models, we show that NF1 in D1R-MSN modulates opioid reward, whereas loss of NF1 in D2R-MSNs delays motor learning by impeding the formation and consolidation of repetitive motor sequences. We found that motor learning deficits upon NF1 loss were associated with the disruption in dopamine signaling to cAMP in D2R-MSN. Restoration of cAMP levels pharmacologically or chemogenetically rescued the motor learning deficits seen upon NF1 loss in D2R-MSN. Our findings illustrate that multiplex signaling capabilities of MSNs are deployed at the level of intracellular pathways to achieve cell-specific control over behavioral outcomes.


Body temperature stability achieved by the large body mass of sea turtles.
To investigate the thermal characteristics of large reptiles living in water, temperature data were continuously recorded from 16 free-ranging loggerhead turtles, Caretta caretta, during internesting periods using data loggers. Core body temperatures were 0.7-1.7°C higher than ambient water temperatures and were kept relatively constant. Unsteady numerical simulations using a spherical thermodynamic model provided mechanistic explanations for these phenomena, and the body temperature responses to fluctuating water temperature can be simply explained by a large body mass with a constant thermal diffusivity and a heat production rate rather than physiological thermoregulation. By contrast, body temperatures increased 2.6-5.1°C in 107-152 min during their emergences to nest on land. The estimated heat production rates on land were 7.4-10.5 times the calculated values in the sea. The theoretical prediction that temperature difference between body and water temperatures would increase according to the body size was confirmed by empirical data recorded from several species of sea turtles. Comparing previously reported data, the internesting intervals of leatherback, green and loggerhead turtles were shorter when the body temperatures were higher. Sea turtles seem to benefit from a passive thermoregulatory strategy, which depends primarily on the physical attributes of their large body masses.


The recurrence of mania: environmental factors and medical treatment.
Three patients experienced recurrent manic episodes while taking lithium at levels that previously had been effective. In each case, the patient's decompensation followed a life stress. These stresses, which had a striking similarity, involved conflictual situations in which the patient felt impelled to pursue activities contrary to his or her own interests and aspirations. The activities, often involving the patient's family, seemed impossible to avoid. These clinical examples, together with several reports from the literature, suggest that pharmacological, psychodynamic, and situational forces may need to be considered together to allow more accurate conceptualization and to prevent recurrence of mania.


Models with Men and Women: Representing Gender in Dynamic Modeling of Social Systems.
Dynamic engineering models have yet to be evaluated in the context of feminist engineering ethics. Decision-making concerning gender in dynamic modeling design is a gender and ethical issue that is important to address regardless of the system in which the dynamic modeling is applied. There are many dynamic modeling tools that operationally include the female population, however, there is an important distinction between females and women; it is the difference between biological sex and the social construct of gender, which is fluid and changes over time and geography. The ethical oversight in failing to represent or misrepresenting gender in model design when it is relevant to the model purpose can have implications for model validity and policy model development. This paper highlights this gender issue in the context of feminist engineering ethics using a dynamic population model. Women are often represented in this type of model only in their biological capacity, while lacking their gender identity. This illustrative example also highlights how language, including the naming of variables and communication with decision-makers, plays a role in this gender issue.


The study of health coaching: the ithaca coaching project, research design, and future directions.
Health coaching (HC) is a process holding tremendous potential as a complementary medical intervention to shape healthy behavior change and affect rates of chronic lifestyle diseases. Empirical knowledge of effectiveness for the HC process, however, is lacking. The purposes of this paper are to present the study protocol for the Ithaca Coaching Project while also addressing research design, methodological issues, and directions for HC research. This is one of the first large-scale, randomized control trials of HC for primary prevention examining impact on physical and emotional health status in an employee population. An additional intent for the project is to investigate self-determination theory as a theoretical framework for the coaching process. Participants (n=300) are recruited as part of a campus-wide wellness initiative and randomly assigned to one of three levels of client-centered HC or a control with standard wellness program care. Repeated measures analyses of covariance will be used to examine coaching effectiveness while path analyses will be used to examine relationships between coaching processes, self-determination variables, and health outcomes. There is a great need for well-designed HC studies that define coaching best practices, examine intervention effectiveness, provide cost:benefit analysis, and address scope of practice. This information will allow a clearer definition of HC to emerge and determination of if, and how, HC fits in modern-day healthcare. This is an exciting but critical time for HC research and for the practice of HC.


Added value of health-related quality of life measurement in cancer clinical trials: the experience of the NCIC CTG.
Health-related quality-of-life (HRQoL) data are often included in Phase III clinical trials. We evaluate and classify the value added to Phase III trials by HRQoL outcomes, through a review of the National Cancer Institute of Canada Clinical Trials Group clinical trials experience within various cancer patient populations. HRQoL may add value in a variety of ways, including the provision of data that may contrast with or may support the primary study outcome; or that assess a unique perspective or subgroup, not addressed by the primary outcome. Thus, HRQoL data may change the study's interpretation. Even in situations where HRQoL measurement does not alter the clinical interpretation of a trial, important methodologic advances can be made. A classification of the added value of HRQoL information is provided, which may assist in choosing trials for which measurement of HRQoL outcomes will be beneficial.


Anti-inflammatory Effects of Aspalathin and Nothofagin from Rooibos (Aspalathus linearis) In Vitro and In Vivo.
Aspalathin (Asp) and nothofagin (Not) are two major active dihydrochalcones found in green rooibos, which have been reported for their anti-oxidant activity. Here, we investigated the anti-inflammatory effects and underlying mechanisms of Asp and Not against lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of Asp and Not were determined by measuring permeability, monocytes adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells (HUVECs) and mice. We found that each compound inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of neutrophils to human endothelial cells. Asp and Not also suppressed LPS-induced hyperpermeability and leukocyte migration in vivo. Furthermore, each compound suppressed the production of tumor necrosis factor-α (TNF-α) or interleukin (IL)-6 and the activation of nuclear factor-κB (NF-κB) or extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, treatment with each compound resulted in reduced LPS-induced lethal endotoxemia. These results suggest that Asp and Not posses anti-inflammatory functions by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.


Large duodenal gastrointestinal stromal tumor presenting with acute bleeding managed by a whipple resection. A review of surgical options and the prognostic indicators of outcome.
Duodenal gastrointestinal stromal tumors (GISTs) are uncommon and constitute a relatively small subset of GISTs which presents a unique dilemma having various surgical options. A case of a large ulcerating duodenal GIST arising from the second and third parts of the duodenum and involving the pancreas which was managed by a Whipple resection is presented. The literature is also reviewed to present the current status on surgical options, outcome, prognostic indicators and the role of imatinib mesylate in its management. A 58-year-old patient presented with acute gastrointestinal bleeding which was diagnosed to be due to a duodenal GIST following CT scan and endoscopic biopsy. The mass which measured about 10x9 cm originated from the 2nd part and extended into the 3rd part of the duodenum. He underwent a Whipple resection, and histopathology confirmed a duodenal GIST having a greater than 10 mitotic count per fifty high power field and areas of necrosis. Postoperatively, he received imatinib mesylate 400 mg bid; however, 4 months later, he presented with multiple disseminated peritoneal metastases and succumbed to the disease 2 months later. GISTs of the duodenum which are small in size and do not involve the papilla of Vater are better resolved using a limited resection of the duodenum since the outcome in terms of operative risk or disease recurrence is not influenced in these cases. However, large tumors with more extensive involvement would require a pancreaticoduodenectomy to achieve adequate tumor clearance. Even though duodenal GISTs have a relatively better prognosis as compared to GISTs at other sites, their aggressiveness ranges from small indolent tumors to aggressive sarcomas. Following tumor resection, a recurrence rate of about 40% has been reported. A more favorable prognosis in duodenal GISTs is attributed to a lower prevalence of P53 loss, the duodenal location of the tumor, a smaller size of the lesion and a low mitotic count. Imatinib mesylate is reported to play a role in neoadjuvant therapy as well as in the management of metastatic and recurrent disease, although some of these tumors may fail to respond.


Impact of community pharmacy-based educational intervention on patients with hypertension in Western Nepal.
There is a paucity of data regarding the feasibility and impact of community pharmacy-based educational interventions on the management of chronic diseases in developing countries. The aim of this study was to establish the feasibility, and to investigate the impact, of community pharmacy-based educational intervention on knowledge, practice, and disease management of patients with hypertension in Western Nepal. A single-cohort pre-/post-intervention study was conducted from August 2012 to April 2013. The participants included in the study were patients diagnosed with hypertension attending a pharmacist-led hypertension clinic. The educational intervention was conducted by pharmacists, was individualised, and consisted of three counselling sessions over a period of six months. The patients' knowledge of hypertension, their practice of lifestyle modification and non-pharmacological approaches concerning hypertension management, and blood pressure were assessed at baseline and again after nine months by using a pre-validated questionnaire. Fifty patients met the inclusion criteria and were enrolled in the study. The median (IQR) knowledge score changed from 6 (4) to 13 (0) after the intervention (p<0.01) with the median (IQR) practice score changing from 7 (4) to 16 (2) (p<0.01). The mean (SD) systolic BP changed from 150.1 (7.8) to 137.7 (9.9) (p<0.01) and the mean (SD) diastolic BP from 104 (9.5) to 94.5 (7.8) after the intervention (p< 0.01). A simple, educational intervention by community pharmacists had improved patients' disease knowledge, practice, and management of their hypertension. Evidence suggests Nepalese community pharmacists need could play an important role in the management of chronic diseases like hypertension through simple interventions such as providing educational support for patients.


Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling.
Mitochondria produce ROS (reactive oxygen species) as a by-product of aerobic respiration. Several studies in mammals and birds suggest that the most physiologically relevant ROS production is from complex I following reverse electron flow, and is highly sensitive to membrane potential. A study of Drosophila mitochondria respiring glycerol 3-phosphate revealed that membrane potential-sensitive ROS production from complex I following reverse electron flow was on the matrix side of the inner membrane. A 10 mV decrease in membrane potential was enough to abolish around 70% of the ROS produced by complex I under these conditions. Another important ROS generator in this model, glycerol-3-phosphate dehydrogenase, produced ROS mostly to the cytosolic side; this ROS production was totally insensitive to a small decrease in membrane potential (10 mV). Thus mild uncoupling may be particularly significant for ROS production from complex I on the matrix side of the mitochondrial inner membrane.


[Effects of electroacupuncture of different acupoints groups on blood pressure and heart rate variability in rats].
To observe the effect of electroacupuncture (EA) of different acupoint groups on mean arterial pressure (MAP) and heart rate variability (HRV) in hypotension rats. A total of 70 Wistar female rats were randomized into model, "Neiguan" (PC 6)-"Daling" (PC 7), "Waiguan" (SJ 4)-"Yangchi" (SJ 5), "Tianshu" (ST 25)-"Wailing" (ST 26), "Dachangshu" (BL 25)-"Qihaishu" (BL 24), "Baihui" (GV 20)-"Qianshencong" (EX-HN), and"Guangming" (GB 37)-"Xuanzhong" (GB 39) groups, with 10 cases in each. Hypotension model was established by bleeding (2.5-3 ml) through carotid artery. Immediately after bleeding, EA (2/15 Hz, 1 mA, 30 min) was applied to the above-mentioned acupoints of the 6 EA groups. MAP and ECG were recorded, then HRV was analyzed by using software Chart 5.2.1. MAP declined significantly after bleeding. Compared with model group, MAP values of PC6-PC7 and GB37-GB39 groups increased significantly 15 min and 30 min after bleeding, and those of ST25-ST26 and GV20-EX-HN groups also increased apparently 30 min after bleeding (P<0.05). No marked effects were observed in EA of SJ4-SJ5 and BL25-BL24 groups (P>0.05). The effect of PC6-PC7 and GB37-GB39 groups was significantly superior to that of SJ4-SJ5, BL25-BL24 and GV20-EX-HN groups in elevating MAP 30 min after bleeding (P<0.05). Compared with model group, heart rate (HR) of PC6-PC7 group was increased significantly 15 min and 30 min after bleeding (P<0.05). After bleeding, low frequency (LF), LF/high frequency (HF) and very low frequency (VLF) increased apparently. Compared with model group, LF, LF/HF and VLF of PC6-PC7 and GB37-GB39 groups decreased significantly 30 min after bleeding (P<0.05), suggesting a better balancing effect of EA of PC6-PC7 and GB37-GB39 on the activities of sympathetic and vagus nerves. EA of different acupoint groups has its own relative specificity in regulating MAP and HR in the rat, and PC6-PC7 EA and GB37-GB39 EA have a better efficacy, which is closely associated with their effects in balancing activities of the autonomic nerve system.


Zebularine partially reverses GST methylation in prostate cancer cells and restores sensitivity to the DNA minor groove binder brostallicin.
Brostallicin is a DNA minor groove binder that shows enhanced antitumor activity in cells with high glutathione S-transferase (GST)/glutathione content. Prostate cancer cells present, almost invariably, methylation of the GSTP1 gene promoter and, as a consequence, low levels of GST-pi expression and activity. In these cells, brostallicin shows very little activity. We tested whether pretreatment of heavily GST-methylated prostate cancer cells with demethylating agents could enhance the activity of brostallicin. Human prostate cancer cells LNCaP and DU145 were used for these studies both in vitro and in vivo. The demethylating agent zebularine was used in combination with brostallicin. Methylation specific PCR and pyrosequencing were used to determine the level of GST methylation. Pretreatment with demethylating agents enhanced the in vitro activity of brostallicin in LNCaP cells. Zebularine, in particular, induced an enhancement of activity in vivo comparable to that obtained by transfecting the human GSTP1 gene in LNCaP cells in vitro. Molecular analysis performed on tumor xenografts in mice pretreated with zebularine failed to detect re-expression of GST-pi and demethylation of GSTP1. However, we found demethylation in the GSTM1 gene, with consequent re-expression of GST-mu at the mRNA level. These results indicate that zebularine, both in vitro and in vivo, enhances the activity of brostallicin and that this enhancement correlates with re-expression of GST-pi and GST-mu. These findings highlight the potential therapeutic value of combining demethylating agents and brostallicin in tumors with GST methylation that poorly respond to brostallicin.


Isolated human cystic artery: responses to common agonist and antagonist drugs.
The extramural artery of the human gall bladder (cystic artery), a small artery (outside diameter 1.3 +/- 0.03 mm) with a thick muscular wall and little elastin within the tunica media, has catecholamine fluorescence localized to the adventitia-medial border. Isolated helical strips of the artery are responsive to norepinephrine (NE), 5-hydroxytryptamine (5HT) and vasopressin (VP) at low concentrations, but at the maximal frequency of transmural electrical stimulation used (16 Hz), the response is only 10--20% of the NE maximum response. Phentolamine (2.7 X 10(-6) M) antagonized responses to NE, 5HT and, to a lesser degree, electrical stimulation and these actions are similar to those reported in other mammalian tissue. In vitro use of reserpine (1.6 X 10(-5) M) and guanethidine (4 X 10(-5) M) also produced effects which were predictable from effects observed in other mammalian tissues; except reserpine diminished responsiveness to NE and 5HT and guanethidine enhanced responses to the early administered electrical stimulation.


Spatial laser-wing suppression in saturated laser-induced fluorescence without spatial selection.
Spatial wings of laser beams are of great concern in saturated laser-induced fluorescence. Their contribution to fluorescence is customarily avoided by resolution of laser peaks in the interaction volume. An alternative and versatile approach is formulated, based on the derivative of fluorescence with respect to laser intensity. It turns out that wing-free data are possible, although they are obtained from wing-dependent fluorescence. The advantages of this approach are exact centerline detection and simplicity of the experimental setup and procedure.


Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities.
Active acromegaly is associated with insulin resistance, but it is uncertain whether inflammation in adipose tissue is a contributing factor. To test if GH/IGF1 promotes inflammation in adipocytes, and if this is relevant for systemic insulin resistance in acromegaly. Furthermore, to investigate the effect of treatment modalities (transsphenoidal surgery (TS), somatostatin analogs (SAs), and pegvisomant (PGV)) on glucose metabolism and inflammatory biomarkers in acromegaly. The in vitro effects of GH/IGF1 on gene expression of adipokines in human adipocytes were investigated. Body composition, glucose metabolism, and circulating adipokines (adiponectin (AD), high-molecular weight AD (HMWAD), leptin, vascular endothelial growth factor-A (VEGF-A), monocyte chemotactic protein 1 (MCP1), and thioredoxin (TRX)) were measured in 37 patients with active acromegaly before and after treatment. In vitro GH, but not IGF1, increased VEGF and MCP1 in human adipocytes. In all treatment groups, body fat increased and IGF1 decreased to the same extent. Fasting glucose decreased in the TS (P=0.016) and PGV (P=0.042) groups, but tended to increase in the SA group (P=0.078). Insulin and HOMA-IR decreased in both TS and SA groups, while the PGV group showed no changes. Serum VEGF and MCP1 decreased significantly in the TS group only (P=0.010, P=0.002), while HMWAD increased with PGV treatment only (P=0.018). A multivariate analysis model identified the changes in GH and VEGF as predictors of improvement in HOMA-IR after treatment (R²=0.39, P=0.002). i) GH directly promotes inflammation of human adipocytes by increasing VEGF and MCP1 levels; ii) glucose metabolism and inflammation (VEGF and MCP1) improve to some extent after treatment, despite an increase in adipose tissue mass; and iii) the decrease in insulin resistance after therapy in acromegaly depends, to some extent, on treatment modalities.


Absorbent products for the containment of urinary and/or faecal incontinence in adults.
Incontinence is a distressing condition with significant medical, social and economic implications. People suffering from incontinence, who cannot be successfully cured, depend, almost exclusively, on the use of containment products to manage their symptoms. Many people with incontinence cannot be cured and so depend on symptomatic management. The objective was to assess the effects of different types of absorbent product for the containment of urinary and/or faecal incontinence. We searched the Cochrane Incontinence Group trials register (March 1999), Embase (to January 1999), Cinahl (to January 1999), HealthSTAR (to January 1999) and the reference lists of relevant articles. We contacted investigators in the field to locate studies. Date of the most recent searches: March 1999. Types of studies All randomised or quasi-randomised trials of absorbent products for the containment of urinary and/or faecal incontinence. Types of participants All adults with urinary and/or faecal incontinence were eligible. The intention was to subdivide participants by severity of underlying incontinence, level of mobility and gender, but this proved not to be feasible. Types of intervention Absorbent products (bodyworns, underpads, and different fabric types for disposable products), for any severity of incontinence. Trials were evaluated for subject relevance and methodological quality using a standard methodological quality assessment form. If applicable, data on relevant outcomes were then abstracted using a standardised data abstraction form. Five studies with a total of 345 participants met the selection criteria. Two studies compared disposable with non-disposable bodyworns, one disposable with non-disposable underpads, two fluff pulp with superabsorbent polymers, and one bodyworns with underpads. Data presented on effects were available for few outcomes and were subject to potential bias. The data were too few and of insufficient quality to provide a firm basis for practice. Disposable products may be more effective than non-disposable products in decreasing the incidence of skin problems and superabsorbent products may perform better than fluff pulp products. However, based on the available evidence, these conclusions can only be tentative.


Quantitative description of mitral valve geometry using real-time three-dimensional echocardiography.
: Leaflet and annular geometry are important determinants of mitral valve (MV) stress. Repair techniques which optimize valvular geometry will reduce stress and potentially increase repair durability. The development of such procedures will require image processing methodologies that provide a quantitative description of three-dimensional valvular geometry. Using three-dimensional echocardiography in conjunction with novel geometric modeling and rendering techniques, we have developed a high-resolution, quantitative, three-dimensional methodology for imaging the human MV. : Five normal adults underwent MV imaging using real-time three-dimensional echocardiography. Using specially designed image analysis software, multiple valvular geometric parameters, including the magnitude and orientation of leaflet curvature, leaflet surface area, annular height, intercommissural width, septolateral annular diameter, and annular area were determined for each subject. Image rendering techniques that allow for the clear and concise presentation of this detailed information are also presented. : Although three-dimensional annular and leaflet geometry were found to be highly conserved among normal human subjects, substantial regional variation in leaflet geometry was observed. Interestingly, leaflet geometric heterogeneity was most pronounced in the midposterior leaflet, the region most commonly involved in leaflet flail in subjects with myxomatous disease. : The image processing and graphical rendering techniques that we have developed can be used to provide a complete description of three-dimensional MV geometry in human subjects. Widespread application of these techniques to normal subjects and patients with MV disease will provide insight into the geometric basis of both valvular pathology and repair durability.


Low-frequency sound exposure causes reversible long-term changes of cochlear transfer characteristics.
Intense, low-frequency sound presented to the mammalian cochlea induces temporary changes of cochlear sensitivity, for which the term 'Bounce' phenomenon has been coined. Typical manifestations are slow oscillations of hearing thresholds or the level of otoacoustic emissions. It has been suggested that these alterations are caused by changes of the mechano-electrical transducer transfer function of outer hair cells (OHCs). Shape estimates of this transfer function can be derived from low-frequency-biased distortion product otoacoustic emissions (DPOAE). Here, we tracked the transfer function estimates before and after triggering a cochlear Bounce. Specifically, cubic DPOAEs, modulated by a low-frequency biasing tone, were followed over time before and after induction of the cochlear Bounce. Most subjects showed slow, biphasic changes of the transfer function estimates after low-frequency sound exposure relative to the preceding control period. Our data show that the operating point changes biphasically on the transfer function with an initial shift away from the inflection point followed by a shift towards the inflection point before returning to baseline values. Changes in transfer function and operating point lasted for about 180 s. Our results are consistent with the hypothesis that intense, low-frequency sound disturbs regulatory mechanisms in OHCs. The homeostatic readjustment of these mechanisms after low-frequency offset is reflected in slow oscillations of the estimated transfer functions.


The roles of benzoic acid and water on the Michael reactions of pentanal and nitrostyrene catalyzed by diarylprolinol silyl ether.
The roles of benzoic acid and water on the Michael reaction of pentanal and nitrostyrene catalyzed by diarylprolinol silyl ether are revealed by density functional theory calculations. The calculations demonstrate that the benzoic acid is ready to attack the catalysts and form a hydrogen bond between the hydrogen atom of the COOH of benzoic acid and one of the N atoms of the catalyst. The complex formed from pentanal, catalyst and benzoic acid attacks nitroalkene and forms transition states. Finally, the transition states hydrolyze and the products are formed. The calculations demonstrate that the stereoselectivity is dominated by the steric hindrance of the 2-substituent groups, and the benzoic acid can increase the reaction rate evidently by decreasing the activation energies; however, H(3)O(+) or strong acid may prevent the formation of the transition states between enamines and nitroalkenes. The employed solvent can decrease the activation energies and promote the proton transfer from benzoic acid onto the catalyst 2. The calculated enantiomeric excess values are in good agreement with the experimental results. These calculations also reveal that the role of benzoic acid is dependent on the sophisticated structures of the catalysts and provide a valuable index for the structural design of new catalysts and selection of additives or co-catalysts.


Zerumbone Suppresses Human Colorectal Cancer Invasion and Metastasis via Modulation of FAk/PI3k/NFκB-uPA Pathway.
The current study explored the basic molecular mechanisms of zerumbone (ZER), an herbal compound, in inhibiting the migration and invasion of colorectal cancer (CRC) cells in vitro. Two types of CRC cells, namely HCT-116 and SW48, were treated with various concentrations of ZER (8, 16, and 24 µM) for 24, 48, and 72 h, respectively. In vitro assays were performed to determine alterations in proliferation ability, mRNA expression and protein levels, and migration and invasion potential of CRC cells. An SYBR Green-based quantitative polymerase chain reaction (PCR) was utilized to detect the gene expression of focal adhesion kinase (FAK), nuclear factor (NF)-κB, and urokinase-type plasminogen activator (uPA) followed by the evaluation of the level of proteins by western blotting. Migration and invasion potentials of HCT-116 and SW48 cells treated by ZER were examined using migration and invasion assay kits, respectively. We compared the results of all experiments with control groups, including FAK inhibitor, ZER + FAK inhibitor-treated cells, NF-β inhibitor, ZER + NF-β inhibitor, and untreated cells. The data in the present study suggest that ZER may exert its antimetastatic effects through inhibition of FAk/PI3k/NF-κB-uPA signaling pathway, thereby possibly representing a novel class of FAK inhibitors.


The Arabidopsis gene MONOPTEROS encodes a transcription factor mediating embryo axis formation and vascular development.
The vascular tissues of flowering plants form networks of interconnected cells throughout the plant body. The molecular mechanisms directing the routes of vascular strands and ensuring tissue continuity within the vascular system are not known, but are likely to depend on general cues directing plant cell orientation along the apical-basal axis. Mutations in the Arabidopsis gene MONOPTEROS (MP) interfere with the formation of vascular strands at all stages and also with the initiation of the body axis in the early embryo. Here we report the isolation of the MP gene by positional cloning. The predicted protein product contains functional nuclear localization sequences and a DNA binding domain highly similar to a domain shown to bind to control elements of auxin inducible promoters. During embryogenesis, as well as organ development, MP is initially expressed in broad domains that become gradually confined towards the vascular tissues. These observations suggest that the MP gene has an early function in the establishment of vascular and body patterns in embryonic and post-embryonic development.


A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.
Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.


Citrin deficiency due to SLC25A13 exon deletion in a Chinese infant: A case report.
Citrin is a calcium-bound aspartate-glutamate carrier protein encoded by the gene SLC25A13, mutations of which can cause citrin deficiency, an autosomal recessive disorder. The manifestations of citrin deficiency include neonatal intrahepatic choledeposits caused by citrin deficiency (NICCD: OMIM#605814), intermediate growth disorders and dyslipidemia caused by citrin deficiency, and citrullinemia type II (OMIM#603471) in adults. NICCD is a classical metabolic disorder that causes cholestasis in newborns. Here, we present the case of a 2-month-old male patient treated in our hospital on March 20, 2023, due to "postnatal skin xanthochromia and transaminases higher than normal values". Since birth, the child's skin had yellowed all over the body, and his condition did not improve after multiple medical treatments. The child underwent full exome gene testing at the age of 2 months and 13 days, and the results indicated heterozygous deletion of exon 3 of the SLC25A13 gene, while genetic testing of the parents revealed no gene mutations. The variant was preliminarily judged as being pathogenic according to the ACMG guidelines, and the patient was diagnosed with "citrin deficiency". Skin yellowing eventually subsided, and liver function returned to normal without special treatment. Here, we report a rare case of citrin deficiency caused by a heterozygous deletion of the SLC25A13 gene. This case increases the clinical phenotypic profile of NICCD, suggesting that clinicians must be vigilant regarding such genetic metabolic diseases in the clinic for early diagnosis and treatment. NICCD should always be considered in the differential diagnosis of neonatal cholestasis.


Assessment of global and regional diffusion changes along white matter tracts in parkinsonian disorders by MR tractography.
The aim of the study was to determine the usefulness of diffusion tensor tractography (DTT) in parkinsonian disorders using a recently developed method for normalization of diffusion data and tract size along white matter tracts. Furthermore, the use of DTT in selected white matter tracts for differential diagnosis was assessed. We quantified global and regional diffusion parameters in major white matter tracts in patients with multiple system atrophy (MSA), progressive nuclear palsy (PSP), idiopathic Parkinson's disease (IPD) and healthy controls). Diffusion tensor imaging data sets with whole brain coverage were acquired at 3 T using 48 diffusion encoding directions and a voxel size of 2×2×2 mm(3). DTT of the corpus callosum (CC), cingulum (CG), corticospinal tract (CST) and middle cerebellar peduncles (MCP) was performed using multiple regions of interest. Regional evaluation comprised projection of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and the apparent area coefficient (AAC) onto a calculated mean tract and extraction of their values along each structure. There were significant changes of global DTT parameters in the CST (MSA and PSP), CC (PSP) and CG (PSP). Consistent tract-specific variations in DTT parameters could be seen along each tract in the different patient groups and controls. Regional analysis demonstrated significant changes in the anterior CC (MD, RD and FA), CST (MD) and CG (AAC) of patients with PSP compared to controls. Increased MD in CC and CST, as well as decreased AAC in CG, was correlated with a diagnosis of PSP compared to IPD. DTT can be used for demonstrating disease-specific regional white matter changes in parkinsonian disorders. The anterior portion of the CC was identified as a promising region for detection of neurodegenerative changes in patients with PSP, as well as for differential diagnosis between PSP and IPD.


Biomonitoring of glyphosate and aminomethylphosphonic acid: Current insights and future perspectives.
Glyphosate is one of the most widely used herbicides globally, raising concerns about its potential impact on human health. Biomonitoring studies play a crucial role in assessing human exposure to glyphosate and providing valuable insights into its distribution and metabolism in the body. This review aims to summarize the current trends and future perspectives in biomonitoring of glyphosate and its major degradation product of aminomethylphosphonic acid (AMPA). A comprehensive literature search was conducted, focusing on studies published between January 2000 and December 2022. The findings demonstrated that glyphosate and AMPA have been reported in different human specimens with urine as the dominance. Sample pretreatment techniques of solid-phase and liquid-liquid extractions coupled with liquid/gas chromatography-tandem mass spectrometry have achieved matrix elimination and accurate analysis. We also examined and compared the exposure characteristics of these compounds among different regions and various populations, with significantly higher levels of glyphosate and AMPA observed in Asian populations and among occupational groups. The median urinary concentration of glyphosate in children was 0.54 ng/mL, which was relatively higher than those in women (0.28 ng/mL) and adults (0.12 ng/mL). It is worth noting that children may exhibit increased susceptibility to glyphosate exposure or have different exposure patterns compared to women and adults. A number of important perspectives were proposed in order to further facilitate the understanding of health effects of glyphosate and AMPA, which include, but are not limited to, method standardization, combined exposure assessment, attention for vulnerable populations, long-term exposure effects and risk communication and public awareness.


Color enhances orthonasal olfactory intensity and reduces retronasal olfactory intensity.
The effect of color on orthonasal and retronasal odor intensities was investigated. When odorants were smelled orthonasally (i.e., through the nostrils), color enhanced odor intensity ratings, consistent with previous reports. However, when odorants were smelled retronasally (i.e., the odorous solution was put in the mouth), color reduced odor intensity ratings. These different effects of color on odor intensity (i.e., enhancement orthonasally and suppression retronasally) appear to be the result of route of olfactory stimulation rather than of any procedural artifact. This supports previous reports that retronasal and orthonasal odors are perceived differently.


Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication.
Viruses interact with multiple host cell factors. Some of these are required to promote viral propagation, others have roles in inhibiting infection. Here, we delineate the function of the cellular factor PHF13 (or SPOC1), a putative HIV-1 restriction factor. Early in the HIV-1 replication cycle PHF13 increased the number of integrated proviral copies and the number of infected cells. However, after HIV-1 integration, high levels of PHF13 suppressed viral gene expression. The antiviral activity of PHF13 is counteracted by the viral accessory protein Vpr, which mediates PHF13 degradation. Altogether, the transcriptional master regulator and chromatin binding protein PHF13 does not have purely repressive effects on HIV-1 replication, but also promotes viral integration. By the functional characterization of the dual role of PHF13 during the HIV-1 replication cycle, we reveal a surprising and intricate mechanism through which HIV-1 might regulate the switch from integration to viral gene expression. Furthermore, we identify PHF13 as a cellular target specifically degraded by HIV-1 Vpr.


The meaning of living with uncertainty for people with motor neurone disease.
To explore the meaning of living with uncertainty for people diagnosed with motor neurone disease (MND). Motor neurone disease is a progressive neurodegenerative condition resulting in multiple needs, arising from the complex nature of the disease trajectory. People with MND are often required to make decisions for symptom management and end-of-life care. Research into the lived experience of MND has previously highlighted the following: the shock of receiving such a diagnosis and prognosis; subsequent concerns relating to the future and loss; and the existential suffering for a person with MND. The lived experiences of MND accentuate the devastating nature of the disease, and this can impact upon how people respond to care. Hermeneutic (interpretive) phenomenology: suitable for studying lifeworld experiences. Life story interviews were conducted with four participants and subjected to interpretive analysis. Three phases of the MND illness trajectory emerged: "body failing prematurely and searching for answers," "body deterioration and responses to care" and "body nearing its end and needing to talk." These phases highlight the phenomenon under study, all relating to uncertainty for people living with MND. This study showed that people with MND are living with uncertainty and other concerns throughout their illness trajectory. People are having to turn to palliative care professionals who are more able to meet their concerns than those caring for other aspects of their disease. Motor neurone disease is a complex disease, and it is important that professionals continue to provide holistic care throughout the illness trajectory. The identification of three distinct phases of the MND illness trajectory will help nurses and other professionals to better understand the meaning of uncertainty and other concerns for people with MND.


Is the fragility of a liquid embedded in the properties of its glass?
When a liquid is cooled below its melting temperature, it usually crystallizes. However, if the quenching rate is fast enough, the system may remain in a disordered state, progressively losing its fluidity upon further cooling. When the time needed for the rearrangement of the local atomic structure reaches approximately 100 seconds, the system becomes "solid" for any practical purpose, and this defines the glass transition temperature Tg. Approaching this transition from the liquid side, different systems show qualitatively different temperature dependencies of the viscosity, and accordingly they have been classified by introducing the concept of "fragility." We report experimental observations that relate the microscopic properties of the glassy phase to the fragility. We find that the vibrational properties of the glass well below Tg are correlated with the fragility value. Consequently, we extend the fragility concept to the glassy state and indicate how to determine the fragility uniquely from glass properties well below Tg.


The European general thoracic surgery database project.
The European Society of Thoracic Surgeons (ESTS) Database is a free registry created by ESTS in 2001. The current online version was launched in 2007. It runs currently on a Dendrite platform with extensive data security and frequent backups. The main features are a specialty-specific, procedure-specific, prospectively maintained, periodically audited and web-based electronic database, designed for quality control and performance monitoring, which allows for the collection of all general thoracic procedures. Data collection is the "backbone" of the ESTS database. It includes many risk factors, processes of care and outcomes, which are specially designed for quality control and performance audit. The user can download and export their own data and use them for internal analyses and quality control audits. The ESTS database represents the gold standard of clinical data collection for European General Thoracic Surgery. Over the past years, the ESTS database has achieved many accomplishments. In particular, the database hit two major milestones: it now includes more than 235 participating centers and 70,000 surgical procedures. The ESTS database is a snapshot of surgical practice that aims at improving patient care. In other words, data capture should become integral to routine patient care, with the final objective of improving quality of care within Europe.


Reducing Facial Stereotype Bias in Consequential Social Judgments: Intervention Success With White Male Faces.
Initial impressions of others based on facial appearances are often inaccurate yet can lead to dire outcomes. Across four studies, adult participants underwent a counterstereotype training to reduce their reliance on facial appearance in consequential social judgments of White male faces. In Studies 1 and 2, trustworthiness and sentencing judgments among control participants predicted whether real-world inmates were sentenced to death versus life in prison, but these relationships were diminished among trained participants. In Study 3, a sequential priming paradigm demonstrated that the training was able to abolish the relationship between even automatically and implicitly perceived trustworthiness and the inmates' life-or-death sentences. Study 4 extended these results to realistic decision-making, showing that training reduced the impact of facial trustworthiness on sentencing decisions even in the presence of decision-relevant information. Overall, our findings suggest that a counterstereotype intervention can mitigate the potentially harmful effects of relying on facial appearance in consequential social judgments.


Fermented foods and gastrointestinal health: underlying mechanisms.
Although fermentation probably originally developed as a means of preserving food substrates, many fermented foods (FFs), and components therein, are thought to have a beneficial effect on various aspects of human health, and gastrointestinal health in particular. It is important that any such perceived benefits are underpinned by rigorous scientific research to understand the associated mechanisms of action. Here, we review in vitro, ex vivo and in vivo studies that have provided insights into the ways in which the specific food components, including FF microorganisms and a variety of bioactives, can contribute to health-promoting activities. More specifically, we draw on representative examples of FFs to discuss the mechanisms through which functional components are produced or enriched during fermentation (such as bioactive peptides and exopolysaccharides), potentially toxic or harmful compounds (such as phytic acid, mycotoxins and lactose) are removed from the food substrate, and how the introduction of fermentation-associated live or dead microorganisms, or components thereof, to the gut can convey health benefits. These studies, combined with a deeper understanding of the microbial composition of a wider variety of modern and traditional FFs, can facilitate the future optimization of FFs, and associated microorganisms, to retain and maximize beneficial effects in the gut.


Dental Hygiene Fear Survey: reliability and validity of the Turkish version.
The aims of the present study were to 1) investigate patient anxiety as it relates to dental hygiene procedures and 2) conduct validity and reliability testing of the Turkish version of the Dental Hygiene Fear Survey (DHFS) to test its psychometric properties in the Turkish culture. The study consisted of 200 periodontal patients. The patients completed the DHFS, the Modified Dental Anxiety Scale (MDAS), and a questionnaire designed to elicit sociodemographic and clinical characteristics. Reliability was estimated by Cronbach's alpha. Validity was examined by correlating the DHFS with measures found in the literature that correlate with dental fear and anxiety. Construct validity was determined using exploratory factor analysis with a direct oblimin (oblique) rotation, which revealed a model with three factors accounting for 62.8 of the variance when item 11, which has the lowest item total correlation, was omitted. The Cronbach alpha coefficients of the subscales in the fifteen-item scale (generalized anxiety, dental hygiene specific anxiety, and catastrophe) were 0.83, 0.86, and 0.79, respectively. The overall reliability of the DHFS was 0.91. Significant negative correlations were found between total DHFS scores and age (p<0.05). Females reported dental hygiene fear more frequently than did males. The DHFS demonstrated good psychometric properties in spite of being translated into another language and used in a culture different from the one where it was originally developed. The Turkish version of the DHFS is a valid and reliable instrument and may be included in assessments designed to measure fear related to dental hygiene treatment procedures.


Genetic and environmental influence on resting state networks in young male and female adults: a cartographer mapping study.
We propose a unique, minimal assumption, approach based on variance analyses (compared with standard approaches) to investigate genetic influence on individual differences on the functional connectivity of the brain using 65 monozygotic and 65 dizygotic healthy young adult twin pairs' low-frequency oscillation resting state functional Magnetic Resonance Imaging (fMRI) data from the Human Connectome Project. Overall, we found high number of genetically-influenced functional (GIF) connections involving posterior to posterior brain regions (occipital/temporal/parietal) implicated in low-level processes such as vision, perception, motion, categorization, dorsal/ventral stream visuospatial, and long-term memory processes, as well as high number across midline brain regions (cingulate) implicated in attentional processes, and emotional responses to pain. We found low number of GIF connections involving anterior to anterior/posterior brain regions (frontofrontal > frontoparietal, frontotemporal, frontooccipital) implicated in high-level processes such as working memory, reasoning, emotional judgment, language, and action planning. We found very low number of GIF connections involving subcortical/noncortical networks such as basal ganglia, thalamus, brainstem, and cerebellum. In terms of sex-specific individual differences, individual differences in males were more genetically influenced while individual differences in females were more environmentally influenced in terms of the interplay of interactions of Task positive networks (brain regions involved in various task-oriented processes and attending to and interacting with environment), extended Default Mode Network (a central brain hub for various processes such as internal monitoring, rumination, and evaluation of self and others), primary sensorimotor systems (vision, audition, somatosensory, and motor systems), and subcortical/noncortical networks. There were >8.5-19.1 times more GIF connections in males than females. These preliminary (young adult cohort-specific) findings suggest that individual differences in the resting state brain may be more genetically influenced in males and more environmentally influenced in females; furthermore, standard approaches may suggest that it is more substantially nonadditive genetics, rather than additive genetics, which contribute to the differences in sex-specific individual differences based on this young adult (male and female) specific cohort. Finally, considering the preliminary cohort-specific results, based on standard approaches, environmental influences on individual differences may be substantially greater than that of genetics, for either sex, frontally and brain-wide. [Correction added on 10 May 2023, after first online publication: added: functional Magnetic Resonance Imaging. Added: individual differences in, twice. Added statement between furthermore … based on standard approaches.].