CO oxidation catalyzed by Pt-embedded graphene: a first-principles investigation.
We addressed the potential catalytic role of Pt-embedded graphene in CO oxidation by first-principles-based calculations. We showed that the combination of highly reactive Pt atoms and defects over graphene makes the Pt-embedded graphene a superior mono-dispersed atomic catalyst for CO oxidation. The binding energy of a single Pt atom onto monovacancy defects is up to -7.10 eV, which not only ensures the high stability of the embedded Pt atom, but also vigorously excludes the possibility of diffusion and aggregation of embedded Pt atoms. This strong interfacial interaction also tunes the energy level of Pt-d states for the activation of O2, and promotes the formation and dissociation of the peroxide-like intermediate. The catalytic cycle of CO oxidation is initiated through the Langmuir-Hinshelwood mechanism, with the formation of a peroxide-like intermediate by the coadsorbed CO and O2, by the dissociation of which the CO2 molecule and an adsorbed O atom are formed. Then, another gaseous CO will react with the remnant O atom and make the embedded Pt atom available for the subsequent reaction. The calculated energy barriers for the formation and dissociation of the peroxide-like intermediate are as low as 0.33 and 0.15 eV, respectively, while that for the regeneration of the embedded Pt atom is 0.46 eV, indicating the potential high catalytic performance of Pt-embedded graphene for low temperature CO oxidation.


Cryo-STEM mapping of solid-liquid interfaces and dendrites in lithium-metal batteries.
Solid-liquid interfaces are important in a range of chemical, physical and biological processes1-4, but are often not fully understood owing to the lack of high-resolution characterization methods that are compatible with both solid and liquid components5. For example, the related processes of dendritic deposition of lithium metal and the formation of solid-electrolyte interphase layers6,7 are known to be key determinants of battery safety and performance in high-energy-density lithium-metal batteries. But exactly what is involved in these two processes, which occur at a solid-liquid interface, has long been debated8-11 because of the challenges of observing such interfaces directly. Here we adapt a technique that has enabled cryo-transmission electron microscopy (cryo-TEM) of hydrated specimens in biology-immobilization of liquids by rapid freezing, that is, vitrification12. By vitrifying the liquid electrolyte we preserve it and the structures at solid-liquid interfaces in lithium-metal batteries in their native state, and thus enable structural and chemical mapping of these interfaces by cryo-scanning transmission electron microscopy (cryo-STEM). We identify two dendrite types coexisting on the lithium anode, each with distinct structure and composition. One family of dendrites has an extended solid-electrolyte interphase layer, whereas the other unexpectedly consists of lithium hydride instead of lithium metal and may contribute disproportionately to loss of battery capacity. The insights into the formation of lithium dendrites that our work provides demonstrate the potential of cryogenic electron microscopy for probing nanoscale processes at intact solid-liquid interfaces in functional devices such as rechargeable batteries.


Profilin II is alternatively spliced, resulting in profilin isoforms that are differentially expressed and have distinct biochemical properties.
We deduced the structure of the mouse profilin II gene. It contains five exons that can generate four different transcripts by alternative splicing. Two transcripts encode different profilin II isoforms (designated IIa and IIb) that have similar affinities for actin but different affinities for polyphosphoinositides and proline-rich sequences. Profilins IIa and IIb are also present in humans, suggesting that all mammals have three profilin isoforms. Profilin I is the major form in all tissues, except in the brain, where profilin IIa is most abundant. Profilin IIb appears to be a minor form, and its expression is restricted to a limited number of tissues, indicating that the alternative splicing is tightly regulated. Western blotting and whole-mount in situ hybridization show that, in contrast to the expression of profilin I, the expression level of profilin IIa is developmentally regulated. In situ hybridization of adult brain sections reveals overlapping expression patterns of profilins I and IIa.


Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.
Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL)-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP) is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida-induced cytokine production through the inhibition of NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.


Tetrandrine downregulates TRPV2 expression to ameliorate myocardial ischemia/reperfusion injury in rats via regulation of cardiomyocyte apoptosis, calcium homeostasis and mitochondrial function.
Our previous study has indicated that tetrandrine (TET) can target miR-202-5p to repress the activation of transient receptor potential vanilloid type 2 (TRPV2), eventually ameliorating the progression of myocardial ischemia/reperfusion injury (MI/RI). This study is aimed to further ascertain the detailed mechanisms between TET and TRPV2 in MI/RI pathogenesis. Here, a myocardial I/R injury rat model and a hypoxia-reoxygenation (H/R) model in rat myocardial cell line (H9C2 cells) were established. We reported that pronounced upregulation of TRPV2 was observed in I/R rats and H/R-induced H9C2 cells. Silencing of TRPV2 could improve cardiac function and myocardial injury, reduced infarction size, and promoted cardiomyocyte proliferation in I/R rats. In I/R rats or H/R-induced H9C2 cells, cardiomyocyte apoptosis was inhibited by knocking-down TRPV2. Meanwhile, the silenced TRPV2 or TET treatment ameliorated the damaged mitochondrial structure, mitigated ROS generation, restored the impaired ΔΨM, inhibited mPTP opening and alleviated Ca2+ overload in H/R-induced H9C2 cells. The results obtained from the overexpression of TRPV2 were contrary to those depicted above. Moreover, TET could downregulate TRPV2 expression, while the overexpression of TRPV2 could reverse the above protective effects of TET in H/R-induced H9C2 cells. The results indicated that TET may function as a TRPV2 blocking agent, thereby attenuating the progression of MI/RI through modulation of cardiomyocyte apoptosis, calcium homeostasis and mitochondrial function. These findings offer a theoretical foundation for potential clinical application of TET therapy in patients with MI/RI.


Left ventricular receptors: physiological controllers or pathological curiosities?
Mechanically and chemically sensitive receptors in the ventricle have been described histologically and electrophysiologically. Early experiments documented the hypotension and bradycardia that resulted from the intracoronary administration of one of the veratrum alkaloids (the Bezold-Jarisch reflex). Mechanical distension of the ventricles also results in a reflex decrease in heart rate and a reduction in peripheral resistance. Skeletal muscle and coronary vascular resistance appear to be most prominently affected by stimulation of ventricular receptors. Coronary ischemia has also been shown to evoke reflex effects which are attributable to stimulation of ventricular receptors. The resultant bradycardia can be especially ominous in acute myocardial infarction. Changes in myocardial inotropic state have been shown to alter ventricular receptor discharge in experimental animals. This stimulus may evoke reflex changes in peripheral hemodynamics. A variety of humoral substances can alter ventricular receptor discharge and evoke Bezold-Jarisch like responses. These include bradykinin and prostaglandins. PGI2, when given intracoronary in small doses or intravenously in larger doses will lower blood pressure while inhibiting the baroreflex induced tachycardia. It has also been shown in some experiments that PGI2 and arachidonic acid can evoke overt bradycardia and hypotension via a reflex mechanism. The role of prostaglandins in cardiovascular reflex control may be important in pathophysiologic states such as coronary ischemia and heart failure. Ventricular receptors can interact centrally with the arterial baroreceptors to attenuate the baroreflex control of both heart rate and peripheral resistance. Finally, the stimulation of ventricular receptors can alter a variety of humoral substances which are important regulators of cardiovascular and fluid volume homeostasis. These include vasopressin, renin and catecholamines. Those studies which have been done within the last 10 years or so, especially in unanesthetized animals, have demonstrated that the Bezold-Jarisch reflex is more important to cardiovascular control than previously thought. Future work will be necessary to determine the precise role ventricular receptors play in various pathological situations.


Laparoscopic removal of a persistent Müllerian duct in a male: case report.
The authors refer to the use of the laparoscopic approach in Persistent Mullerian Duct Syndrome, starting from a case of "male vagina" with an anomaly inserted left ductus deferens inside the mullerian persistent duct. This patient was operated on using the laparoscopic technique.


Decreased synaptic activity shifts the calcium dependence of release at the mammalian neuromuscular junction in vivo.
We examined the mechanism underlying increased quantal content after block of activity at the mouse neuromuscular junction in vivo. We found that, when quantal content was measured in solution containing normal extracellular calcium, block of activity had no effect on either quantal content or the response to repetitive stimulation. However, when quantal content was measured in low extracellular calcium, there was a large increase in quantal content after block of activity. The increase in quantal content was accompanied by increased depression during repetitive stimulation. The explanation for these findings was that there was a shift in the calcium dependence of release after block of activity that manifested as an increase in probability of release in low extracellular calcium. Block of presynaptic P/Q channels eliminated the increase in probability of release. We propose that activity-dependent regulation of presynaptic calcium entry may contribute to homeostatic regulation of quantal content.


Lake nutrient stoichiometry is less predictable than nutrient concentrations at regional and sub-continental scales.
Production in many ecosystems is co-limited by multiple elements. While a known suite of drivers associated with nutrient sources, nutrient transport, and internal processing controls concentrations of phosphorus (P) and nitrogen (N) in lakes, much less is known about whether the drivers of single nutrient concentrations can also explain spatial or temporal variation in lake N:P stoichiometry. Predicting stoichiometry might be more complex than predicting concentrations of individual elements because some drivers have similar relationships with N and P, leading to a weak relationship with their ratio. Further, the dominant controls on elemental concentrations likely vary across regions, resulting in context dependent relationships between drivers, lake nutrients and their ratios. Here, we examine whether known drivers of N and P concentrations can explain variation in N:P stoichiometry, and whether explaining variation in stoichiometry differs across regions. We examined drivers of N:P in ~2,700 lakes at a sub-continental scale and two large regions nested within the sub-continental study area that have contrasting ecological context, including differences in the dominant type of land cover (agriculture vs. forest). At the sub-continental scale, lake nutrient concentrations were correlated with nutrient loading and lake internal processing, but stoichiometry was only weakly correlated to drivers of lake nutrients. At the regional scale, drivers that explained variation in nutrients and stoichiometry differed between regions. In the Midwestern U.S. region, dominated by agricultural land use, lake depth and the percentage of row crop agriculture were strong predictors of stoichiometry because only phosphorus was related to lake depth and only nitrogen was related to the percentage of row crop agriculture. In contrast, all drivers were related to N and P in similar ways in the Northeastern U.S. region, leading to weak relationships between drivers and stoichiometry. Our results suggest ecological context mediates controls on lake nutrients and stoichiometry. Predicting stoichiometry was generally more difficult than predicting nutrient concentrations, but human activity may decouple N and P, leading to better prediction of N:P stoichiometry in regions with high anthropogenic activity.


Study on the In Vitro Activity of Five Disinfectants against Nosocomial Bacteria.
Nosocomial infections cause significant morbidity and mortality worldwide, and the pathogenic organisms responsible for such infections can develop resistance to antimicrobial agents. Understanding the activity of disinfectants against clinical and environmental bacterial isolates is therefore crucial. We analysed the in vitro activity of five antimicrobial products (phenolic compounds, didecyldimethylammonium chloride (DDAC), sodium hypochlorite, isopropanol + ammonium compounds (IACs), hydrogen peroxide) against 187 bacterial strains comprising clinical isolates, as well as 30 environmental isolates of Pseudomonas aeruginosa from hospital water samples. Disk diffusion assays were employed to assess antimicrobial activity. Hydrogen peroxide was significantly more active (p < 0.0001) than the other disinfectants against all P. aeruginosa, Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus aureus strains. It was also the only disinfectant with activity against both clinical and environmental strains of P. aeruginosa. DDAC and IAC-based disinfectants were ineffective against Gram-negative strains, but showed significant activity (particularly IACs, p < 0.0001) against the Gram-positive strains. Compared with IACs, DDAC was significantly more active on E. faecalis and less active on S. aureus (p < 0.0001). Sodium hypochlorite and phenol compounds, by contrast, were inactive against all bacterial strains. The development of disinfection procedures that are effective against all microorganisms is essential for limiting the spread of nosocomial infections.


Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo.
Cumulative evidence supports bidirectional interactions between astrocytes and neurons, suggesting glial involvement of neuronal information processing in the brain. Cytosolic calcium (Ca(2+)) concentration is important for astrocytes as Ca(2+) surges co-occur with gliotransmission and neurotransmitter reception. Cerebral cortex is organized in layers which are characterized by distinct cytoarchitecture. We asked if astrocyte-dominant layer 1 (L1) of the somatosensory cortex was different from layer 2/3 (L2/3) in spontaneous astrocytic Ca(2+) activity and if it was influenced by background neural activity. Using a two-photon laser scanning microscope, we compared spontaneous Ca(2+) activity of astrocytic somata and processes in L1 and L2/3 of anesthetized mature rat somatosensory cortex. We also assessed the contribution of background neural activity to the spontaneous astrocytic Ca(2+) dynamics by investigating two distinct EEG states ("synchronized" vs. "de-synchronized" states). We found that astrocytes in L1 had nearly twice higher Ca(2+) activity than L2/3. Furthermore, Ca(2+) fluctuations of processes within an astrocyte were independent in L1 while those in L2/3 were synchronous. Pharmacological blockades of metabotropic receptors for glutamate, ATP, and acetylcholine, as well as suppression of action potentials did not have a significant effect on the spontaneous somatic Ca(2+) activity. These results suggest that spontaneous astrocytic Ca(2+) surges occurred in large part intrinsically, rather than neural activity-driven. Our findings propose a new functional segregation of layer 1 and 2/3 that is defined by autonomous astrocytic activity.


[The cell 100 years ago].
Eduard Strasburgers monograph "On Cell Formation and Cell Division" appeared in Jena in 1875. At that time the existence of the cell nucleus was established, but the scientists were still discussing a possibility of free formation of cells as suggested by Schwann and Schleiden. Nuclear structure and the processes of mitosis were still uninvestigated. The original observations which are reproduced show the first tentative efforts at a generalised description. Comparison with the opinions of Haeckel and Flemming show the uncertainty of cytology in that early phase, because the lack of microscopic technique did not yet permit of any detailed evidence.


Genetic manipulation of AML1-ETO-induced expansion of hematopoietic precursors in a Drosophila model.
Among mutations in human Runx1/AML1 transcription factors, the t(8;21)(q22;q22) genomic translocation that creates an AML1-ETO fusion protein is implicated in etiology of the acute myeloid leukemia. To identify genes and components associated with this oncogene we used Drosophila as a genetic model. Expression of AML1-ETO caused an expansion of hematopoietic precursors in Drosophila, which expressed high levels of reactive oxygen species (ROS). Mutations in functional domains of the fusion protein suppress the proliferative phenotype. In a genetic screen, we found that inactivation of EcRB1 or activation of Foxo and superoxide dismutase-2 (SOD2) suppress the AML1-ETO-induced phenotype by reducing ROS expression in the precursor cells. Our studies indicate that ROS is a signaling factor promoting maintenance of normal as well as the aberrant myeloid precursors and suggests the importance of antioxidant enzymes and their regulators as targets for further study in the context of leukemia.


Rates of induction of mitochondrial aldehyde dehydrogenase in rat liver.
Aldehyde dehydrogenase activities in liver mitochondria isolated from rats given ethanol at hourly intervals by gastric intubation showed a brief lag period followed by a rapid increase in specific activities until a maximum was attained at about 3h.


Hallucinations in psychiatrically disordered children: preliminary communication.
In a retrospective study children with hallucinations and nonorganic psychiatric conditions were compared with matched controls. Hallucinations were found to be a rare symptom except in children with a diagnosis of psychosis of late onset where they were commonly present. Children with hallucinations were older than the majority of subjects seen in the Child Psychiatric Clinic. The perceptual symptoms were associated with precipitants of illness and mood changes. In the nonpsychotic subjects, they were also associated with symptoms suggestive of minor brain dysfunction. The results are discussed and ideas for future research suggested.


Role of surgery in the management of otogenic meningitis.
Meningitis is a life-threatening complication of otitis media. The appropriate management and the role of surgical intervention are still controversial, and there are no evidence-based guidelines in this regard. We report three cases of otogenic meningitis, initially treated with parenteral antibiotics and myringotomy, followed by surgery. Two patients had an emergency mastoidectomy and one patient underwent surgery one month post-recovery due to the suspicion of bone erosion on a computed tomography scan. In two cases, a canal wall up procedure was performed, and one patient underwent revision of a radical mastoidectomy. In all cases, no pus or granulations were seen in the mastoid. Two patients fully recovered and one patient died. We review the literature and critically discuss the role, timing and preferred type of surgery for otogenic meningitis.


Crimean-Congo hemorrhagic fever virus, Greece.
Seroprevalence of Crimean-Congo hemorrhagic fever virus (CCHFV) is high in some regions of Greece, but only 1 case of disease has been reported. We used 4 methods to test 118 serum samples that were positive for CCHFV IgG by commercial ELISA and confirmed the positive results. A nonpathogenic or low-pathogenicity strain may be circulating.


Birth weight in pregnancies complicated by maternal heart disease.
To assess median and percentile birthweight distribution in women with various groups of heart disease relative to a contemporaneous comparison group. Data on birth weight and gestational age were collected from 1321 pregnancies ≥24 weeks' gestation in 1053 women with heart disease from seven UK maternity units. Women were assigned to one of 16 groups according to their cardiac lesion. In units where it was possible, data on two births, one delivering before and one after index cases, were collected, giving 2307 comparators. Birthweight percentiles (corrected for gestational age, sex and parity) were calculated using Aberdeen norms. We assessed the association of birth weight with cardiac lesion, maternal hypoxaemia (saturations <90%), systemic ventricular function and beta-blockers. 1321 pregnancies in women with heart disease and 2307 comparators were studied. Almost all groups with heart disease had lower median and percentile birth weights than comparators, significantly in 10 groups, the biggest effect seen in women with Fontan circulation, pulmonary hypertension, prosthetic heart valves, systemic right ventricle, Marfan syndrome, repaired tetralogy of Fallot and cardiomyopathy (in that order). In 307 pregnancies, women took beta-blockers; median birth weight adjusted for maternal age, parity and the effect of the cardiac lesion was 3116.7 g (IQR 790.4) when beta-blockers were used and 3354.3 g (IQR 634.1) when they were not (p<0.001). 17 women had saturations <90%, and median birth weight was significantly lower, 3105.4 g (IQR 1288.9) versus 3387.7 g (IQR 729.8) (p=0.006). Our findings identify specific groups of women with heart disease at risk of having a small baby.


Statin Therapy Is Associated With a Lower Risk of Heart Failure in Patients With Atrial Fibrillation: A Population-Based Study.
Whether statin use can reduce the risk of heart failure (HF) remains controversial. The present study evaluates the association between statin use and HF in patients with atrial fibrillation. Patients with newly diagnosed atrial fibrillation from 2010 to 2018 were included. An inverse probability of treatment weighting was used to balance baseline covariates between statin users (n=23 239) and statin nonusers (n=29 251). The primary outcome was incident HF. Cox proportional hazard models with competing risk regression were used to evaluate the risk of HF between statin users and nonusers. The median age of the cohort was 74.7 years, and 47.3% were women. Over a median follow-up of 5.1 years, incident HF occurred in 3673 (15.8%) statin users and 5595 (19.1%) statin nonusers. Statin use was associated with a 19% lower risk of HF (adjusted subdistribution hazard ratio, 0.81 [95% CI, 0.78-0.85]). Restricted to the statin users, duration of statin use was measured during follow-up; compared with short-term use (3 months to <2 years), there was a stepwise reduction in the risk of incident HF among those with 2 to <4 years of statin use (subdistribution hazard ratio, 0.86 [95% CI, 0.84-0.88]), 4 to <6 years of statin use (subdistribution hazard ratio, 0.74 [95% CI, 0.72-0.76]), and ≥6 years of statin use (subdistribution hazard ratio, 0.71 [95% CI, 0.69-0.74]). Subgroup analysis showed consistent reductions in the risk of HF with statin use. Statin use was associated with a decreased risk of incident HF in a duration-dependent manner among patients with atrial fibrillation.


Laser induced surface acoustic wave combined with phase sensitive optical coherence tomography for superficial tissue characterization: a solution for practical application.
Mechanical properties are important parameters that can be used to assess the physiologic conditions of biologic tissue. Measurements and mapping of tissue mechanical properties can aid in the diagnosis, characterisation and treatment of diseases. As a non-invasive, non-destructive and non-contact method, laser induced surface acoustic waves (SAWs) have potential to accurately characterise tissue elastic properties. However, challenge still exists when the laser is directly applied to the tissue because of potential heat generation due to laser energy deposition. This paper focuses on the thermal effect of the laser induced SAW on the tissue target and provides an alternate solution to facilitate its application in clinic environment. The solution proposed is to apply a thin agar membrane as surface shield to protect the tissue. Transient thermal analysis is developed and verified by experiments to study the effects of the high energy Nd:YAG laser pulse on the surface shield. The approach is then verified by measuring the mechanical property of skin in a Thiel mouse model. The results demonstrate a useful step toward the practical application of laser induced SAW method for measuring real elasticity of normal and diseased tissues in dermatology and other surface epithelia.


Effect of fasting on thyroid hormone levels, and TR(alpha) and TR(beta) mRNA accumulation in late-stage embryo and juvenile rainbow trout, Oncorhynchus mykiss.
The accumulation of mRNA encoding for hepatic and intestinal T3-receptor (TR) and body and liver masses were measured in fed and 3-week fasted juvenile and swim up stage rainbow trout embryos. Plasma and total body thyroid hormone (TH) levels were measured for juvenile and swim up stages, respectively. Fasted juveniles exhibited a lower hepatosomatic index (HSI), liver mass and plasma T4 and T3 concentrations than fed animals, but there were no changes in body mass or the accumulation of mRNA encoding for either of the TR(alpha) or TR(beta) isoforms in liver or intestine. TR(beta) mRNA accumulation was greater than TR(alpha) mRNA accumulation in both tissues. Fasted embryos had lower whole body TH levels and body, liver and intestinal tract masses, in addition to a lower intestinosomatic index. However, there was no change in HSI. Fasting did not affect whole body or hepatic TR(alpha) and TR(beta) mRNA accumulation, although intestinal tract TR(alpha) and TR(beta) mRNA accumulation was lower in the fasted embryos. The HSI and body mass changes in fasted juvenile and embryo stages, respectively, indicated that both developmental stages were impacted by fasting. Both stages also showed evidence of decreased TH production. The lower TR gene expression in the intestinal tract of fasted embryos may suggest a role for THs in the transitional stage of intestinal development during this period of development.


Cytarabine and neurologic toxicity.
Cytarabine is an effective drug in the treatment of certain hematologic malignancies and its common toxicities are myelosuppression and gastrointestinal disturbance. In the past decade, neurotoxicity has been an increasingly recognized cytarabine effect. Intrathecal (IT) cytarabine may result in myelopathy that is incompletely reversible. Combined IT drug and cranial irradiation may lead to necrotizing leukoencephalopathy. Intravenous (IV) therapy may cause a peripheral neuropathy that varies greatly in its severity. The high IV cytarabine doses now commonly used can cause seizures, cerebral dysfunction, or an acute cerebellar syndrome with an incidence up to 14%. Patient age (greater than 60 years) appears to be the most important risk factor, but drug dose/schedule, cumulative drug dose, renal and hepatic dysfunction, and concomitant use of neurotropic antiemetic agents may also influence the risk of neurotoxicity. A better understanding of the pathophysiology and pharmacology of such cytarabine-induced neuronal injury will allow this drug to be used with greater efficacy and safety.


Prospective assessment of disease-specific quality of life in adults with eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is an important cause of upper gastrointestinal dysfunction in children and adults. The EoE-quality of life (QOL)-A was validated as a disease-specific measure of quality of life in EoE. This study characterized the extent of QOL concerns in a cohort of adult EoE patients and delineated the relationships between QOL and other disease activity measures. One hundred sixty-seven patients enrolled in this prospective cohort study. Patients with established and suspected EoE undergoing endoscopy at a single university-based medical center were recruited. EoE was diagnosed on the basis of the clinical criteria and histologic demonstration of ≥15 eos/hpf while on proton pump inhibition therapy. Sixty five patients undergoing repeat endoscopy during the enrollment period participated twice. Patients provided demographic information and completed symptom assessments and the EoE-QOL-A. Analyses included comparisons with overall QOL as well as QOL subscales. Outcome measures included endoscopic activity using a validated instrument, the EoE Endoscopic Reference Score, and histology. Overall QOL was significantly correlated with dysphagia frequency, intensity, and severity (P < 0.001). Patients who experienced a food impaction in the last 30 days had significantly worse overall QOL (P = 0.009). There was no correlation between overall QOL and years since diagnosis, symptom duration, endoscopic features, or histologic findings. Patient symptoms correlated with endoscopic features of edema, rings, and stricture severity. Histologic activity was highly correlated with severity of endoscopic features. Patients who underwent repeat endoscopy with histologic response demonstrated improved eating and social QOL; however, overall QOL was unchanged. In adults with EoE, patient reported QOL is associated with symptom severity but not endoscopic or histologic features. Disease-specific QOL may complement parameters of biologic activity in the assessment of overall disease burden in EoE.


Intervertebral disc properties: challenges for biodevices.
Intervertebral disc biodevices that employ motion-preservation strategies (e.g., nucleus replacement, total disc replacement and posterior stabilization devices) are currently in use or in development. However, their long-term performance is unknown and only a small number of randomized controlled trials have been conducted. In this article, we discuss the following biodevices: interbody cages, nuclear pulposus replacements, total disc replacements and posterior dynamic stabilization devices, as well as future biological treatments. These biodevices restore some function to the motion segment; however, contrary to expectations, the risk of adjacent-level degeneration does not appear to have been reduced. The short-term challenge is to replicate the complex biomechanical function of the motion segment (e.g., biphasic, viscoelastic behavior and nonlinearity) to improve the quality of motion and minimize adjacent level problems, while ensuring biodevice longevity for the younger, more active patient. Biological strategies for regeneration and repair of disc tissue are being developed and these offer exciting opportunities (and challenges) for the longer term. Responsible introduction and rigorous assessment of these new technologies are required. In this article, we will describe the properties of the disc, explore biodevices currently in use for the surgical treatment of low back pain (with an emphasis on lumbar total disc replacement) and discuss future directions for biological treatments. Finally, we will assess the challenges ahead for the next generation of biodevices designed to replace the disc.


Mental health, sexual identity, and interpersonal violence: Findings from the Australian longitudinal Women's health study.
We examined the relationships among experiences of interpersonal violence, mental health, and sexual identity in a national sample of young adult women in Australia. We used existing data from the third (2003) wave of young adult women (aged 25-30) in the Australian Longitudinal Study on Women's Health (ALSWH). We conducted bivariate analyses and fit multiple and logistic regression models to test experiences of six types of interpersonal violence (physical abuse, severe physical abuse, emotional abuse, sexual abuse, harassment, and being in a violent relationship), and the number of types of violence experienced, as predictors of mental health. We compared types and number of types of violence across sexual identity subgroups. Experiences of interpersonal violence varied significantly by sexual identity. Controlling for demographic characteristics, compared to exclusively heterosexual women, mainly heterosexual and bisexual women were significantly more likely to report physical, sexual, and emotional abuse. Mainly heterosexual and lesbian women were more likely to report severe physical abuse. Mainly heterosexual women were more than three times as likely to have been in a violent relationship in the past three years, and all three sexual minority subgroups were two to three times as likely to have experienced harassment. Bisexual women reported significantly higher levels of depression than any of the other sexual identity groups and scored lower on mental health than did exclusively heterosexual women. In linear regression models, interpersonal violence strongly predicted poorer mental health for lesbian and bisexual women. Notably, mental health indicators were similar for exclusively heterosexual and sexual minority women who did not report interpersonal violence. Experiencing multiple types of interpersonal violence was the strongest predictor of stress, anxiety and depression. Interpersonal violence is a key contributor to mental health disparities, especially among women who identify as mainly heterosexual or bisexual. More research is needed that examines within-group differences to determine which subgroups are at greatest risk for various types of interpersonal violence. Such information is critical to the development of effective prevention and intervention strategies.


[Isradipine in arterial hypertension in motor vehicle drivers].
The study covered influence of Isradipine (2.5 mg administered twice daily during 6 weeks) on blood circulation in the heart and occupationally important functions and traits among 30 drivers having mild and moderate arterial hypertension (AH). Systolic and diastolic pressure demonstrate reliable decrease in all the examinees with mild AH and in 93.8% of the examinees with moderate AH. Isradipine proved to influence positively decrease of hypertensive reactions and subclinical myocardial ischemia. Isradipine presented statistically significant improvement of the studied psychophysiologic parameters (quickness of latent and motor visual reaction, number of errors in color choice, exactness in following the mobile object). Thus, all above enables to recommend Isradipine (Lomir) as effective and safe method correcting arterial hypertension in drivers.


The Effect of Hamstring Tendon Autograft Harvest on the Restoration of Knee Stability in the Setting of Concurrent Anterior Cruciate Ligament and Medial Collateral Ligament Injuries.
A hamstring autograft is commonly used in anterior cruciate ligament (ACL) reconstruction (ACLR); however, there is evidence to suggest that the tendons harvested may contribute to medial knee instability. We tested the hypothesis that the gracilis (G) and semitendinosus (ST) tendons significantly contribute to sagittal, coronal, and/or rotational knee stability in the setting of ACLR with a concurrent partial medial collateral ligament (MCL) injury. Controlled laboratory study. Twelve human cadaveric knees were subject to static forces applied to the tibia including an anterior-directed force as well as varus, valgus, and internal and external rotation moments to quantify laxity at 0°, 30°, 60°, and 90° of flexion. The following ligament conditions were tested on each specimen: (1) ACL intact/MCL intact, (2) ACL deficient/MCL intact, (3) ACL deficient/partial MCL injury, and (4) ACLR/partial MCL injury. To quantify the effect of muscle loads, the quadriceps, semimembranosus, biceps femoris, sartorius (SR), ST, and G muscles were subjected to static loads. The loads on the G, ST, and SR could be added or removed during various test conditions. For each ligament condition, the responses to loading and unloading the G/ST and SR were determined. Three-dimensional positional data of the tibia relative to the femur were recorded to determine tibiofemoral rotations and translations. ACLR restored anterior stability regardless of whether static muscle loads were applied. There was no significant increase in valgus motion after ACL transection. However, when a partial MCL tear was added to the ACL injury, there was a 30% increase in valgus rotation ( P < .05). ACLR restored valgus stability toward that of the intact state when the G/ST muscles were loaded. A load on the SR muscle without a load on the G/ST muscles restored 19% of valgus rotation; however, it was still significantly less stable than the intact state. After ACLR in knees with a concurrent partial MCL injury, the absence of loading on the G/ST did not significantly alter anterior stability. Simulated G/ST harvest did lead to increased valgus motion. These results may have important clinical implications and warrant further investigation to better outline the role of the medial hamstrings, particularly among patients with a concomitant ACL and MCL injury. A concurrent ACL and MCL injury is a commonly encountered clinical problem. Knowledge regarding the implications of hamstring autograft harvest techniques on joint kinematics may help guide management decisions.


DNA microarrays to study gene expression in allergic airways.
Allergic rhinitis results from interactions between a large number of cells and mediators in different compartments of the body. DNA microarrays allow simultaneous measurement of expression of thousands of genes in the same tissue sample. To study gene expression in nasal mucosal biopsies from patients with allergic rhinitis using DNA micro-arrays. Nasal biopsies were obtained from 14 patients with symptomatic birch pollen-induced allergic rhinitis and five healthy controls. RNA was extracted from the biopsies and pooled into one patient pool and one control pool. These were analysed in duplicate with DNA micro-arrays containing more than 12 000 known genes. Approximately half of the genes were expressed in the patient and control samples. Guided by the current literature we chose 32 genes of possible relevance to allergic airway inflammation and investigated their relative expression. Among these, transcripts encoding immunoglobulins and their receptors were most abundant. The expression of cytokines and growth factors was low, whereas their corresponding receptors and cell surface markers displayed higher expression levels. IgA had the highest expression of all 12 626 genes. RT-PCR showed that IgA1 was the predominant subclass. This was confirmed by the protein level in nasal fluids. Allergen-specific IgA was significantly higher in patients than in controls and correlated significantly with eosinophil granulae proteins. DNA micro-array analysis can be used to identify genes of possible relevance to allergic airway inflammation. In this study, the expression profile in the nasal mucosa was quantitatively dominated by immunoglobulins, particularly IgA. Protein analyses in nasal fluids indicated a role for allergen-specific IgA in eosinophil degranulation.


Hypotensive activity of tetrandrine in rats. Investigation into its mode of action.
The influence of tetrandrine on arterial pressure and heart rate of pentobarbitone-anaesthetized and conscious normotensive and hypertensive rats (SH rats, renal hypertensive rats, DOCA-salt hypertensive rats) was investigated. Tetrandrine administered intravenously (i.v.) to these animals caused an acute, long-lasting and dose-dependent decrease in mean arterial pressure. Heart rate was not significantly altered. In pithed rats, tetrandrine injected intraarterially 15 min previously impaired the increase in diastolic pressure induced by i.v. B-HT 920, a highly selective alpha 2-adrenoceptor-stimulating agent, in a dose-dependent manner. In a low dose, a parallel displacement to the right was observed, whereas for higher doses the shift was non-parallel. A high dose of tetrandrine shifted the pressor response curve of the alpha 1-adrenoceptor agonist, methoxamine, only slightly to the right and did not depress the maximal response. Tetrandrine also caused a moderate rightward shift of the vasopressor effect curve of vasopressin applied i.v. Tetrandrine displayed only minor affinities for specific binding sites in rat brain membranes for [3H]-prazosin (alpha 1-adrenoceptors) and for [3H]-clonidine (alpha 2-adrenoceptors). The results obtained suggest that the hypotensive effect of tetrandrine may be related to an impairment of vasoconstrictor tone mediated by vascular postsynaptic alpha 2-adrenoceptors.


Co-occurring eating and psychiatric symptoms in Taiwanese college students: effects of gender and parental factors.
To test whether gender and parental factors moderate the relationships between symptoms of eating disorder (ED) and other psychiatric symptoms. A total of 5,015 new entrants completed several questionnaires and 541 individuals with ED symptoms were identified by the Adult Self-Report Inventory-4 that assessed a wide range of Diagnostic and Statistical Manual of Mental Disorders Fourth Edition psychopathology. The participants also reported on their parents' attitude toward them before their ages of 16. ED symptoms, female gender, less parental care, and more parental protection were associated with more severe co-occurring psychiatric symptoms. Gender and parental factors also demonstrated differential moderating effects on the relationships between ED and co-occurring psychiatric symptoms. Parenting counseling may be individualized to young adults with ED symptoms and different co-occurring psychiatric symptoms.


Specializations of the mandibular anatomy and dentition of Segnosaurus galbinensis (Theropoda: Therizinosauria).
Definitive therizinosaurid cranial materials are exceptionally rare, represented solely by an isolated braincase and tooth in the North American taxon Nothronychus mckinleyi, the remarkably complete skull of the Asian taxon Erlikosaurus andrewsi, and the lower hemimandibles of Segnosaurus galbinensis. To date, comprehensive descriptions of the former taxa are published; however, the mandibular materials of S. galbinensis have remained largely understudied since their initial description in 1979. Here we provide a comprehensive description of the well-preserved hemimandibles and dentition of S. galbinensis (MPC-D 100/80), from the Upper Cretaceous Bayanshiree Formation, Gobi Desert, Mongolia. The subrectangular and ventrally displaced caudal hemimandible, extreme ventral deflection of the rostral dentary, and edentulism of the caudal dentary of S. galbinensis are currently apomorphic among therizinosaurians. Unique, unreported dental traits including lingually folded mesial carinae, development of a denticulated triangular facet on the distal carinae near the cervix, and extracarinal accessory denticles, suggest a highly specialized feeding strategy in S. galbinensis. The presence of triple carinae on the distalmost lateral tooth crowns is also unique, although may represent an abnormality. Contrasted with the simplistic dentition of the contemporaneous therizinosaurid E. andrewsi, the dentition of S. galbinensis is indicative of niche partitioning in food acquisition, processing, or resources among known therizinosaurids inhabiting Asian ecosystems in the Late Cretaceous. Although not quantitatively correlated with diet, this suite of specializations is otherwise unique among theropod dinosaurs and supports derived inferences of facultative or obligate herbivory in therizinosaurids, ultimately adding novel information to our understanding of ecomorphology in theropods.


Lymphocyte-specific protein 1 expression in eukaryotic cells reproduces the morphologic and motile abnormality of NAD 47/89 neutrophils.
Despite its name, the actin-binding protein lymphocyte-specific protein1 (LSP1) is found in all hematopoetic cells, and yet its role in cell function remains unclear. Recently, LSP1 was identified as the 47-kD protein overexpressed in the polymorphonuclear neutrophils of patients with a rare neutrophil disorder, neutrophil actin dysfunction with abnormalities of 47-kD and 89-kD proteins (NAD 47/89). These neutrophils are immotile, defective in actin polymerization in response to agonists, and display distinctive, fine, "hairlike" F-actin-rich projections on their cell surfaces. We now show that overexpression of LSP1 produces F-actin bundles that are likely responsible for the morphologic and motile abnormalities characteristic of the NAD 47/89 phenotype. Coincident with LSP1 overexpression, cells from each of several different eukaryotic lines, including a highly motile human melanoma line, develop hairlike surface projections that branch distinctively and contain F-actin and LSP1. The hairlike projections are supported at their core by thick actin bundles, composed of actin filaments of mixed polarity, which periodically anastomose to generate a branching structure. The motility of the melanoma cells is inhibited even at low levels of LSP1 expression. Therefore, these studies show that overexpression of LSP1 alone can recreate the morphologic and motile defects seen in NAD 47/89 and suggest that LSP1 is distinct from other known actin binding proteins in its effect on F-actin network structure.


[Serum concentrations of estradiol and testosterone in patients with oligoasthenozoospermia and asthenozoospermia].
In order to study the possible influence of circulating concentrations of estradiol (E2) and testosterone (T) on the spermatogenesis, 43 subjects, 21 to 43 years of age; 16 of them with oligoasthenozoospermia; 16 with "pure" asthenozoospermia, and 11 with normal semen study, were studied. This last group was taken as control for results evaluation and comparison. In all the cases, the presence of genitourinary infection, as well as testicular lesions and varicocele, was previously discarded. Serum concentrations of estradiol, testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL), were determined by radio-analysis, in fasting blood samples. The results are shown as average values +/- standard error (mean +/- SE). Statistical analysis of differences between the groups, was done by "t" Student test in paired samples. Patients with oligoasthenozoospermia showed a significant increase (56.9%) (less than 0.001) in estradiol circulating levels, while T, FSH, LH and PRL concentrations were below normal band, and there were not significant differences between the three groups. These results suggest that the excess of estradiol or of some of its metabolites could affect normal production of spermatozoa, maybe due to a direct effect on germinal epithelium of testicle.


A generalized Gaussian image model for edge-preserving MAP estimation.
The authors present a Markov random field model which allows realistic edge modeling while providing stable maximum a posterior (MAP) solutions. The model, referred to as a generalized Gaussian Markov random field (GGMRF), is named for its similarity to the generalized Gaussian distribution used in robust detection and estimation. The model satisfies several desirable analytical and computational properties for map estimation, including continuous dependence of the estimate on the data, invariance of the character of solutions to scaling of data, and a solution which lies at the unique global minimum of the a posteriori log-likelihood function. The GGMRF is demonstrated to be useful for image reconstruction in low-dosage transmission tomography.


Flow cytometric analysis of cellular immune responses in dogs experimentally infected with a North American isolate of Leishmania infantum.
Canine leishmaniasis caused by Leishmania infantum is endemic in the foxhound population in North America. Studies of canine leishmaniasis in the Mediterranean basin indicate a role for both CD4+ and CD8+ lymphocytes with clinical illness and in asymptomatic dogs. Limited information is available on the strain of L. infantum infecting foxhounds in North America. The present study investigated changes in cellular immune responses in dogs experimentally infected with 1x10(7) (low dose, LD; N=4) or 2x10(8) (high dose, HD; N=4) promastigotes of a United States isolate of L. infantum and control dogs (N=2) for 72 weeks. Density gradient separation was used to enrich for peripheral blood lymphocytes from canine blood. Lymphocyte subsets (CD4+ and CD8+) were quantified by flow cytometric analysis. Lymphocyte population expression levels over the course of the present study were compared to clinical status of the dog and antibody responses in infected and control dogs. No significant differences (P>0.05) were observed in either CD4+ or CD8+ lymphocyte expression in of the groups over the experimental period. This study suggests that the cellular immune responses to North American L. infantum in experimentally infected dogs may differ from other strains of L. infantum.


Metastatic behavior of human melanoma cell lines in nude mice correlates with urokinase-type plasminogen activator, its type-1 inhibitor, and urokinase-mediated matrix degradation.
Five out of six human melanoma cell lines tested were able to degrade in vitro a smooth muscle cell extracellular matrix in a plasmin-dependent way. In three of these five cell lines, this process was mediated by tissue-type plasminogen activator (t-PA) and in the other two cell lines by urokinase-type plasminogen activator (u-PA). All melanoma cell lines produced t-PA mRNA and protein, whereas only the two cell lines showing u-PA-mediated matrix degradation produced u-PA mRNA and protein. These latter cell lines also produced plasminogen activator inhibitor type-1 (PAI-1) and type-2 (PAI-2) mRNA and protein. u-PA receptor (u-PA-R) mRNA and binding of radiolabeled u-PA was found in all melanoma cell lines. The metastatic capacity of these cell lines was studied in nude mice. All cell lines were able to develop primary tumors at the subcutaneous inoculation site. The production of plasminogen activators, their inhibitors and urokinase receptor by subcutaneous tumors corresponded with the production by the parental cell lines in vitro. The two u-PA and PAI-1 producing cell lines showed the highest frequency to form spontaneous lung metastases after subcutaneous inoculation, whereas five of the six cell lines formed lung colonies after intravenous inoculation. In conclusion, u-PA mediated matrix degradation in vitro and production of u-PA and PAI-1 by human melanoma cell lines correlated with their ability to form spontaneous lung metastasis in nude mice. No correlation was found with the ability to form lung colonies after intravenous injection. These findings suggest a role for u-PA and PAI-1 in a relatively early stage of melanoma metastasis.


Visuomotor Figure Construction and Visual Figure Delayed Recall and Recognition in Primary Progressive Aphasia.
Individuals with primary progressive aphasia (PPA) develop visuospatial deficits over time, and those with logopenic variant (lvPPA) are at greatest risk of developing such deficits. However, not all previous studies of visuospatial deficits in PPA have ensured equivalent duration of disease across variants and few have measured deficits longitudinally. The aims of our study were to: 1) investigate differences in baseline visuomotor figure construction, visual figure delayed recall, and figure recognition in PPA variants with similar symptom duration at baseline, and 2) explore patterns of decline in these areas. Ninety-three individuals with PPA [39 lvPPA, 24 nonfluent agrammatic PPA (nfaPPA), and 30 semantic variant PPA (svPPA)] were administered the Benson Complex Figure Copy, Benson Complex Figure Delay (Recall), and Benson Figure Recognition. Thirty individuals completed this testing 3 to 47 months post baseline. Participants with lvPPA and svPPA showed lower mean scores than those with nfaPPA on visual figure delayed recall at baseline, even though there were no differences in estimated time from disease onset or correlation with disease severity as reflected by naming performance, F(2, 90) = 5.78, p < .004. Those with nfaPPA performed significantly better than those with lvPPA, Tukey HSD p < .05, and those with svPPA, Tukey HSD p < .01. There were no differences between variants in rate of decline in visuomotor figure construction, visual figure delayed recall, and figure recognition. These findings revealed relatively spared visuospatial memory in nfaPPA, which may aid in the differential diagnosis of PPA and contribute to designing therapy or compensatory strategies.


Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy.
Uracil in DNA is an important cause of mutagenesis. SMUG1 is a uracil-DNA glycosylase that removes uracil through base excision repair. SMUG1 also processes radiation-induced oxidative base damage as well as 5-fluorouracil incorporated into DNA during chemotherapy. We investigated SMUG1 mRNA expression in 249 primary breast cancers. SMUG1 protein expression was investigated in 1,165 breast tumours randomised into two cohorts [training set (n = 583) and test set (n = 582)]. SMUG1 and chemotherapy response was also investigated in a series of 315 ER-negative tumours (n = 315). For mechanistic insights, SMUG1 was correlated to biomarkers of aggressive phenotype, DNA repair, cell cycle and apoptosis. Low SMUG1 mRNA expression was associated with adverse disease specific survival (p = 0.008) and disease-free survival (p = 0.008). Low SMUG1 protein expression (25 %) was associated with high histological grade (p < 0.0001), high mitotic index (p < 0.0001), pleomorphism (p < 0.0001), glandular de-differentiation (p = 0.0001), absence of hormonal receptors (ER-/PgR-/AR) (p < 0.0001), presence of basal-like (p < 0.0001) and triple-negative phenotypes (p < 0.0001). Low SMUG1 protein expression was associated with loss of BRCA1 (p < 0.0001), ATM (p < 0.0001) and XRCC1 (p < 0.0001). Low p27 (p < 0.0001), low p21 (p = 0.023), mutant p53 (p = 0.037), low MDM2 (p < 0.0001), low MDM4 (p = 0.004), low Bcl-2 (p = 0.001), low Bax (p = 0.003) and high MIB1 (p < 0.0001) were likely in low SMUG1 tumours. Low SMUG1 protein expression was associated with poor prognosis in univariate (p < 0.001) and multivariate analysis (p < 0.01). In ER+ cohort that received adjuvant endocrine therapy, low SMUG1 protein expression remains associated with poor survival (p < 0.01). In ER- cohort that received adjuvant chemotherapy, low SMUG1 protein expression is associated with improved survival (p = 0.043). Our study suggests that low SMUG1 expression may correlate to adverse clinicopathological features and predict response to adjuvant therapy in breast cancer.


Automated analysis of written narratives reveals abnormalities in referential cohesion in youth at ultra high risk for psychosis.
Schizophrenia and at-risk populations are suggested to exhibit referential cohesion deficits in language production (e.g., producing fewer pronouns or nouns that clearly link to concepts from previous sentences). Much of this work has focused on transcribed speech samples, while no work to our knowledge has examined referential cohesion in written narratives among ultra high risk (UHR) youth using Coh-Metrix, an automated analysis tool. In the present study, written narratives from 84 individuals (UHR=41, control=43) were examined. Referential cohesion variables and relationships with symptoms and relevant cognitive variables were also investigated. Findings reveal less word "stem" overlap in narratives produced by UHR youth compared to controls, and correlations with symptom domains and verbal learning. The present study highlights the potential usefulness of automated analysis of written narratives in identifying at-risk youth and these data provide critical information in better understanding the etiology of psychosis. As writing production is commonly elicited in educational contexts, markers of aberrant cohesion in writing represent significant potential for identifying youth who could benefit from further screening, and utilizing software that is easily accessible and free may provide utility in academic and clinical settings.


Status of metal levels and their potential sources of contamination in Southeast Asian rivers.
To assess the concentration and status of metal contaminants in four major Southeast Asian river systems, water were collected from the Tonle Sap-Bassac Rivers (Cambodia), Citarum River (Indonesia), lower Chao Phraya River (Thailand), and Saigon River (Vietnam) in both dry and wet seasons. The target elements were Be, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Ag, Cd, Ba, Tl, and Pb and the concentrations exceeded the background metal concentrations by 1- to 88-fold. This distinctly indicates enrichment by human urban area activities. The results of a normalization technique used to distinguish natural from enriched metal concentrations confirmed contamination by Al, Cd, Co, Mn, Ni, Pb, and Zn. Cluster analysis revealed the probable source of metals contamination in most sampling sites on all rivers studied to be anthropogenic, including industrial, commercial, and residential activities. Stable lead isotopes analyses applied to track the sources and pathways of anthropogenic lead furthermore confirmed that anthropogenic sources of metal contaminated these rivers. Discharges of wastewater from both industrial and household activities were major contributors of Pb into the rivers. Non-point sources, especially road runoff and street dust, also contributed contamination from Pb and other metals.


How developments in cryobiology, reproductive technologies and conservation genomics could shape gene banking strategies for (farm) animals.
Many local breeds are currently at risk because of replacement by a limited number of specialized commercial breeds. Concurrently, for many breeds, allelic diversity within breeds declines because of inbreeding. Gene banking of germplasm may serve to secure the breeds and the alleles for any future use, for instance to recover a lost breed, to address new breeding goals, to support breeding schemes in small populations to minimize inbreeding, and for conservation genetics and genomics research. Developments in cryobiology and reproductive technology have generated several possibilities for preserving germplasm in farm animals. Furthermore, in some mammalian and bird species, gene banking of material is difficult or impossible, requiring development of new alternative methods or improvement of existing methods. Depending on the species, there are interesting possibilities or research developments in the use of epididymal spermatozoa, oocytes and embryos, ovarian and testicular tissue, primordial germ cells, and somatic cells for the conservation of genetic diversity in farm- and other animal species. Rapid developments in genomics research also provide new opportunities to optimize conservation and sampling strategies and to characterize genome-wide genetic variation. With regard to gene banks for farm animals, collaboration between European countries is being developed through a number of organizations, aimed at sharing knowledge and expertise between national programmes. It would be useful to explore further collaboration between countries, within the framework of a European gene banking strategy that should minimize costs of conservation and maximize opportunities for exploitation and sustainable use of genetic diversity.


Protection of telomeres by the Ku protein in fission yeast.
Schizosaccharomyces pombe cells survive loss of telomeres by a unique pathway of chromosome circularization. Factors potentially involved in this survival mechanism include the heterodimeric Ku protein and ligase IV, both of which are involved in the repair of DNA double-strand breaks in mammalian cells. Furthermore, Ku plays a role in telomere maintenance as well as in DNA double-strand break repair in Saccharomyces cerevisiae. We have identified Ku and ligase IV homologues in S. pombe and analyzed their functions during normal growth and in cells undergoing senescence. In the absence of either a Ku subunit (pku70(+)) or ligase IV (lig4(+)), nonhomologous DNA end-joining was severely reduced. Lack of functional Ku led to shorter but stable telomeres and caused striking rearrangements of telomere-associated sequences, indicating a function for Ku in inhibiting recombinational activities near chromosome ends. In contrast to S. cerevisiae, concurrent deletion of pku70(+) and the gene for the catalytic subunit of telomerase (trt1(+)) was not lethal, allowing for the first time the dissection of the roles of Ku during senescence. Our results support a model in which Ku protects chromosome termini from nucleolytic and recombinational activities but is not involved in the formation of chromosome end fusions during senescence. The conclusion that nonhomologous end-joining is not required for chromosome circularization was further supported by analysis of survivors in strains lacking the genes for both trt1(+) and lig4(+).


Assessing the accuracy and certainty in interpreting chest X-rays in the medical division.
The chest X-ray (CXR) is an important diagnostic tool in diagnosing and monitoring a spectrum of diseases. Despite our universal reliance on the CXR, our ability to confidently diagnose and accurately document our findings can be unreliable. We sought to assess the diagnostic accuracy and certainty of making a diagnosis based on 10 short clinical histories with one CXR each. We conclude from our study that specialist registrars (StRs) and consultants scored the highest marks with the highest average certainty levels. Junior trainees felt least certain about making their diagnosis and were less likely to be correct. We recommend that StRs and consultants review all the CXRs requested to ensure accuracy of diagnosis. There also needs to be discussion with the Joint Royal Colleges of Physicians Training Board (JRCPTB) about the need of including a separate CXR competency as part of a trainee's generic curriculum on the e-portfolio, something which is currently lacking.


[Comorbid mood and anxiety disorders in victims of violence with posttraumatic stress disorder].
To review studies that have evaluated the comorbidity between posttraumatic stress disorder and mood disorders, as well as between posttraumatic stress disorder and other anxiety disorders. We searched Medline for studies, published in English through April, 2009, using the following keywords: 'posttraumatic stress disorder', 'PTSD', 'mood disorder', 'major depressive disorder', 'major depression', 'bipolar disorder', 'dysthymia', 'anxiety disorder', 'generalized anxiety disorder', 'agoraphobia', 'obsessive-compulsive disorder', 'panic disorder', 'social phobia', and 'comorbidity'. Major depression is one of the most frequent comorbid conditions in posttraumatic stress disorder individuals, but individuals with posttraumatic stress disorder are also more likely to present with bipolar disorder, other anxiety disorders and suicidal behaviors. These comorbid conditions are associated with greater clinical severity, functional impairment, and impaired quality of life in already compromised individuals with posttraumatic stress disorder. Depression symptoms also mediate the association between posttraumatic stress disorder and severity of pain among patients with chronic pain. Available studies suggest that individuals with posttraumatic stress disorder are at increased risk of developing affective disorders compared with trauma-exposed individuals who do not develop posttraumatic stress disorder. Conversely, pre-existing affective disorders increase a person's vulnerability to the posttraumatic stress disorder--inducing effects of traumatic events. Also, common genetic vulnerabilities can help to explain these comorbidity patterns. However, because the studies addressing this issue are few in number, heterogeneous and based on a limited sample, more studies are needed in order to adequately evaluate these comorbidities, as well as their clinical and therapeutic implications.


[Case report: The child- and adolescent psychiatric phenotype of a brother and sister with 16p11.2 microduplication].
16p11.2 microduplication is linked with a vulnerability for a range of psychiatric and somatic problems, with variable expression and penetration rate. We discuss the phenotypical expression of this microduplication with the case of a brother and sister. Both subjects went through child psychiatric diagnostics and treatment, where a varying degree of developmental delay and symptoms that match an attention deficit/hyperactivity disorder were observed in combination with short stature and low body mass index.


Vibrational coherence transfer in the ultrafast intersystem crossing of a diplatinum complex in solution.
We investigate the ultrafast transient absorption response of tetrakis(μ-pyrophosphito)diplatinate(II), [Pt2(μ-P2O5H2)4]4- [hereafter abbreviated Pt(pop)], in acetonitrile upon excitation of its lowest singlet 1A2u state. Compared with previously reported solvents [van der Veen RM, Cannizzo A, van Mourik F, Vlček A, Jr, Chergui M (2011) J Am Chem Soc 133:305-315], a significant shortening of the intersystem crossing (ISC) time (<1 ps) from the lowest singlet to the lowest triplet state is found, allowing for a transfer of vibrational coherence, observed in the course of an ISC in a polyatomic molecule in solution. Density functional theory (DFT) quantum mechanical/molecular mechanical (QM/MM) simulations of Pt(pop) in acetonitrile and ethanol show that high-lying, mostly triplet, states are strongly mixed and shifted to lower energies due to interactions with the solvent, providing an intermediate state (or manifold of states) for the ISC. This suggests that the larger the solvation energies of the intermediate state(s), the shorter the ISC time. Because the latter is smaller than the pure dephasing time of the vibrational wave packet, coherence is conserved during the spin transition. These results underscore the crucial role of the solvent in directing pathways of intramolecular energy flow.


Free-Living Peak Cadence in Multiple Sclerosis: A New Measure of Real-World Walking?
Physical function and walking performance have become important outcomes in clinical trials and rehabilitation involving persons with multiple sclerosis (MS). However, assessments conducted in controlled settings may not reflect real-world capacity and movement in a natural environment. Peak cadence via accelerometry might represent a novel measure of walking intensity and prolonged natural effort under free-living conditions. We compared peak 30-minute cadence, peak 1-minute cadence, and time spent in incremental cadence bands between persons with MS and healthy controls, and examined the associations between peak cadence and laboratory-assessed physical function and walking performance. Participants (147 MS and 54 healthy controls) completed questionnaires on disability status and self-reported physical activity, underwent the Short Physical Performance Battery, Timed 25-Foot Walk, Timed Up and Go, and 6-Minute Walk, and wore an accelerometer for 7 days. We performed independent samples t-tests and Spearman bivariate and partial correlations adjusting for daily steps. The MS sample demonstrated lower physical function and walking performance scores, daily steps, and peak cadence (P < .001), and spent less time in purposeful steps and slow-to-brisk walking (40-119 steps/minutes), but accumulated more incidental movement (1-19 steps/minutes) than healthy controls. The associations between peak cadence and performance outcomes were strong in MS (|rs| = 0.59-0.68) and remained significant after controlling for daily steps (|prs| = 0.22-0.44), P-values < .01. Peak cadence was inversely correlated with age and disability, regardless of daily steps (P < .01). Our findings provide preliminary evidence for the potential use of peak cadence with step-based metrics for comprehensively evaluating free-living walking performance in MS.


Cholangitis and subsequent gastrointestinal cancer risk: a Danish population-based cohort study.
While patients with gastrointestinal cancer are at increased risk of cholangitis, it is less clear whether cholangitis is also a marker for occult gastrointestinal cancer. If an undiagnosed cancer obstructs the bile duct system and causes cholangitis, the short-term risk of cancer will appear increased. However, an increased long-term risk of cancer may originate from chronic inflammatory processes. We assessed the risk of a gastrointestinal cancer diagnosis subsequent to a cholangitis diagnosis during a 17-year period in Denmark. We conducted a nationwide population-based cohort study by linking Danish medical registries during 1994-2010. We quantified the excess risk of cancer in cholangitis patients using relative (standardised incidence ratio; SIR) and absolute (excess absolute risk per 1000 person-years at risk; EAR) risk calculations. 4333 patients with cholangitis (including 178 with primary sclerosing cholangitis) were followed for 17 222 person-years. During the follow-up period, 477 gastrointestinal cancers occurred versus 59 expected, corresponding to a SIR of 8.12 (95% CI 7.41 to 8.88). Risk was increased mainly for cancer in the small intestine (SIR 18.2; 95% CI 8.69 to 33.4), liver (SIR 16.3; 95% CI 11.6 to 22.2), gallbladder and biliary tract (SIR 70.9; 95% CI 59.0 to 84.4) and pancreas (SIR 31.7; 95% CI 27.8 to 36.0). During the first 6 months of follow-up, 314 patients were diagnosed with gastrointestinal cancer, corresponding to a SIR of 49.8 (95% CI 44.4 to 55.6) and an EAR of 175. Cholangitis is a marker of occult gastrointestinal cancer.


Metastatic tumor antigen 1 short form (MTA1s) associates with casein kinase I-gamma2, an estrogen-responsive kinase.
Recent studies have shown that metastasis-associated protein-1 short form (MTA1s) - metastatic tumor antigen 1 short form sequesters estrogen receptor-alpha (ER-alpha) in the cytoplasm of breast cancer cells. Using a yeast two-hybrid screening to clone MTA1s-interacting proteins, we identified casein kinase I-gamma 2 (CKI-gamma2, a ubiquitously expressed cytoplasmic kinase) as an MTA1s-binding protein. We show that MTA1s interacts with CKI-gamma2 both in vitro and in vivo and colocalizes in the cytoplasm. In addition, we found that CKI-gamma2 can phosphorylate MTA1s, but not ER, in an antiestrogen-dependent manner and that estrogen stimulates CKI-gamma2 activity that could be effectively blocked by a specific inhibitor of CKI. CKI-gamma2 could further potentiate the ER corepressive function of MTA1s. Kinase dead CK1-gamma2 could not repress estrogen-induced ER transactivation functions. Results from mutagenesis studies suggest that substitution of the serine residue at 321 to alanine, which is a possible CKI-gamma2 phopshorylation site in MTA1s, results in a significant reduction in the ability of MTA1s to repress ER transactivation. These findings identified MTA1s as a target of CKI-gamma2, and provided new evidence to suggest that CKI-gamma2 phosphorylates and modulates the functions of MTA1s, and that these extranuclear effects of estrogen might have important implications in regulating the functions of MTA1s in human mammary epithelial and cancer cells.


The impact of Internet and PC addiction in school performance of Cypriot adolescents.
In this paper we present the results of a cross-sectional survey designed to ascertain Internet and personal computer (PC) addiction in the Republic of Cyprus. This is a follow-up to a pilot study conducted one year earlier. Data were collected from a representative sample of the adolescent student population of the first and fourth grades of high school. Total sample was 2684 students, 48.5% of them male and 51.5% female. Research material included extended demographics and an Internet security questionnaire, the Young's Diagnostic questionnaire (YDQ), the Adolescent Computer Addiction Test (ACAT). Results indicated that the Cypriot population had comparable addiction statistics with other Greek-speaking populations in Greece; 15.3% of the students were classified as Internet addicted by their YDQ scores and 16.3% as PC addicted by their ACAT scores. Those results are among the highest in Europe. Our results were alarming and have led to the creation of an Internet and PC addiction prevention program which will focus on high-school professor training and the creation of appropriate prevention material for all high-schools, starting immediately after the conclusion of the pan-Cypriot survey, focusing especially on those areas where the frequency of addictive behaviors will be highest.


Mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3-LAG3 axis.
Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8+ T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8+ T cells. We found CD8+ T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.


Decision-making abilities in patients with frontal low-grade glioma.
Decisions in daily life are often quite complex, especially when one has to decide about his/her own health, as it is the case for patients with brain tumours. The integrity of the prefrontal cortex (and of the orbito-frontal in particular) is crucial in humans for practical decision-making. We investigated decision-making in 22 right-handed patients with a left frontal low-grade glioma, by means of a more complex, computerized version of the Iowa gambling task and we compared their performance with that of 26 neurologically-unimpaired subjects. After the experiment, we also administered a questionnaire to evaluate subjects' conscious comprehension level of the task and two self-report scales to verify potential effects of individual personality differences. Patients chose significantly less cards than controls from the advantageous deck, without modifying their behaviour over time, and this correlated with abstract reasoning abilities. In both groups, level of comprehension, significantly affected performance. An improvement was found post-surgery. In conclusion, the performance in the Gambling Task suggests that patients with left frontal low-grade gliomas can be impaired in decision-making, apparently requiring more time to understand the task: therefore, a particular attention and care should be taken to explain risks and consequences of his/her illness and treatment in order to obtain an informed decision from the patient.


Hormonal induction of Dopa decarboxylase in the epidermis of Drosophila is mediated by the Broad-Complex.
The 2B5 early puff locus corresponds to the Broad-Complex BR-C) and encodes a family of transcription factors whose members are induced by the molting hormone ecdysone. Mutations in the br subcomplementation group substantially reduce the levels of Dopa decarboxylase (DDC) in the epidermis of mature third instar larvae but not in mature second instar organisms. Enzyme levels are normal in the central nervous system of the two mutants examined. The specificity of these effects suggests that a product of the BR-C locus mediates the rapid appearance of DDC in mature third instar larvae experiencing an elevated titer of ecdysone. The likely identity of this protein has been confirmed by pursuing the observation that the br28 allele caused by the insertion of a P element into the Z2 DNA-binding domain. Both the transcript and a protein carrying this domain are present in the epidermis and a BR-C recombinant protein carrying the Z2 finger binds to the first intron of the Ddc gene. Five binding sites have been identified within the intron by DNAase I footprinting and a core consensus sequence has been derived which shares some identity with the consensus binding site of the Z2 protein to the Sgs-4 regulatory region. Our demonstration that Ddc is a target of BR-C in the epidermis is the first direct evidence of a role for this early gene in a tissue other than the salivary glands. The data reinforce the idea that BR-C, which clearly mediates a salivary gland-specific response to ecdysone, may play a widespread role in the hormone's activation of gene cascades in other target tissues.


Melanoma in situ of the oral mucosa in an adolescent with dysplastic nevus syndrome.
We describe a case of melanoma in situ occurring on the oral mucosa in an adolescent male patient who has dysplastic nevus syndrome. This association has not been previously reported and is of interest both because of the rarity of melanoma involving the oral mucosa, particularly in childhood, and because of the lack of any previous reports of oral mucosal melanoma in association with the dysplastic nevus syndrome.


[Determination of tobacco-specific N'-nitrosamines in mainstream smoke from Japanese cigarettes].
Mainstream smoke from cigarettes contains tobacco-specific N'-nitrosamines (TSNAs) listed as Group 1 and 3 carcinogens by the International Agency for Research on Cancer (IARC). Herein, we report on a method of measuring the concentrations of TSNAs in mainstream smoke from the ten top-selling Japanese cigarette brands using an ISO regime by International Organization for Standardization (ISO) and HCI regime of Health Canada. Tar in mainstream smoke was collected on a Cambridge filter pad using a smoking machine. The filter pad was immersed in 40 mL of ammonium acetate (pH 6.8) and shaken for 30 min. The extract was then loaded into a C18 column. After washing with 5 mL of 10% methanol and eluting with 5 mL of 70% methanol, the eluate was concentrated to 1 mL for LC-MS/MS analysis. The concentrations of TSNAs in all cigarette brands were higher when determined using the HCI regime than when determined using the ISO regime. Furthermore, the concentrations of TSNAs measured using both the ISO and HCI regimes showed negligible correlation to the tar and nicotine concentrations indicated on package labels. The cigarette samples used in the study were categorized into four classes: ultralow-, low-, medium-, and high-yield brands, which corresponded to 1, 3-6, 8-10, and 14 mg tar/cigarette, respectively. The concentration of TSNAs in ultralow-yield cigarettes was 210 ng/cigarette, as measured using the HCI regime, which was nearly equal to that in high-yield cigarettes (180 ng/cigarette). Exposure to TSNAs from mainstream smoke from ultralow-yield cigarettes is comparable to that from high-yield cigarettes. To properly evaluate the risk of smoking, not only the concentrations of tar and nicotine but also those of other chemicals, including TSNAs, should be printed on package labels.


[Environmental effects on the course of active rheumatism in a migrant Siberian population].
To characterize antistreptococcal immune response in healthy subjects with cryoglobulinemia and rheumatic manifestations as well as a rheumatism course in population who came to Siberia to build and operate Baikal-Amur railway. Siberian migrants were examined. Among them there were 203 patients with rheumatic fever and rheumatic heart disease, and 1275 healthy subjects. 65 patients had active rheumatism, 106 healthy subjects had rheumatic manifestations and cryoglobulinemia with adaptation cryoglobulinemia syndrome. All the patients underwent examination of the cardiovascular system, standard laboratory tests and tests for antistreptolysine-0, antistreptokinase, antistreptohyaluronidase, streptococcal antigen, microbiological tests. The diagnosis of rheumatic fever was established on the basis of Kisel-Jones-Nesterov and revised Jones criteria. The adaptation cryoglobulinemia syndrome in healthy persons was associated with cardialgia, arthralgia, lumbalgia, myalgia, lymphadenopathy and Raynaud's phenomenon. Patients with rheumatic fever and adaptation cryoglobulinemia syndrome were predisposed to chronicity of primary rheumatic carditis, development of compound and combined valvular defects, arrhythmia and hemodynamic disturbances. The presence of the adaptation cryoglobulinemia syndrome aggravates the course of rheumatic fever and promotes its chronicity.


Continuous flow-through peritoneal dialysis (CFPD): comparison of efficiency to IPD, TPD, and CAPD in an animal model.
To determine whether continuous flow-through peritoneal dialysis (CFPD), a treatment schedule in which peritoneal dialysate is infused continuously into one part of the abdomen (over the liver) and is drained from a distant part of the abdomen (the pelvis), can provide greater clearance than continuous ambulatory peritoneal dialysis (CAPD), tidal peritoneal dialysis (TPD), or intermittent peritoneal dialysis (IPD). A prospective study comparing four schedules of peritoneal dialysis in the awake, normal dog, using glucose clearance as a substitute for urea clearance. We placed two chronic dialysis catheters into the abdomen of anesthetized dogs (with intraperitoneal portions of fluted or miniature column-disc design). On successive days, with the dogs awake and prone, we performed peritoneal dialysis for 4 hours with 1.5% dialysate according to one of four schedules, each with 2 L maximum intraperitoneal volume: CFPD (unidirectional flow at an average of 3.6 L/hr), IPD (2 L/hr), TPD (average of 3.6 L/hr, 1 L residual volume), and CAPD (2 L/4 hr). Glucose and urea clearances were calculated from blood and peritoneal concentrations and dialysate flow rates. Stabilized glucose clearances (from 60 to 240 minutes) averaged 11 +/- 5 mL/min for IPD, TPD, and CFPD, and 5 +/- 2 mL/min for CAPD. However, glucose clearances of CFPD were 13 +/- 6 mL/min when the intraperitoneal volume was maintained at 800-100 mL, and 16.5 +/- 6 mL/min when flow rate was 6 L/hr. Urea clearances were twice the measured glucose clearances. When CFPD is performed with an appropriate intraperitoneal volume and flow, it is the most chemically effective method of peritoneal dialysis in removing small molecules like urea.


[Experience of arterial hypertension in the patient-family relationship in a care context].
Objective To understand how the narrative and conversational experience of arterial hypertension is configured in the relationships established among patients, family members, physicians and researchers-auditors, placing the illness in a care context to facilitate the dissemination of wellbeing narratives. Method Qualitative research with reflective and contextual conversational-narrative design, which involveda patient diagnosed with hypertension, his family and two doctors. The methods of constructing information was semi structured interviews, reflective observation and literature review. The systematization of information was carried out using frameworks designed for that purpose. For the interpretation of results, narrative and conversational analyses were used. Results In the process of constructing the experience of hypertension by family members or the physician, important aspects are not taken into account such as: the listening request, a demand for bonding, the experience of illness and in this case, the daily experience of old age. In this context, these kinds of relationships can lead to discomfort and suffering in the patient's experience of the illness. The conversation generated by all stakeholders enables the construction of dialogic-reflexive spaces that provide an opportunity to reshape relationships and experience of illness Conclusions The construction of contexts of care where one can talk and hear about issues without families and doctors facilitates the reconfiguration of the experience of illness, allowing for the inclusion of family and physicians in the generation of conversational-narrative positions. This implies personal and collective agency in order to mobilize and organize the resources they have, consistent with the patient's age and diagnosis.


The Effect of Exercise on Neural Activation and Cognition: A Review of Task-Based fMRI Studies.
Numerous studies have stressed the importance of exercise in promoting physical and mental health and for aiding in cognition. Encouragingly, physical exercise has been shown to reduce the risk of developing Alzheimer's disease and to mitigate hemiparesis experienced by stroke patients. Additionally, today where over 1.9 billion are overweight, physical exercise is imperative to save lives and to mitigate the burden on the healthcare system. Although the benefits of physical exercise have been explored, the underlying mechanisms to enact these benefits have not been well-characterized. Here we review exercise-induced changes in regional brain activation and modulation. Paradigms differing in intensity, duration, and type of motor movement have been used to assess exercise effects on memory, cognition, and disease mitigation in youth and elderly populations. To evaluate exercise-induced changes in neural activity, the noninvasive imaging technique, functional magnetic resonance imaging (fMRI), is employed. fMRI is recorded either during or after exercise intervention. Post-exercise fMRI is often paired with in-bore tests of cognition to provide insight into the associated brain regions. Whereas, during intervention, fMRI is used to detail muscle-associated neural activation profiles. Characterization of the region and magnitude of brain activation has been used to perform comparative studies and identify specific characteristics from individuals with varying motor and cognitive abilities. Further fMRI and exercise research, with the use of these metrics, could facilitate the development of tools for disease diagnosis or to assess level of dysfunction or progression.


Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts.
Mouse myocyte contractility and the changes induced by pressure overload are not fully understood. We studied contractile reserve in isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) during compensatory hypertrophy (4-week AS) and the later stage of early failure (7-week AS) and from control mice. Myocyte contraction and [Ca(2+)](i) transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L [Ca(2+)](o), 25 degrees C), the amplitude of myocyte shortening and peak-systolic [Ca(2+)](i) in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of [Ca(2+)](i) transients were slower. In response to the challenge of high [Ca(2+)](o), fractional cell shortening was severely depressed with reduced peak-systolic [Ca(2+)](i) in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic [Ca(2+)](i) increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high [Ca(2+)](o) and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na(+)-Ca(2+) exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca(2+)-ATPase to phospholamban protein levels was depressed in 7-week AS compared with controls but not in 4-week AS. This was associated with an impaired capacity to increase sarcoplasmic reticulum Ca(2+) load during high work states in 7-week AS myocytes. In hypertrophied failing mouse myocytes, depressed contractile reserve is related to an impaired augmentation of systolic [Ca(2+)](i) and SR Ca(2+) load and simulates findings in human failing myocytes.


MEK inhibition suppresses metastatic progression of KRAS-mutated gastric cancer.
Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. To elucidate the mechanism underlying the oncogene-induced gastric tumor progression, we have developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRASG12V -expressing GAN-p53KO (GAN-KP) organoids were generated by genetic manipulation of GAN mouse-derived tumor (GAN wild-type [WT]) organoids. In contrast with GAN-WT and GAN-p53KO organoids, which manifested Wnt addiction, GAN-KP organoids showed a Wnt-independent phenotype and the ability to proliferate without formation of a Wnt-regulated three-dimensional epithelial architecture. After transplantation in syngeneic mouse stomach, GAN-p53KO cells formed only small tumors, whereas GAN-KP cells gave rise to invasive tumors associated with the development of hypoxia as well as to liver metastasis. Spatial transcriptomics analysis suggested that hypoxia signaling contributes to the metastatic progression of GAN-KP tumors. In particular, such analysis identified a cluster of stromal cells located at the tumor invasive front that expressed genes related to hypoxia signaling, angiogenesis, and cell migration. These cells were also positive for phosphorylated extracellular signal-regulated kinase (ERK), suggesting that mitogen-activated protein kinase (MAPK) signaling promotes development of both tumor and microenvironment. The MEK (MAPK kinase) inhibitor trametinib suppressed the development of GAN-KP gastric tumors, formation of a hypoxic microenvironment, tumor angiogenesis, and liver metastasis. Our findings therefore establish a rationale for application of trametinib to suppress metastatic progression of KRAS-mutated gastric cancer.


Mortality monitoring in Switzerland.
The Federal Statistical Office publishes weekly national and regional mortality reports online for Switzerland for the age groups 0 to <65 and 65+ years, which refer to deaths up to 9 days prior to the publication date. In addition to observed numbers of death events, expected numbers are reported, which allows detection of periods of excess mortality and its quantification. As with previous periods of excess mortality, in 2020 the monitoring detected and quantified excess mortality during the two waves of the SARS-CoV-2 epidemic in Switzerland. During the year, the epidemic resulted in well over 10% more deaths than expected, mainly in individuals aged 65 years and above. Because of the profound impact of the epidemic, interest in the weekly mortality publication and its underlying methodology increased sharply. From inquiries and from newspaper and tabloid publications on the matter it became abundantly evident that the principles of the mortality monitoring were not well understood in general; mortality monitoring was even regularly confused with cause of death statistics. The present article therefore aims at elucidating the methodology of national mortality monitoring in Switzerland and at putting it into its public health context.


Hyperuricemia and metabolic syndrome: lessons from a large cohort from Israel.
There is a striking increase in the number of people with metabolic syndrome (MetS) as a result of the global epidemic of obesity and diabetes. Increasing evidence suggests that uric acid may play a role in MetS. To assess the prevalence of MetS in a large cohort from Israel and its association with hyperuricemia using the latest three definitions of MetS. We conducted a retrospective analysis of the database from a screening center in Israel, using the revised National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), the International Diabetes Federation (IDF) and the Harmonizing definitions of MetS, to assess 12,036 subjects with an age range of 20-80 years. The mean age of the study sample was 46.1 +/- 10.2 years and 69.8% were male. The prevalence of MetS was 10.6%, 18.2% and 20.2% in the revised NCEP ATP III, the IDF and the Harmonizing definitions respectively. The prevalence of hyperuricemia in subjects with MetS, for all three MetS definitions, was similar: 20.0%, 19.9% and 19.1% respectively. There was a graded increase in the prevalence of MetS among subjects with increasing levels of uric acid. The increasing trend persisted after stratifying for age and gender and after multivariate analysis (P for trend (0.001). This large cohort shows a high prevalence of MetS in Israel, but is still lower than the prevalence in western countries. Hyperuricemia is common in those subjects and might be considered a potential clinical parameter in the definition of MetS.


[Occupational asthma in a teacher after repeated exposure to tear gas].
Acute exposure to tear gas causes generally reversible cutaneous and mucosal irritations. Lasting respiratory manifestations after exposure are exceptional. We report the case of a 26-year-old female teacher with no history of respiratory disease who developed asthma after repeated exposure to tear gas discharged in her class room. The disorders occurring during these repeated exposures to the irritating gas were consistent with the recently described low level reactive airway dysfunction syndrome (low level RADS).


[Effect of the hydrophobin HFBI-fusion tag on exogenous protein accumulation in tobacco plant].
To explore the mechanisms by which HFBI fusions increase recombinant fusion protein accumulation in plants. The HFBI sequence from Trichoderma reesei was synthesized and two plant expression vectors for expression of green fluorescence protein (GFP) and GFP-HFBI were constructed. The vectors were inoculated in Nicotiana benthamiana plants through agroinfiltration, and the expression levels and mRNA accumulation levels of GFP in Nicotiana leaves were examined by Western blotting, ELISA and RT-PCR. The HFBI fusion tag significantly enhanced the accumulation of GFP in the leaves of N. benthamiana without causing toxic effects. Endoplasmic reticulum-targeted GFP-HFBI fusion induced the formation of spherical protein particles in the plant cells. HFBI fusions can increase the accumulation of its fusion partner in plants by forming stable protein particles, which probably shields the target protein from endogenous protease-induced degadation. HFBI fusion technology provides an alternative to improving recombinant protein expression in plants from agroinfection-compatible expression vectors.


The response of nutrient assimilation and biochemical composition of Arctic seaweeds to a nutrient input in summer.
Twenty-one species of macroalgae (four Chlorophyta, eight Rhodophyta, and nine Phaeophyta) from the Kongsfjord (Norwegian Arctic) were examined for their response to nutrient enrichment (nitrate and phosphate) in the summer period. The enzymatic activities related to nutrient assimilation, external carbonic anhydrase (CAext, EC 188.8.131.52), nitrate reductase (NR, EC 184.108.40.206), and alkaline phosphatase (AP, EC 18.104.22.168), as well as the biochemical composition (total C and N, soluble carbohydrates, soluble proteins, and pigments) were measured. CAext activity was present in all species, and showed a general decrease after nutrient enrichment. Inversely, NR activity increased in most of the species examined. Changes in pigment ratios pointed to the implication of light harvesting system in the acclimation strategy. Despite enzymatic and pigmentary response, the Arctic seaweeds can be regarded as not being N-limited even in summer, as shown by the slight effect of nutrient enrichment on biochemical composition. The exception being the nitrophilic species Monostroma arcticum and, to a lesser extent, Acrosiphonia sp. For the rest of the species studied, changes in total internal C and N, soluble proteins, soluble carbohydrates, pigment content, and the internal pool of inorganic N were recorded only for particular species and no general pattern was shown. Acclimation to unexpected nutrient input seemed to ensure the maintenance of a stable biomass composition, rather than an optimized use of the newly available resource (except for the nitrophilic species). This indicates a high degree of resilience of the algal community to a disruption in the natural nutrient availability pattern.