Seizures following surgery for supratentorial extratemporal low-grade tumors in children: a multicenter retrospective study.
Resection of brain tumors may lead to new-onset seizures but may also reduce seizure rates in patients presenting with seizures. Seizures are seen at presentation in about 24% of patients with brain tumors. For lesional epilepsy in general, early resection is associated with improved seizure control. However, the literature is limited regarding the occurrence of new-onset postoperative seizures, or rates of seizure control in those presenting with seizures, following resections of extratemporal low-grade gliomas (LGGs) in children. Data were collected retrospectively from 4 large tertiary centers for children (< 18 years of age) who underwent resection of a supratentorial extratemporal (STET) LGG. The patients were divided into 4 groups based on preoperative seizure history: no seizures, up to 2 seizures, more than 2 seizures, and uncontrolled or refractory epilepsy. The authors analyzed the postoperative occurrence of seizures and the need for antiepileptic drugs (AEDs) over time for the various subgroups. The study included 98 children. Thirty patients had no preoperative seizures, 18 had up to 2, 16 had more than 2, and 34 had refractory or uncontrolled epilepsy. The risk for future seizures was higher if the patient had seizures within 1 month of surgery. The risk for new-onset seizures among patients with no seizures prior to surgery was low. The rate of seizures decreased over time for children with uncontrolled or refractory seizures. The need for AEDs was higher in the more active preoperative seizure groups; however, it decreased with time. The resection of STET LGGs in children is associated with a low rate of postoperative new-onset epilepsy. For children with preoperative seizures, even with uncontrolled epilepsy, most have a significant improvement in the seizure activity, and many may be weaned off their AEDs.


Spatial patterning of metabolism by mitochondria, oxygen, and energy sinks in a model cytoplasm.
Metabolite gradients might guide mitochondrial localization in cells and angiogenesis in tissues. It is unclear whether they can exist in single cells, because the length scale of most cells is small compared to the expected diffusion times of metabolites. For investigation of metabolic gradients, we need experimental systems in which spatial patterns of metabolism can be systematically measured and manipulated. We used concentrated cytoplasmic extracts from Xenopus eggs as a model cytoplasm, and visualized metabolic gradients formed in response to spatial stimuli. Restriction of oxygen supply to the edge of a drop mimicked distance to the surface of a single cell, or distance from a blood vessel in tissue. We imaged a step-like increase of Nicotinamide adenine dinucleotide (NAD) reduction approximately 600 microm distant from the oxygen source. This oxic-anoxic switch was preceded on the oxic side by a gradual rise of mitochondrial transmembrane potential (Deltapsi) and reactive oxygen species (ROS) production, extending over approximately 600 microm and approximately 300 microm, respectively. Addition of Adenosine triphosphate (ATP)-consuming beads mimicked local energy sinks in the cell. We imaged Deltapsi gradients with a decay length of approximately 50-300 microm around these beads, in the first visualization of an energy demand signaling gradient. Our study demonstrates that mitochondria can pattern the cytoplasm over length scales that are suited to convey morphogenetic information in large cells and tissues and provides a versatile model system for probing of the formation and function of metabolic gradients.


Association between hypertension and retinal vascular features in ultra-widefield fundus imaging.
Changes to the retinal vasculature are known to be associated with hypertension independently of traditional risk factors. We investigated whether measurements of retinal vascular calibre from ultra-widefield fundus imaging were associated with hypertensive status. We retrospectively collected and semiautomatically measured ultra-widefield retinal fundus images from a subset of participants enrolled in an ongoing population study of ageing, categorised as normotensive or hypertensive according to thresholds on systolic/diastolic blood pressure (140/90 mm Hg) measured in a clinical setting. Vascular calibre in the peripheral retina was measured to calculate the nasal-annular arteriole:venule ratio (NA-AVR), a novel combined parameter. Left and right eyes were analysed from 440 participants (aged 50-59 years, mean age of 54.6±2.9 years, 247, 56.1% women), including 151 (34.3%) categorised as hypertensive. Arterioles were thinner and the NA-AVR was smaller in people with hypertension. The area under the receiver operating characteristic curve of NA-AVR for hypertensive status was 0.73 (95% CI 0.68 to 0.78) using measurements from left eyes, while for right eyes, it was 0.64 (95% CI 0.59 to 0.70), representing evidence of a statistically significant difference between the eyes (p=0.020). Semiautomated measurements of NA-AVR in ultra-widefield fundus imaging were associated with hypertension. With further development, this may help screen people attending routine eye health check-ups for high blood pressure. These individuals may then follow a care pathway for suspected hypertension. Our results showed differences between left and right eyes, highlighting the importance of investigating both eyes of a patient.


Strong Photocurrent Amplification in Perovskite Solar Cells with a Porous TiO2 Blocking Layer under Reverse Bias.
We investigate two different types of TiO2 blocking layer (BL) deposition techniques commonly used in solid-state methylammonium lead triiodide perovskite (MaPbI3)-based solar cells. Although these BLs lead to similar photovoltaic device performance, their structure and blocking capability is actually very different. In one case, the "blocking" layer is porous, allowing an intimate contact of the perovskite with the fluorine-doped tin-dioxide (FTO)-covered glass substrate serving as transparent electron collector. This interface between the perovskite and the FTO shows rectifying behavior. Reverse biasing of such a solar cell allows the determination of the valence-band position of the MaPbI3 and the theoretical maximum attainable photovoltage. We show that under reverse bias strong photocurrent amplification is observed, permitting the cell to work as a high-gain photodetector at low voltage. Without BL, the solar-cell performance decreased, but the photocurrent amplification increased. At 1 V reverse bias, the photocurrent amplification is above a factor of 10 for AM 1.5 solar light and over 100 for lower light intensities.


Use of recombinant activated Factor VII for refractory after lung transplant bleeding as an effective strategy to restrict blood transfusion and associated complications.
Recombinant activated factor VIIa (rFVIIa) has been increasingly used to stop massive bleeding after cardiothoracic surgical procedures. However, the risk : benefit profile of such a potent hemostatic agent remains unclear in the postsurgical patient, and the cost benefit is even less clear. In patients after lung transplantation, volume of blood transfused is of major concern, and all attempts are made to minimize large blood transfusions in this cohort. We report our experience with rFVIIa in patients with refractory bleeding after lung transplant surgery. All lung transplant patients who underwent single- or double-lung transplantation who received rFVIIa in the 5-year period, from January 2005 to June 2011, were included. A total of 15 patients were identified from a total of 95 lung transplant cases operated during this study period. Patient demographics, intra- and postoperative records were reviewed to assess the efficacy and safety of rFVIIa treatment. Patients with major bleeding treated with rFVIIa showed improved hemostasis with rapid normalization of coagulation variables. rFVIIa treatment was not associated with an increase in mechanical ventilation time, length of intensive care unit stay, or hospital stay compared to other lung transplant patients. In addition, the use of rFVIIa was associated with reduction in transfusion requirements of red blood cells, fresh-frozen plasma, and platelets (all p < 0.001). No definite thromboembolic-related event was recorded in our cohort. These data demonstrate that rFVIIa was associated with reduced blood loss, improvement of coagulation variables, and decreased need for transfusions. This reduction in losses led to a reduced requirement for blood transfusion, which may translate to a decrease in transfusion-related complications. Further investigation is needed to determine rFVIIa's safety and its efficacy in improving postoperative morbidity and mortality specifically in the field of post-lung transplantation surgery.


Complete mitochondrial genome of the Pigeye Shark Carcharhinus amboinensis (Carcharhiniformes: Carcharhinidae).
In this manuscript we describe the first complete mitochondrial sequence for the Data Deficient Pigeye Shark Carcharhinus amboinensis. The mitogenome is 16,704 bp long and consists of 1 control region, 2 rRNA genes, 22 tRNA genes and 13 protein-coding genes with an overall base composition of 31.6% A, 24.9% C, 13.1% G and 30.4% T. The gene arrangement pattern and transcriptional direction were typical for a vertebrate species. The tRNA-Ser2 lacks the dihydrouridine arm and forms a simple loop, therefore it cannot be folded into the typical cloverleaf secondary structures like other tRNAs.


Serotonin and poor neonatal adaptation after antidepressant exposure in utero.
Infants exposed to selective antidepressants (SADs) in utero are at risk to develop poor neonatal adaptation (PNA) postpartum. As symptoms are non-specific and the aetiology of PNA is unknown, the diagnostic process is hampered. We hypothesised that the serotonin metabolism plays a role in the aetiology of PNA. In this controlled study, infants admitted postpartum from February 2012 to August 2013 were included and followed for 3 days. Infants exposed to SADs during at least the last 2 weeks of fetal life were included in the patient group (n=63). Infants not exposed to psychotropic medication and admitted postpartum for another reason were included in the control group (n=126). The neonatal urinary 5-hydroxyindoleacetid acid (5-HIAA) levels of SAD-exposed infants who developed PNA, SAD-exposed infants who did not develop PNA and control infants were compared. The course of the 5-HIAA levels over the first 3 days postpartum differed between infants with and without PNA (p≤0.001) with higher 5-HIAA levels in infants with PNA on day 1 (2.42 mmol/mol, p=0.001). Presence of maternal psychological distress modified this relationship. A transient disturbance of the neonatal serotonergic system may play a role in the aetiology of PNA. Other factors, including the presence of maternal psychological distress, also seem to play a role.


Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: a post hoc analysis of pooled data from short- and long-term aripiprazole trials.
The objective of this article is to assess the clinical characteristics of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder receiving aripiprazole, haloperidol, olanzapine, or placebo. We conducted post hoc analyses of pooled safety data from trials in patients with schizophrenia, schizoaffective disorder, and bipolar I disorder. Outcome measures included the incidence of akathisia, time to onset, duration, severity, and discontinuation due to akathisia, concomitant use of benzodiazepines and/or anticholinergics, Barnes Akathisia Rating Scale (BARS) scores, and the correlation between antipsychotic efficacy and akathisia. The results for schizophrenia and schizoaffective disorder were as follows: akathisia in 9% of aripiprazole- and 6% of placebo-treated patients; 12.5% of aripiprazole- versus 24% of haloperidol-treated patients; 11% of aripiprazole- versus 6% of olanzapine-treated patients. Bipolar I disorder: akathisia in 18% of aripiprazole- and 5% of placebo-treated patients. The clinical characteristics of akathisia were similar between each data set, regardless of disease. Akathisia was generally mild-to-moderate in severity. Discontinuation due to akathisia was low in both the schizophrenia trials (aripiprazole 0.3%; placebo 0%; aripiprazole 0.9%; haloperidol 2.3%; aripiprazole 1.2%; olanzapine 0.2%) and the bipolar trials (aripiprazole 2.3%; placebo 0%). Treatment-emergent akathisia was not associated with a poorer clinical response. In conclusion, akathisia with aripiprazole occurred early in treatment, was mild-to-moderate in severity, led to few study discontinuations, and did not compromise therapeutic efficacy.


Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.
Only a minority of patients with type 1 diabetes develop diabetic nephropathy (DN). Poor glycemic control cannot fully explain DN risk, and family studies suggest genetic susceptibility factors. To understand familial DN concordance, we evaluated glomerular structure in families with type 1 diabetic sibling pairs. Kidney function and biopsy studies were performed in 21 probands (P) (first to develop diabetes) and 21 siblings (S) (second to develop diabetes), most with normal urinary albumin excretion rates (UAER). Glomerular structure was measured by morphometry. Intrafamilial correlation was estimated by one-way random-effects ANOVA and by mixed-effects ANOVA, adjusting for age and duration of diabetes. Diabetes duration was, by definition, longer in P than in S, while age and sex were similar. HbA1c over 5 years and blood pressure were not different in P and S and were without familial effect. UAER was greater in P than in S (P < 0.05), with strong familial effect (P = 0.03). A strong concordance among siblings for mesangial fractional volume (P < or = 0.01) remained significant after adjustment for diabetes duration and age (P = 0.04). Results were similar for mesangial cell (P = 0.01; adjusted P = 0.04) and mesangial matrix fractional volumes (P < 0.01; adjusted P = 0.06). There was also clustering of the patterns of glomerular lesions. For example, if P had relatively marked glomerular basement membrane thickening compared with mesangial matrix expansion, S had a similar pattern (chi2, P < 0.025). Strong concordance in severity and patterns of glomerular lesions in type 1 diabetic siblings, despite lack of concordance in glycemia, supports an important role for genetic factors in DN risk.


Production and possible function of serine protease during sporulation of Bacillus subtilis.
The production of extracellular protease during sporulation in Bacillus subtilis 168 was investigated. Two proteases are produced, an alkaline serine protease and a neutral metalloprotease. In vivo inhibition of the serine protease with phenylmethylsulfonylfluoride indicated that the metalloprotease was degraded by the serine protease during sporulation. The experiments with phenylmethylsulfonylfluoride also show that the serine protease is necessary for the sequential process of sporulation and that it is required continuously for the first 2 to 3 h of the 8-h process.


Insights into distinct regulatory modes of nucleosome positioning.
The nucleosome is the fundamental unit of eukaryotic genomes. Experimental evidence suggests that the genomic DNA sequence and a variety of protein factors contribute to nucleosome positioning in vivo. However, how nucleosome positioning is determined locally is still largely unknown. We found that transcription factor binding sites (TFBSs) with particular nucleosomal contexts show a preference to reside on specific chromosomes. We identified four typical gene classes associated with distinct regulatory modes of nucleosome positioning, and further showed that they are distinguished by transcriptional regulation patterns. The first mode involves the cooperativity between chromatin remodeling and stable transcription factor (TF)-DNA binding that is linked to high intrinsic DNA binding affinities, evicting nucleosomes from favorable DNA sequences. The second is the DNA-encoded low nucleosome occupancy that is associated with high gene activity. The third is through chromatin remodeling and histone acetylation, sliding nucleosomes along DNA. This mode is linked to more cryptic sites for TF binding. The last consists of the nucleosome-enriched organization driven by other factors that overrides nucleosome sequence preferences. In addition, we showed that high polymerase II (Pol II) occupancy is associated with high nucleosome occupancy around the transcription start site (TSS). We identified four different regulatory modes of nucleosome positioning and gave insights into mechanisms that specify promoter nucleosome location. We suggest two distinct modes of recruitment of Pol II, which are selectively employed by different genes.


Nicotine Directly Induces Endoplasmic Reticulum Stress Response in Rat Placental Trophoblast Giant Cells.
Nicotine exposure during pregnancy leads to placental insufficiency impairing both fetal and neonatal development. Previous studies from our laboratory have demonstrated that in rats, nicotine augmented endoplasmic reticulum (ER) stress in association with placental insufficiency; however, the underlying mechanisms remain elusive. Therefore, we sought to investigate the possible direct effect of nicotine on ER stress in Rcho-1 rat placental trophoblast giant (TG) cells during differentiation. Protein and/or mRNA expression of markers involved in ER stress (eg, phosphorylated PERK, eIF2α, CHOP, and BiP/GRP78) and TG cell differentiation and function (eg, Pl-1, placental growth factor [Pgf], Hsd11b1, and Hsd11b2) were quantified via Western blot or real-time polymerase chain reaction. Nicotine treatment led to dose-dependent increases in the phosphorylation of PERK[Thr981] and eIF2α[Ser51], whereas pretreatment with a nicotinic acetylcholine receptor (nAChR) antagonist (mecamylamine hydrochloride) blocked the induction of PERK phosphorylation, verifying the direct involvement of nicotine and nAChR binding. We next investigated select target genes known to play essential roles in placental TG cell differentiation and function (Pl-1, Pgf, Hsd11b1, and Hsd11b2), and found that nicotine significantly augmented the mRNA levels of Hsd11b1 in a dose-dependent manner. Furthermore, using tauroursodeoxycholic acid, a safe bile acid known to improve protein chaperoning and folding, we were able to prevent nicotine-induced increases in both PERK phosphorylation and Hsd11b1 mRNA levels, revealing a potential novel therapeutic approach to reverse the deleterious effects of nicotine exposure in pregnancy. Collectively, these results implicate that nicotine, acting through its receptor, can directly augment ER stress and impair placental function.


Photoperiod regulates lean mass accretion, but not adiposity, in growing F344 rats fed a high fat diet.
In this study the effects of photoperiod and diet, and their interaction, were examined for their effects on growth and body composition in juvenile F344 rats over a 4-week period. On long (16L:8D), relative to short (8L:16D), photoperiod food intake and growth rate were increased, but percentage adiposity remained constant (ca 3-4%). On a high fat diet (HFD), containing 22.8% fat (45% energy as fat), food intake was reduced, but energy intake increased on both photoperiods. This led to a small increase in adiposity (up to 10%) without overt change in body weight. These changes were also reflected in plasma leptin and lipid levels. Importantly while both lean and adipose tissue were strongly regulated by photoperiod on a chow diet, this regulation was lost for adipose, but not lean tissue, on HFD. This implies that a primary effect of photoperiod is the regulation of growth and lean mass accretion. Consistent with this both hypothalamic GHRH gene expression and serum IGF-1 levels were photoperiod dependent. As for other animals and humans, there was evidence of central hyposomatotropism in response to obesity, as GHRH gene expression was suppressed by the HFD. Gene expression of hypothalamic AgRP and CRH, but not NPY nor POMC, accorded with the energy balance status on long and short photoperiod. However, there was a general dissociation between plasma leptin levels and expression of these hypothalamic energy balance genes. Similarly there was no interaction between the HFD and photoperiod at the level of the genes involved in thyroid hormone metabolism (Dio2, Dio3, TSHβ or NMU), which are important mediators of the photoperiodic response. These data suggest that photoperiod and HFD influence body weight and body composition through independent mechanisms but in each case the role of the hypothalamic energy balance genes is not predictable based on their known function.


The Schizosaccharomyces pombe corepressor Tup11 interacts with the iron-responsive transcription factor Fep1.
The Schizosaccharomyces pombe fep1(+) gene encodes a GATA transcription factor that represses the expression of iron transport genes in response to elevated iron concentrations. This transcriptional response is altered only in strains harboring a combined deletion of both tup11(+) and tup12(+) genes. This suggests that Tup11 is capable of negatively regulating iron transport gene expression in the absence of Tup12 and vice versa. The tup11(+)- and tup12(+)-encoded proteins resemble the Saccharomyces cerevisiae Tup1 corepressor. Using yeast two-hybrid analysis we show that Tup11 and Fep1 physically interact with each other. The C-terminal region from amino acids 242 to 564 of Fep1 is required for interaction with Tup11. Within this region, a minimal domain encompassing amino acids 405-541 was sufficient for Tup11-Fep1 association. Deletion mapping analysis revealed that the WD40-repeat sequence motifs of Tup11 are necessary for its interaction with Fep1. Analysis of Tup11 mutants with single amino acid substitutions in the WD40 repeats suggested that the Fep1 transcription factor interacts with a putative flat upper surface on the predicted beta-propeller structure of this motif. Further analysis by in vivo coimmunoprecipitation showed that Tup11 and Fep1 are physically associated. In vitro pull-down experiments further verified a direct interaction between the Fep1 C terminus and the Tup11 C-terminal WD40 repeat domain. Taken together, these results describe the first example of a physical interaction between a corepressor and an iron-sensing factor controlling the expression of iron uptake genes.


Molecular and cellular characterization of the biological effects of ruthenium(II) complexes incorporating 2-pyridyl-2-pyrimidine-4-carboxylic acid.
A great majority of the Ru complexes currently studied in anticancer research exert their antiproliferative activity, at least partially, through ligand exchange. In recent years, however, coordinatively saturated and substitutionally inert polypyridyl Ru(II) compounds have emerged as potential anticancer drug candidates. In this work, we present the synthesis and detailed characterization of two novel inert Ru(II) complexes, namely, [Ru(bipy)(2)(Cpp-NH-Hex-COOH)](2+) (2) and [Ru(dppz)(2)(CppH)](2+) (3) (bipy = 2,2'-bipyridine; CppH = 2-(2'-pyridyl)pyrimidine-4-carboxylic acid; Cpp-NH-Hex-COOH = 6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoic acid; dppz = dipyrido[3,2-a:2',3'-c]phenazine). 3 is of particular interest as it was found to have IC(50) values comparable to cisplatin, a benchmark standard in the field, on three cancer cell lines and a better activity on one cisplatin-resistant cell line than cisplatin itself. The mechanism of action of 3 was then investigated in detail and it could be demonstrated that, although 3 binds to calf-thymus DNA by intercalation, the biological effects that it induces did not involve a nuclear DNA related mode of action. On the contrary, confocal microscopy colocalization studies in HeLa cells showed that 3 specifically targeted mitochondria. This was further correlated by ruthenium quantification using High-resolution atomic absorption spectrometry. Furthermore, as determined by two independent assays, 3 induced apoptosis at a relatively late stage of treatment. The generation of reactive oxygen species could be excluded as the cause of the observed cytotoxicity. It was demonstrated that the mitochondrial membrane potential in HeLa was impaired by 3 as early as 2 h after its introduction and even more with increasing time.


Serum Total Bilirubin, not Cholelithiasis, is Influenced by UGT1A1 Polymorphism, Alpha Thalassemia and β(s) Haplotype: First Report on Comparison between Arab-Indian and African β(s) Genes.
We explored the potential relationship between steady state serum bilirubin levels and the incidence of cholelithiasis in the context of UGT1A1 gene A(TA)nTAA promoter polymorphism in Omani sickle cell anemia (SCA) patients, homozygotes for African (Benin and Bantu) and Arab-Indian β(S) haplotypes, but sharing the same microgeographical environment and comparable life style factors. 136 SCA patients were retrospectively studied in whom imaging data including abdominal CT scan, MRI or Ultrasonography were routinely available. Available data on the mean steady state hematological/biochemical parameters (n=136), β(s) haplotypes(n=136), α globin gene status (n=105) and UGT1A1 genotypes (n=133) were reviewed from the respective medical records. The mean serum total bilirubin level was significantly higher in the homozygous UGT1A1(AT)7 group as compared to UGT1A1(AT)6 group. Thus, not cholelithiasis but total serum bilirubin was influenced by UGT1A1 polymorphism in this SCA cohort. As observed in other population groups, the UGT1A1 (AT)7 homozygosity was significantly associated with raised serum total bilirubin level, but the prevalence of gallstones in the Omani SCA patients was not associated with α thalassaemia, UGT1A1 polymorphism, or β(s) haplotypes.


Prevalence and risk factors of feline leukaemia virus and feline immunodeficiency virus in peninsular Malaysia.
Feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) are major causes of morbidity and mortality in domestic and wild felids. Despite the clinical importance of feline retroviruses and the growing interest in cats as pets, information about FeLV and FIV in Malaysia is presently insufficient to properly advise veterinarians and pet owners. A cross-sectional study was carried out from January 2010 to December 2010 to determine the prevalence and risk factors associated with FeLV and FIV among domestic cats in peninsular Malaysia. Plasma samples were harvested from the blood of 368 domestic cats and screened for evidence of FeLV p27 antigen and FIV antibodies, using an immunochromatographic kit. Additionally, data on cat demographics and health were collected using a structured questionnaire, and were evaluated as potential risk factors for FeLV or FIV status. Of the 368 cats that were evaluated in this study, 12.2% (45/368; 95% CI = 8.88 - 15.58) were positive for FeLV p27 antigen, 31.3%, (115/368; 95% CI = 26.51 - 35.99) were seropositive to FIV antibodies, and 4.3% (16/368; 95% CI = 2.27 - 6.43) had evidence of both viruses. Factors found to significantly increase the risk for FeLV seropositivity include sex, age, behaviour, sickness, and living in a multi-cat household. Seropositive response to FIV was significantly associated with sex, neuter status, age, behaviour, and health status. The present study indicates that FeLV and FIV are common among domestic cats in peninsular Malaysia, and that factors related to cat demographics and health such as age, sex, behaviour, health status and type of household are important predictors for seropositive status to FeLV or FIV in peninsular Malaysia. High prevalence of FeLV or FIV observed in our study is of concern, in view of the immunosuppressive potentials of the two pathogens. Specific measures for control and prevention such as screening and routine vaccination are needed to ensure that FeLV and FIV are controlled in the cat population of peninsular Malaysia.


The dynamics of sperm cooperation in a competitive environment.
Sperm cooperation has evolved in a variety of taxa and is often considered a response to sperm competition, yet the benefit of this form of collective movement remains unclear. Here, we use fine-scale imaging and a minimal mathematical model to study sperm aggregation in the rodent genus Peromyscus. We demonstrate that as the number of sperm cells in an aggregate increase, the group moves with more persistent linearity but without increasing speed. This benefit, however, is offset in larger aggregates as the geometry of the group forces sperm to swim against one another. The result is a non-monotonic relationship between aggregate size and average velocity with both a theoretically predicted and empirically observed optimum of six to seven sperm per aggregate. To understand the role of sexual selection in driving these sperm group dynamics, we compared two sister-species with divergent mating systems. We find that sperm of Peromyscus maniculatus (highly promiscuous), which have evolved under intense competition, form optimal-sized aggregates more often than sperm of Peromyscus polionotus (strictly monogamous), which lack competition. Our combined mathematical and experimental study of coordinated sperm movement reveals the importance of geometry, motion and group size on sperm velocity and suggests how these physical variables interact with evolutionary selective pressures to regulate cooperation in competitive environments.


Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.
The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists of two parallel beta-sheets of Alzheimer Amyloid-beta 16-22 peptides (Ac-K(16)-L(17)-V(18)-F(19)-F(20)-A(21)-E(22)-NH2). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residues (L(17), F(19), A(21)), with the two charged residues (K(16), E(22)) pointing to the solvent. Our simulations reveal a subtle interplay between a water mediated assembly and one driven by favorable energetic interactions between specific residues forming the interior of the protofilament. A dewetting transition, in which water expulsion precedes hydrophobic collapse, is observed for some, but not all molecular dynamics trajectories. In the trajectories in which no dewetting is observed, water expulsion and hydrophobic collapse occur simultaneously, with protofilament assembly driven by direct interactions between the hydrophobic side chains of the peptides (particularly between F-F residues). For those same trajectories, a small increase in the temperature of the simulation (on the order of 20 K) or a modest reduction in the peptide-water van der Waals attraction (on the order of 10%) is sufficient to induce a dewetting transition, suggesting that the existence of a dewetting transition in simulation might be sensitive to the details of the force field parametrization.


A novel method to assess initial sensitivity and acute functional tolerance to hypnotic effects of ethanol.
Loss of righting reflex (LRR) has traditionally been used to estimate hypnotic sensitivity to ethanol in rodents. Traditional methods of monitoring ethanol-induced sedation seems to lack accuracy in estimating blood ethanol concentration (BEC) at initial LRR, a measure of initial sensitivity. Herein, we present a novel method that improves detection of the onset of LRR by using a new apparatus and a loss-of-function criterion of 5 s. DBA/2J and C57BL/6J mice were placed in cylindrical restrainers after injection of 3 g/kg (20% v/v) ethanol. Restrainers were then turned until mice were no longer able to right themselves within 5 s from a position on their back, which represented the endpoint of the initial loss of righting reflex. Initial sensitivity and acute functional tolerance (AFT) to ethanol were assessed in the same group of mice by quantifying BEC at the initial loss and subsequent recoveries of righting reflex over four sequential injections [3 g/kg + (3 x 0.5 g/kg)]. Initial brain sensitivity was calculated from BEC at the first LRR, using the parameters of ethanol uptake kinetics. These values of initial sensitivity were similar for the two strains. On the other hand, DBA/2J mice recovered at higher BEC than C57BL/6J animals. AFT calculated as a difference between the maximum BEC at any recovery and the value of initial sensitivity was greater in DBA/2J mice. These results show that the novel method is a sensitive tool for the measurement of initial sensitivity and detection of AFT to the hypnotic effects of ethanol.


Effect of Antiadhesion Barrier Solution and Fibrin on Capsular Formation After Silicone Implant Insertion in a White Rat Model.
One of the most serious complications of breast reconstruction and augmentation using silicone implants is capsular contracture. Several preventive treatments, including vitamin E, steroids, antibiotics, and cysteinyl leukotriene inhibitors, have been studied, and their clinical effects have been reported. However, the problem of capsular contracture has not yet been completely resolved. This study was performed to compare anti-adhesion barrier solution (AABS) and fibrin in their ability to prevent fibrotic capsule formation and simultaneously evaluated their effect when used in combination by capsular thickness analysis and quantitative analysis of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and type I collagen within the fibrous capsule. This study used female six-week-old Sprague-Dawley rats. Eighty rats were equally subdivided into the four following groups: AABS-treated, fibrin-treated, AABS and fibrin combined-treated, and untreated control groups. Each rat received two silicone chips under the panniculus carnosus muscle layer. The test materials were applied around the silicon chips. Four weeks later, the implantation sites including the skin and muscle were excised to avoid the risk of losing the fibrous capsule around the implants. The capsular thickness was analyzed by Masson's trichrome stain. Quantitative analysis of type I collagen, MMPs, and TIMPs was performed by real-time PCR, Western blot, and zymography. The mean capsular thickness was 668.10 ± 275.12 μm in the control group, 356.97 ± 112.11 μm in the AABS-treated group, 525.96 ± 130.97 μm in the fibrin-treated group, and 389.24 ± 130.51 μm in the AABS and fibrin combined-treated group. Capsular thickness was significantly decreased in all experimental groups (p < 0.05). Capsular thickness was greater in the fibrin-treated group than in the AABS-treated group (p < 0.05). There was no statistically significant difference in capsular thickness between the AABS and fibrin combined-treated group and the AABS- or fibrin-treated group (p > 0.05). Compared to the control group, the experimental groups had significantly lower expressions of type I collagen and MMP-1 (p < 0.05), but there was no statistically significant difference in expressions of type I collagen and MMP-1 between the AABS-, fibrin-, and AABS and fibrin combined-treated groups (p > 0.05). The expressions of MMP-2 and TIMP-2 were not significantly different between the control and the experimental groups (p > 0.05). AABS is more effective in reducing capsular thickness compared with fibrin treatment in a white rat model.


The frequency of early-activated hapten-specific B cell subsets predicts the efficacy of vaccines for nicotine dependence.
Therapeutic vaccines for nicotine addiction show pre-clinical efficacy. Yet, clinical evaluation of the first-generation nicotine vaccines did not meet expectations because only a subset of immunized subjects achieved effective serum antibody levels. Recent studies suggest that vaccine design affects B cell activation, and that the frequency of the hapten-specific B cell subsets contributes to vaccine efficacy against drugs of abuse. To extend this hypothesis to nicotine immunogens, we synthesized a novel hapten containing a carboxymethylureido group at the 2-position of the nicotine structure (2CMUNic) and compared its efficacy to the previously characterized 6CMUNic hapten. Haptens were conjugated to the keyhole limpet hemocyanin (KLH) carrier protein, and evaluated for efficacy against nicotine in mice using the clinically approved alum adjuvant. Using a novel fluorescent antigen-based magnetic enrichment strategy paired with multicolor flow cytometry analysis, polyclonal hapten-specific B cell subsets were measured in mice immunized with either 6CMUNic-KLH or 2CMUNic-KLH. The 6CMUNic-KLH showed significantly greater efficacy than 2CMUNic-KLH on nicotine distribution to serum and to the brain. The 6CMUNic-KLH elicited higher anti-nicotine serum antibody titers, and greater expansion of hapten-specific B cells than 2CMUNic-KLH. Within the splenic polyclonal B cell population, a higher number of hapten-specific IgM(high) and germinal centre B cells predicted greater vaccine efficacy against nicotine distribution. These early pre-clinical findings suggest that hapten structure affects activation of B cells, and that variations in the frequency of early-activated hapten-specific B cell subsets underlie individual differences in vaccine efficacy.


Determining Chronic Disease Prevalence in Local Populations Using Emergency Department Surveillance.
We sought to improve public health surveillance by using a geographic analysis of emergency department (ED) visits to determine local chronic disease prevalence. Using an all-payer administrative database, we determined the proportion of unique ED patients with diabetes, hypertension, or asthma. We compared these rates to those determined by the New York City Community Health Survey. For diabetes prevalence, we also analyzed the fidelity of longitudinal estimates using logistic regression and determined disease burden within census tracts using geocoded addresses. We identified 4.4 million unique New York City adults visiting an ED between 2009 and 2012. When we compared our emergency sample to survey data, rates of neighborhood diabetes, hypertension, and asthma prevalence were similar (correlation coefficient = 0.86, 0.88, and 0.77, respectively). In addition, our method demonstrated less year-to-year scatter and identified significant variation of disease burden within neighborhoods among census tracts. Our method for determining chronic disease prevalence correlates with a validated health survey and may have higher reliability over time and greater granularity at a local level. Our findings can improve public health surveillance by identifying local variation of disease prevalence.


Ontogenetic study of the supraorbital region in modern humans: a longitudinal test of the spatial model.
The structural significance of the hominid supraorbital torus and its morphological variation have always been a controversial topic in physical anthropology. Understanding the function of browridge variation in living and fossil human populations is relevant to questions of human evolution. This study utilizes radiograph images to evaluate the spatial model in modern humans during ontogeny. This structural model attributes variation in the supraorbital region to the positional relationship between the neurocranium and the orbits. The relationship between measurements of the antero-posterior supraorbital length and the factors specified in the spatial model were assessed by correlation and partial correlation analyses. Growth rates were also examined to study ontogenetic trajectories and infer aspects of developmental relationships between critical variables. Results agree with previous research supporting the existence of spatial influences between the neural and orbital-upper facial regions on browridge length during ontogeny.


Fast Noninvasive Measurement of Brown Adipose Tissue in Living Mice by Near-Infrared Fluorescence and Photoacoustic Imaging.
Aberrant brown adipose tissue (BAT) metabolism is linked to obesity as well as other metabolic disorders. However, the paucity of imaging tools limits the study of in vivo BAT metabolism in animal models. The current work evaluated a heptamethine dye (CyHF-8) in living mice as a dual-modality BAT-avid molecular probe for two imaging approaches, including near-infrared fluorescence imaging (NIRF) and photoacoustic imaging (PAI). CyHF-8 exhibited favorable spectral properties in the near-infrared window (786/787/805 nm) and accumulated in the subcellular mitochondria of brown adipocytes. After intravenous injection of CyHF-8, NIRF and PAI were both capable of noninvasively detecting interscapular BAT at early time points in living mice. Quantitative analysis of NIRF and PAI images showed that CyHF-8 signals respond to dynamic BAT changes in mice stimulated by norepinephrine (NE) and in diabetic mice induced by streptozotocin (STZ). In summary, dual-modality NIRF/PAI probe CyHF-8 can be used for both NIRF and PAI to noninvasively assess BAT metabolism in living animals.


Molecular containers assembled through the hydrophobic effect.
This review focuses on molecular containers formed by assembly processes driven by the hydrophobic effect, and summarizes the progress made in the field over the last ten years. This small but growing facet of supramolecular chemistry discusses three classes of molecules used by researchers to investigate how self-assembly can be applied to form discrete, mono-dispersed, and structurally well-defined supramolecular entities. The approaches demonstrate the importance of preorganization of arrays of rigid moieties to define a specific form predisposed to bind, fold, or assemble. As the examples demonstrate, studying these systems and their properties is teaching us how to control supramolecular chemistry in water, shedding light on aspects of aqueous solutions chemistry, and illustrating novel applications that harness the unique properties of the hydrophobic effect.


Cost-effectiveness of tenofovir instead of zidovudine for use in first-line antiretroviral therapy in settings without virological monitoring.
The most recent World Health Organization (WHO) antiretroviral treatment guidelines recommend the inclusion of zidovudine (ZDV) or tenofovir (TDF) in first-line therapy. We conducted a cost-effectiveness analysis with emphasis on emerging patterns of drug resistance upon treatment failure and their impact on second-line therapy. We used a stochastic simulation of a generalized HIV-1 epidemic in sub-Saharan Africa to compare two strategies for first-line combination antiretroviral treatment including lamivudine, nevirapine and either ZDV or TDF. Model input parameters were derived from literature and, for the simulation of resistance pathways, estimated from drug resistance data obtained after first-line treatment failure in settings without virological monitoring. Treatment failure and cost effectiveness were determined based on WHO definitions. Two scenarios with optimistic (no emergence; base) and pessimistic (extensive emergence) assumptions regarding occurrence of multidrug resistance patterns were tested. In the base scenario, cumulative proportions of treatment failure according to WHO criteria were higher among first-line ZDV users (median after six years 36% [95% simulation interval 32%; 39%]) compared with first-line TDF users (31% [29%; 33%]). Consequently, a higher proportion initiated second-line therapy (including lamivudine, boosted protease inhibitors and either ZDV or TDF) in the first-line ZDV user group 34% [31%; 37%] relative to first-line TDF users (30% [27%; 32%]). At the time of second-line initiation, a higher proportion (16%) of first-line ZDV users harboured TDF-resistant HIV compared with ZDV-resistant viruses among first-line TDF users (0% and 6% in base and pessimistic scenarios, respectively). In the base scenario, the incremental cost effectiveness ratio with respect to quality adjusted life years (QALY) was US$83 when TDF instead of ZDV was used in first-line therapy (pessimistic scenario: US$ 315), which was below the WHO threshold for high cost effectiveness (US$ 2154). Using TDF instead of ZDV in first-line treatment in resource-limited settings is very cost-effective and likely to better preserve future treatment options in absence of virological monitoring.


Effects of rosuvastatin on ADMA, rhokinase, NADPH oxidase, caveolin-1, hsp 90 and NFkB levels in a rat model of myocardial ischaemia-reperfusion.
Endothelial dysfunction, oxidative stress and inflammation are among the most important mechanisms of ischaemia-reperfusion (I/R) injury. Besides their cholesterol-lowering effects, statins are known to provide protection against myocardial dysfunction and vascular endothelial injury via nitric oxide-dependent mechanisms. The aim of this study was to investigate the effects of rosuvastatin on certain intermediates involved in the generation of nitric oxide (asymmetrical dimethyl arginin, ADMA, caveolin-1 and hsp 90), oxidative stress (rhokinase, NADPH oxidase) and inflammation (NFkB), using an in vivo model of myocardial infarction in the rat. Adult male Sprague Dawley rats were divided into three groups (control, I/R and I/R after 15 days of rosuvastatin administration). Reperfusion was applied for 120 min following left anterior descending coronary artery ischaemia for 30 min. Caveolin-1, hsp 90 and NFkB levels were evaluated with the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and ADMA, rhokinase and NADPH oxidase levels were evaluated with ELISA. While NFkB and hsp 90 levels were higher in the I/R group, their levels were significantly lower in the rosuvastatin group. While ADMA and NADPH oxidase levels significantly increased with I/R, they were lower in the rosuvastatin-treated group, but not statistically significant. Rhokinase levels were significantly lower in the rosuvastatin group. Caveolin-1 levels were not different between the groups. Our results suggest that ADMA, rhokinase, NADPH oxidase, hsp 90 and NFkB could facilitate I/R injury, and rosuvastatin significantly reduced levels of these parameters. These results indicate that rosuvastatin may have a protective role in I/R injury via mechanisms targeting inflammation, endothelial dysfunction and oxidative stress.


[Violence-related deaths in Argentina: two case studies in the cities of Venado Tuerto and San Rafael].
This article presents the results of a comparative study of two Argentinian cities, namely Venado Tuerto and San Rafael, which revealed different trends in the rates of firearm-related homicides. The methodology combined two strategies of analysis: semi-structured interviews with key informants (municipal and provincial government agents in different areas of management, as well as members of non-governmental organizations) and focus groups with actors involved in medical care, education, and religious institutions. The results suggest little difference between cities in which rates have increased and those in which rates have decreased. The most significant difference was that in Venado Tuerto a greater fragility of public institutions was observed due to the lack of articulation between such institutions. In San Rafael, the actors interviewed attribute the low level of conflict to a violence prevention network in which provincial and municipal agencies interact. Although neither city is violent at the most critical Latin American levels, the different results shown in Venado Tuerco and San Rafael indicate the possibility of bringing institutions together in a joint framework of conversations, agreements and policies.


Distinct firing patterns of identified basket and dendrite-targeting interneurons in the prefrontal cortex during hippocampal theta and local spindle oscillations.
The medial prefrontal cortex is involved in working memory and executive control. However, the collective spatiotemporal organization of the cellular network has not been possible to explain during different brain states. We show that pyramidal cells in the prelimbic cortex fire synchronized to hippocampal theta and local spindle oscillations in anesthetized rats. To identify which types of interneurons contribute to the synchronized activity, we recorded and juxtacellularly labeled parvalbumin- and calbindin-expressing (PV+/CB+) basket cells and CB-expressing, PV-negative (CB+/PV-) dendrite-targeting interneurons during both network oscillations. All CB+/PV- dendrite-targeting cells strongly decreased their firing rate during hippocampal theta oscillations. Most PV+/CB+ basket cells fired at the peak of dorsal CA1 theta cycles, similar to prefrontal pyramidal cells. We show that pyramidal cells in the ventral hippocampus also fire around the peak of dorsal CA1 theta cycles, in contrast to previously reported dorsal hippocampal pyramidal cells. Therefore, prefrontal neurons might be driven by monosynaptic connections from the ventral hippocampus during theta oscillations. During prefrontal spindle oscillations, the majority of pyramidal cells and PV+/CB+ basket cells fired preferentially at the trough and early ascending phase, but CB+/PV- dendrite-targeting cells fired uniformly at all phases. We conclude that PV+/CB+ basket cells contribute to rhythmic responses of prefrontal pyramidal cells in relation to hippocampal and thalamic inputs and CB+/PV- dendrite-targeting cells modulate the excitability of dendrites and spines regardless of these field rhythms. Distinct classes of GABAergic interneuron in the prefrontal cortex contribute differentially to the synchronization of pyramidal cells during network oscillations.


Interactions of the C Terminus of Metabotropic Glutamate Receptor Type 1α with Rat Brain Proteins: Evidence for a Direct Interaction with Tubulin.
Metabotropic glutamate receptors (mGluRs) are coupled to G protein second messenger pathways and modulate glutamate neurotransmission in the brain, where they are targeted to specific synaptic locations. As part of a strategy for defining the mechanisms for the specific targeting of mGluR1 α, rat brain proteins which interact with the intracellular carboxy terminus of mGluR1 α have been characterized, using affinity chromatography on a glutathione S-transferase fusion protein that contains the last 86 amino acids of mGluR1 α. Three of the proteins specifically eluted from the affinity column yielded protein sequences, two of which were identified as glyceraldehyde-3-phosphate dehydrogenase and β-tubulin ; the other was an unknown protein. The identity of tubulin was confirmed by western immunoblotting. Using a solid-phase binding assay, the mGluR1 α-tubulin interaction was shown to be direct, specific, and saturable with a KD of 2.3 ± 0.4 μM. In addition, mGluR1 α, but not mGluR2/3 or mGluR4, could be coimmunoprecipitated from solubilized brain extracts with tubulin using anti-β-tubulin antibodies. However, mGluR1 α could not be coimmunoprecipitated with the tubulin binding protein gephyrin, nor could it be coimmunoprecipitated with PSD95. Collectively these data demonstrate that the last 86 amino acids of the carboxyl-terminal tail of mGluR1 α are sufficient to determine its interaction with tubulin and that there is an association of this receptor with tubulin in rat brain.


Transcranial magnetic stimulation: applications in neuropsychiatry.
In the 1990s, it is difficult to open a newspaper or watch television and not find someone claiming that magnets promote healing. Rarely do these claims stem from double-blind, peer-reviewed studies, making it difficult to separate the wheat from the chaff. The current fads resemble those at the end of the last century, when many were falsely touting the benefits of direct electrical and weak magnetic stimulation. Yet in the midst of this popular interest in magnetic therapy, a new neuroscience field has developed that uses powerful magnetic fields to alter brain activity--transcranial magnetic stimulation. This review examines the basic principles underlying transcranial magnetic stimulation, and describes how it differs from electrical stimulation or other uses of magnets. Initial studies in this field are critically summarized, particularly as they pertain to the pathophysiology and treatment of neuropsychiatric disorders. Transcranial magnetic stimulation is a promising new research and, perhaps, therapeutic tool, but more work remains before it can be fully integrated in psychiatry's diagnostic and therapeutic armamentarium.


Hydrophobins from Aspergillus species cannot be clearly divided into two classes.
Hydrophobins are a family of small secreted proteins with a characteristic pattern of eight cysteine residues found exclusively in filamentous fungi. They have originally been divided into two classes based on their physical properties and hydropathy patterns, and are involved in the attachment of hyphae to hydrophobic structures, the formation of aerial structures and appear to be involved in pathogenicity. Analysis of nine genome sequences from seven Aspergilli revealed fifty hydrophobins, where each species displayed between two to eight hydrophobins. Twenty of the identified hydrophobins have not previously been described from these species. Apart from the cysteines, very little amino acid sequence homology was observed. Twenty-three of the identified hydrophobins could be classified as class I hydrophobins based on their conserved cysteine spacing pattern and hydropathy pattern. However twenty-six of the identified hydrophobins were intermediate forms. Notably, a single hydrophobin, ATEG_04730, from Aspergillus terreus displayed class II cysteine spacing and had a class II hydropathy pattern. Fifty hydrophobins were identified in Aspergillus, all containing the characteristic eight cysteine pattern. Aspergillus terreus exhibited both class I and class II hydrophobins. This is the first report of an Aspergillus species with the potential to express both class I and class II hydrophobins. Many of the identified hydrophobins could not directly be allocated to either class I or class II.


Prevalence and possible predictors of sexual dysfunction and self-reported needs related to the sexual life of advanced cancer patients.
Background: Sexual dysfunction and problems are common late effects after treatment of cancer. However, little is known about the prevalence and risk factors for sexual dysfunction in patients with advanced cancer. The aim of this study was to investigate the prevalence and predictors of sexual problems and needs in a large sample of Danish patients with advanced cancer. Methodology: The data derived from a representative cross-sectional study of patients with advanced cancer. Patients who had been in contact with 1 of 54 hospital departments were invited to fill out a questionnaire on symptoms and problems. Five items asked about sexuality. Ordinal logistic regression was used to identify variables associated with sexual functioning in explorative analyses. Results: A total of 1,447 patients completed the questionnaire and of those, 961 patients (66%) completed the sexuality items. More than half of the patients (60%) had not been sexually active within the previous month, despite a high prevalence of desire for sexual intimacy (62%). More than half of the patients (57%) experienced that their physical condition or treatment had impaired their sex life. Of those, 52% experienced an unmet need for help with sexual problems from the health care system. Older patients were less likely to report sexual problems than younger patients. Having prostate or gynecologic cancer was associated with the feeling that one's sexual life was negatively influenced. Conclusion: Sexual problems are common among patients with advanced cancer and should be addressed by the health care system.


Elevated levels of soluble total and hyperphosphorylated tau result in early behavioral deficits and distinct changes in brain pathology in a new tau transgenic mouse model.
Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr(181), Ser(199), Thr(231) and Thr(235)), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser(396) and Ser(404) in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.


Primary constitutional MLH1 epimutations: a focal epigenetic event.
Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.


Keeping patients safe: an interventional hand hygiene study at an oncology center.
Healthcare-associated infections (HCIs) continue to affect patient morbidity and mortality and contribute to the rising cost of health care. Factors associated with the rise of HCIs in patients with cancer may include an increase in antimicrobial resistance and treatment effects of radiation and chemotherapeutic agents. Infection control and prevention practices can decrease infection rates among patients with cancer. In an effort to reduce HCIs and increase awareness, an interventional study was conducted at an oncology center to investigate hand hygiene compliance of healthcare professionals before and after the introduction of a handheld sanitizer spray. Although healthcare professionals had a positive response to the spray, it did not improve compliance rates.


Naturally acquired immunity against immature Plasmodium falciparum gametocytes.
The recent decline in global malaria burden has stimulated efforts toward Plasmodium falciparum elimination. Understanding the biology of malaria transmission stages may provide opportunities to reduce or prevent onward transmission to mosquitoes. Immature P. falciparum transmission stages, termed stages I to IV gametocytes, sequester in human bone marrow before release into the circulation as mature stage V gametocytes. This process likely involves interactions between host receptors and potentially immunogenic adhesins on the infected red blood cell (iRBC) surface. Here, we developed a flow cytometry assay to examine immune recognition of live gametocytes of different developmental stages by naturally exposed Malawians. We identified strong antibody recognition of the earliest immature gametocyte-iRBCs (giRBCs) but not mature stage V giRBCs. Candidate surface antigens (n = 30), most of them shared between asexual- and gametocyte-iRBCs, were identified by mass spectrometry and mouse immunizations, as well as correlations between responses by protein microarray and flow cytometry. Naturally acquired responses to a subset of candidate antigens were associated with reduced asexual and gametocyte density, and plasma samples from malaria-infected individuals were able to induce immune clearance of giRBCs in vitro. Infected RBC surface expression of select candidate antigens was validated using specific antibodies, and genetic analysis revealed a subset with minimal variation across strains. Our data demonstrate that humoral immune responses to immature giRBCs and shared iRBC antigens are naturally acquired after malaria exposure. These humoral immune responses may have consequences for malaria transmission potential by clearing developing gametocytes, which could be leveraged for malaria intervention.


The Gutenberg discontinuity: melt at the lithosphere-asthenosphere boundary.
The lithosphere-asthenosphere boundary (LAB) beneath ocean basins separates the upper thermal boundary layer of rigid, conductively cooling plates from the underlying ductile, convecting mantle. The origin of a seismic discontinuity associated with this interface, known as the Gutenberg discontinuity (G), remains enigmatic. High-frequency SS precursors sampling below the Pacific plate intermittently detect the G as a sharp, negative velocity contrast at 40- to 75-kilometer depth. These observations lie near the depth of the LAB in regions associated with recent surface volcanism and mantle melt production and are consistent with an intermittent layer of asthenospheric partial melt residing at the lithospheric base. I propose that the G reflectivity is regionally enhanced by dynamical processes that produce melt, including hot mantle upwellings, small-scale convection, and fluid release during subduction.


Polarizabilities and van der Waals C6 coefficients of fullerenes from an atomistic electrodynamics model: Anomalous scaling with number of carbon atoms.
The van der Waals C6 coefficients of fullerenes are shown to exhibit an anomalous dependence on the number of carbon atoms N such that C6 ∝ N(2.2) as predicted using state-of-the-art quantum mechanical calculations based on fullerenes with small sizes, and N(2.75) as predicted using a classical-metallic spherical-shell approximation of the fullerenes. We use an atomistic electrodynamics model where each carbon atom is described by a polarizable object to extend the quantum mechanical calculations to larger fullerenes. The parameters of this model are optimized to describe accurately the static and complex polarizabilities of the fullerenes by fitting against accurate ab initio calculations. This model shows that C6 ∝ N(2.8), which is supportive of the classical-metallic spherical-shell approximation. Additionally, we show that the anomalous dependence of the polarizability on N is attributed to the electric charge term, while the dipole-dipole term scales almost linearly with the number of carbon atoms.


Chemical vapor growth and delamination of α-RuCl3 nanosheets down to the monolayer limit.
The 2D layered honeycomb magnet α-ruthenium(iii) chloride (α-RuCl3) is a promising candidate to realize a Kitaev spin model. As alteration of physical properties on the nanoscale is additionally intended, new synthesis approaches to obtain phase pure α-RuCl3 nanocrystals have been audited. Thermodynamic simulations of occurring gas phase equilibria were performed and optimization of synthesis conditions was achieved based on calculation results. Crystal growth succeeded via chemical vapor transport (CVT) in a temperature gradient of 973 K to 773 K on YSZ substrates. Single crystal sheets of high crystallinity with heights ≤30 nm were obtained via pure CVT. The crystal properties were characterized by means of optical and electron microscopy, AFM, SAED, micro-Raman and XPS proving their composition, morphology, crystallinity and phase-purity. A highlight of our study is the successful individualization of nanocrystals and the delamination of nanosheets on YSZ substrates down to the monolayer limit (≤1 nm) which was realized by means of substrate exfoliation and ultrasonication in a very reproducible way.


The costs of chronic noise exposure for terrestrial organisms.
Growth in transportation networks, resource extraction, motorized recreation and urban development is responsible for chronic noise exposure in most terrestrial areas, including remote wilderness sites. Increased noise levels reduce the distance and area over which acoustic signals can be perceived by animals. Here, we review a broad range of findings that indicate the potential severity of this threat to diverse taxa, and recent studies that document substantial changes in foraging and anti-predator behavior, reproductive success, density and community structure in response to noise. Effective management of protected areas must include noise assessment, and research is needed to further quantify the ecological consequences of chronic noise exposure in terrestrial environments.


Prevalence and outcomes of antimicrobial treatment for Staphylococcus aureus bacteremia in outpatients with ESRD.
Staphylococcus bacteremia is a common and life-threatening medical emergency, but it is treatable with appropriate antibiotic therapy. To identify opportunities that may reduce morbidity and mortality associated with S. aureus, we analyzed data from 293,094 chronic hemodialysis outpatients to characterize practices of antibiotic selection. In the study population, the overall rate of bacteremia was 15.4 per 100 outpatient-years; the incidence rate for methicillin-sensitive (MSSA) was 2.1 per 100 outpatient-years, and the incidence rate for methicillin-resistant (MRSA) S. aureus was 1.9 per 100 outpatient-years. One week after the collection of the index blood culture, 56.1% of outpatients with MSSA bacteremia were receiving vancomycin, and 16.7% of outpatients with MSSA were receiving cefazolin. Among MSSA-bacteremic patients who did not die or get hospitalized 1 week after blood culture collection, use of cefazolin was associated with a 38% lower risk for hospitalization or death compared with vancomycin (adjusted HR=0.62, 95% CI=0.46-0.84). In conclusion, vancomycin is commonly used to treat MSSA bacteremia in outpatients receiving chronic dialysis, but there may be more risk of treatment failure than observed among those individuals who receive a β-lactam antibiotic such as cefazolin.


Troponin I can be Determined in Intraosseous Aspirates in a Porcine Shock Model.
Determination of troponin I may be important in the management of the critically ill patient. In medical emergencies, especially when vascular access is difficult to achieve, the use of intraosseous (10) needles is recommended. We aimed to perform a descriptive study, aiming to elucidate whether IO needles can be used to evaluate troponin I in a porcine model of human shock. Eight pigs were anesthetized and challenged with a 6 hours continuous intravenous infusion of E. coli endotoxin. An IO needle (EZ-IO®) was inserted in the proximal tibia of each pig. Circulatory variables were monitored and troponin I was sampled from arterial and venous blood and also from bone marrow aspirates. Circulatory deterioration developed in all endotoxemic animals, which was reflected by a profound deterioration of left ventricular stroke work index. Troponin I levels were nearly identical in both arterial, venous, and IO samples during the first hour of endotoxemia. At 1 hour, all mean troponin I levels had more than doubled as compared to baseline. The troponin I levels continued to increase over time and were markedly elevated versus baseline levels during the 2nd and 6th hours, regardless of sampling site. At 3 hours, IO troponin I reached a plateau, whereas troponin I in both arterial and venous blood continued to increase. This investigation has shown that troponin I can be analyzed in bone marrow aspirates in a shock model. This may be useful in medical emergencies, where cardiac damage is suspected to be involved. The levels of IO troponin I increased during the first 3 hours of shock, after which it remained at a high level. During this initial period there was, in parallel, a progressive circulatory deterioration.


A Genome-Wide Association Study to Identify Diagnostic Markers for Human Pathogenic Campylobacter jejuni Strains.
Campylobacter jejuni is a leading human enteric pathogen worldwide and despite an improved understanding of its biology, ecology, and epidemiology, limited tools exist for identifying strains that are likely to cause disease. In the current study, we used subtyping data in a database representing over 24,000 isolates collected through various surveillance projects in Canada to identify 166 representative genomes from prevalent C. jejuni subtypes for whole genome sequencing. The sequence data was used in a genome-wide association study (GWAS) aimed at identifying accessory gene markers associated with clinically related C. jejuni subtypes. Prospective markers (n = 28) were then validated against a large number (n = 3,902) of clinically associated and non-clinically associated genomes from a variety of sources. A total of 25 genes, including six sets of genetically linked genes, were identified as robust putative diagnostic markers for clinically related C. jejuni subtypes. Although some of the genes identified in this study have been previously shown to play a role in important processes such as iron acquisition and vitamin B5 biosynthesis, others have unknown function or are unique to the current study and warrant further investigation. As few as four of these markers could be used in combination to detect up to 90% of clinically associated isolates in the validation dataset, and such markers could form the basis for a screening assay to rapidly identify strains that pose an increased risk to public health. The results of the current study are consistent with the notion that specific groups of C. jejuni strains of interest are defined by the presence of specific accessory genes.


Anaerobes and Gardnerella vaginalis in non-specific vaginitis.
Clinical evidence of bacterial vaginosis was present in 25 (35%) of 72 patients attending a London venereology clinic and correlated significantly with abnormal organic acids in vaginal secretions (24/25), with Gardnerella vaginalis on culture (17/25), with complaints of vaginal malodour (15/25), and with a relative scarcity of white blood cells in vaginal secretions. Anaerobic vaginal flora were presumptively identified by gas-liquid chromatographic analysis of organic acids found in vaginal secretions. The clinical criteria used to diagnose bacterial vaginosis included the presence of at least three of the four following characteristics: (a) a vaginal pH greater than or equal to 4.5, vaginal secretions that (b) were homogeneous, (c) contained "clue" cells, and (d) released a "fishy" amine odour when mixed with 10% potassium hydroxide. Because 17 of the 25 patients with clinical bacterial vaginosis had both chromatographic bacterial vaginosis and G vaginalis, causative organisms were difficult to identify. None of the six patients who had G vaginalis but not chromatographic bacterial vaginosis had clinical bacterial vaginosis, but seven of the 10 women with chromatographic bacterial vaginosis but not G vaginalis had clinical bacterial vaginosis (p less than 0.02, chi 2 with Yates's correction). This finding supports the recent suggestions that anaerobes are important in the production of clinical signs of bacterial vaginosis.


Imaging of dynamic changes of the actin cytoskeleton in microextensions of live NIH3T3 cells with a GFP fusion of the F-actin binding domain of moesin.
The cell surface undergoes continuous change during cell movement. This is characterized by transient protrusion and partial or complete retraction of microspikes, filopodia, and lamellipodia. This requires a dynamic actin cytoskeleton, moesin, components of Rho-mediated signal pathways, rearrangement of membrane constituents and the formation of focal adhesion sites. While the immunofluorescence distribution of endogenous moesin is that of a membrane-bound molecule with marked enhancement in some but not all microextensions, the C-terminal fragment of moesin co-distributes with filamentous actin consistent with its actin-binding activity. By taking advantage of this property we studied the spontaneous protrusive activity of live NIH3T3 cells, expressing a fusion of GFP and the C-terminal domain of moesin. C-moesin-GFP localized to stress fibers and was enriched in actively protruding cellular regions such as filopodia or lamellipodia. This localization was reversibly affected by cytochalasin D. Multiple types of cytoskeletal rearrangements were observed that occurred independent of each other in adjacent regions of the cell surface. Assembly and disassembly of actin filaments occurred repeatedly within the same space and was correlated with either membrane protrusion and retraction, or no change in shape when microextensions were adherent. Shape alone provided an inadequate criterion for distinguishing between retraction fibers and advancing, retracting or stable filopodia. Fluorescence imaging of C-moesin-GFP, however, paralleled the rapid and dynamic changes of the actin cytoskeleton in microextensions. Regional regulatory control is implicated because opposite changes occurred in close proximity and presumably independent of each other. This new and sensitive tool should be useful for investigating mechanisms of localized actin dynamics in the cell cortex.


Cholesterol crystals as an etiological factor in non-resolving chronic inflammation: an experimental study in guinea pigs.
The presence of cholesterol crystals has been suggested to be a factor interfering with periapical healing after conventional endodontic treatment. This investigation addresses the role of cholesterol crystals in impairing healing by studying the tissue response to the crystals, which were implanted in animals. Pure cholesterol crystals, prepared to a mushy form, were placed in Teflon cages that were implanted subcutaneously in guinea pigs. The cage-contents were retrieved after 2, 4 and 32 wk of implantation and processed for light and electron microscopy. The cages revealed delicate connective tissue that grew in through perforations on the cage-wall. The crystals were densely surrounded by numerous macrophages and multinucleated giant cells, forming a well-circumscribed area of tissue reaction. The cells, however, were unable to eliminate the crystals during an observation period of 8 months. The congregation of macrophages and giant cells, known to be major sources of apical inflammatory and bone resorptive mediators, suggest that accumulation of cholesterol crystals can be a factor in the failure of certain apical periodontitis lesions to resolve after conventional root-filling therapy.


Antioxidant, Antinociceptive, and Anti-Inflammatory Activities from Actinidia callosa var. callosa In Vitro and In Vivo.
Actinidia callosa var. callosa has been widely used to treat antipyretic, analgesic, anti-inflammation, abdominal pain, and fever in Taiwan. The aim of this study was to evaluate the antioxidant, antinociceptive, and anti-inflammatory lipopolysaccharide-(LPS-)induced nitric oxide (NO) production in RAW264.7 macrophages and pawedema induced by λ-carrageenan activities of the methanol extract from A. callosa. In HPLC analysis, the fingerprint chromatogram of ethyl-acetate fraction of A. callosa (EAAC) was established. EAAC showed the highest TEAC and DPPH radical scavenging activities, respectively. We evaluated that EAAC and the reference compound of catechin and caffeic acid decreased the LPS-induced NO production in RAW264.7 cells. Treatment of male ICR mice with EAAC significantly inhibited the numbers of acetic acid-induced writhing response and the formalin-induced pain in the late phase. Administration of EAAC showed a concentration-dependent inhibition on paw edema development after Carr treatment in mice. Anti-inflammatory mechanisms of EAAC might be correlated to the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and heme oxygenase-1 (HO-1) in vitro and in vivo. Overall, the results showed that EAAC demonstrated antioxidant, antinociceptive, and anti-inflammatory activity, which supports previous claims of the traditional use for inflammation and pain.


Pathogenic role of macrophages in intradermal infection of methicillin-resistant Staphylococcus aureus in thermally injured mice.
Intradermal infection of methicillin-resistant Staphylococcus aureus (MRSA) in burned mice was pathogenically analyzed. An abscess was formed in normal mice intradermally infected with 10(8) CFU/mouse of MRSA, and all of these mice survived after the infection; however, abscess formation was not demonstrated to occur in burned mice similarly exposed to the pathogen, and all of these mice died within 5 days of infection. In burned mice, MRSA infected at the burn site intradermal tissues spread quickly throughout the whole body, while in normal mice, the pathogen remained localized at the infection site. Macrophages (Mφ) isolated from the infection site tissues of normal mice produced interleukin-12 (IL-12) but not IL-10 and were characterized as M1Mφ. These M1Mφ were not isolated from the infection site tissues of burned mice. When normal-mouse infection site tissue Mφ were adoptively transferred to burned mice at the MRSA infection site, an abscess formed, and the infection did not develop into sepsis. In contrast, an abscess did not form and sepsis developed in normal mice that were inoculated with burned-mouse infection site tissue Mφ. These Mφ produced IL-10 but not IL-12 and were characterized as M2Mφ. These results indicate that abscess formation is a major mechanism of host resistance against intradermal MRSA infection. M1Mφ in the tissues surrounding the infection site play a pivotal role in abscess formation; however, the abscess is not formed in burned mice where M2Mφ predominate. M2Mφ have been described as inhibitor cells for Mφ conversion from resident Mφ to M1Mφ.


[Autophagy contributes to the initiation of pancreatic cancer].
The pancreatic adenocarcinoma initiation results from the interaction of genetic events combined with multiple other factors. Among the genetic alterations that contribute to the pathogenesis of this disease, the mutation of the KRAS oncogene is required but not sufficient to trigger this cancer. Pancreatitis, an inflammatory disease, facilitates and accelerates the transformation of pancreatic cells when the KRAS oncogene is mutated. Of note, the repertoire of molecular mediators of pancreatitis which are responsible of the promotion of KRAS-mediated transformation is not completely defined. Importantly, autophagy has been proposed as one of the cellular mechanisms contributing to pancreatic carcinogenesis, especially in the initial phases, in which the oncogene KRAS appears to play its leading role. In addition, autophagy is strongly induced during pancreatitis. Although some aspects of autophagy in pancreatic cancer development are not completely established, we can affirm that overexpression of VMP1, an inducer of autophagy which is specifically activated in pancreas during pancreatitis, improves the development of pancreatic precancerous lesions PanINs when the oncogene KRAS is mutated. In addition, inhibition of the autophagic flux with chloroquine inhibits the KRAS pro-tumor effect in the pancreas. In conclusion, activation of expression of VMP1 improves the pro-tumor role of KRAS in pancreas.


Molecular chaperone machines: chaperone activities of the cyclophilin Cyp-40 and the steroid aporeceptor-associated protein p23.
Molecular chaperones are essential proteins that participate in the regulation of steroid receptors in eukaryotes. The steroid aporeceptor complex contains the molecular chaperones Hsp90 and Hsp70, p48, the cyclophilin Cyp-40, and the associated proteins p23 and p60. In vitro folding assays showed that Cyp-40 and p23 functioned as molecular chaperones in a manner similar to that of Hsp90 or Hsp70. Although neither Cyp-40 nor p23 could completely refold an unfolded substrate, both proteins interacted with the substrate to maintain a nonnative folding-competent intermediate. Thus, the steroid aporeceptor complexes have multiple chaperone components that maintain substrates in an intermediate folded state.


Rayleigh scattering of a spherical sound wave.
Acoustic Green's functions for a homogeneous medium with an embedded spherical obstacle arise in analyses of scattering by objects on or near an interface, radiation by finite sources, sound attenuation in and scattering from clouds of suspended particles, etc. An exact solution of the problem of diffraction of a monochromatic spherical sound wave on a sphere is given by an infinite series involving products of Bessel functions and Legendre polynomials. In this paper, a simple, closed-form solution is obtained for scattering by a sphere with a radius that is small compared to the wavelength. Soft, hard, impedance, and fluid obstacles are considered. The solution is valid for arbitrary positions of the source and receiver relative to the scatterer. Low-frequency scattering is shown to be rather sensitive to boundary conditions on the surface of the obstacle. Low-frequency asymptotics of the scattered acoustic field are extended to transient incident waves. The asymptotic expansions admit an intuitive interpretation in terms of image sources and reduce to classical results in appropriate limiting cases.


Metal-organic frameworks: versatile heterogeneous catalysts for efficient catalytic organic transformations.
Novel catalytic materials are highly demanded to perform a variety of catalytic organic reactions. MOFs combine the benefits of heterogeneous catalysis like easy post reaction separation, catalyst reusability, high stability and homogeneous catalysis such as high efficiency, selectivity, controllability and mild reaction conditions. The possible organization of active centers like metallic nodes, organic linkers, and their chemical synthetic functionalization on the nanoscale shows potential to build up MOFs particularly modified for catalytic challenges. In this review, we have summarized the recent research progress in heterogeneous catalysis by MOFs and their catalytic behavior in various organic reactions, highlighting the key features of MOFs as catalysts based on the active sites in the framework. Examples of their post functionalization, inclusion of active guest species and metal nanoparticles have been discussed. Finally, the use of MOFs as catalysts for asymmetric heterogeneous catalysis and stability of MOFs has been presented as separate sections.


Values and risk perceptions: a cross-cultural examination.
This article examines the relationship between values and risk perceptions regarding terror attacks. The participants in the study are university students from Turkey (n = 536) and Israel (n = 298). Schwartz value theory (1992, 1994) is applied to conceptualize and measure values. Cognitive (perceived likelihood and perceived severity) and emotional (fear, helplessness, anger, distress, insecurity, hopelessness, sadness, and anxiety) responses about the potential of (i) being personally exposed to a terror attack, and (ii) a terror attack that may occur in one's country are assessed to measure risk perceptions. Comparison of the two groups suggests that the Turkish participants are significantly more emotional about terror risks than the Israeli respondents. Both groups perceive the risk of a terror attack that may occur in their country more likely than the risk of being personally exposed to a terror attack. No significant differences are found in emotional representations and perceived severity ratings regarding these risks. Results provide support for the existence of a link between values and risk perceptions of terror attacks. In both countries, self-direction values are negatively related to emotional representations, whereas security values are positively correlated with emotions; hedonism and stimulation values are negatively related to perceived likelihood. Current findings are discussed in relation to previous results, theoretical approaches (the social amplification of risk framework and cultural theory of risk), and practical implications (increasing community support for a course of action, training programs for risk communicators).


Additive effects of cognitive function and depressive symptoms on mortality in elderly community-living adults.
Poor cognitive function and depressive symptoms are common in the elderly, frequently coexist, and are interrelated. Both risk factors are independently associated with mortality. Few studies have comprehensively described how the combination of poor cognitive function and depressive symptoms affect the risk for mortality. Our aim was to examine whether the combination of varying levels of cognitive function and depressive symptoms affect the risk of mortality in community-living elderly adults. We studied 6301 elderly adults (mean age, 77 years; 62% women; 81% white) enrolled in the Asset and Health Dynamics Among the Oldest Old (AHEAD) study, a prospective study of community-living participants conducted from 1993 to 1995. Cognitive function and depressive symptoms were measured using two validated measures developed for the AHEAD study. On each measure, participants were divided into tertiles representing the best, middle, and worst scores, and then placed into one of nine mutually exclusive groups ranging from best functioning on both measures to worst functioning on both measures. Mortality rates were assessed in each of the nine groups. Cox proportional hazards models were used to control for potentially confounding characteristics such as demographics, education, income, smoking, alcohol consumption, comorbidity, and baseline functional impairment. During 2 years of follow-up, 9% (548) of the participants died. Together, cognitive function and depressive symptoms differentiated between elderly adults at markedly different risk for mortality, ranging from 3% in those with the best function on both measures to 16% in those with the worst function on both measures (p <.001). Furthermore, for each level of cognitive function, more depressive symptoms were associated with higher mortality rates, and for each level of depressive symptoms, worse cognitive function was associated with higher mortality rates. In participants with the best cognitive function, mortality rates were 3%, 5%, and 9% in participants with low, middle, and high depressive symptoms, respectively (p <.001 for trend). The corresponding rates were 6%, 7%, and 12% in participants with the middle level of cognitive function (p <.001 for trend), and 10%, 13%, and 16% in participants with the worst level of cognitive function (p <.001 for trend). After adjustment for confounders, participants with the worst function on both measures remained at considerably higher risk for death than participants with the best function on both measures (adjusted hazard ratio, 3.1; 95% confidence interval, 2.0-4.7). Cognitive function and depressive symptoms can be used together to stratify elderly adults into groups that have significantly different rates of death. These two risk factors are associated with an increased risk in mortality in a progressive, additive manner.


Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer's disease.
Infectious agents have been proposed as potential causes of Alzheimer's disease (AD). Recently, we documented a high prevalence of Helicobacter pylori (Hp) infection in patients with AD. We aim to access the effect of Hp eradication on the AD cognitive (MMSE: Mini Mental State Examination and CAMCOG: Cambridge Cognitive Examination for the Elderly) and functional (FRSSD: Functional Rating Scale for Symptoms of Dementia) status parameters. In the first part of the study, a total of 50 consecutive patients with AD and 30 age-matched anaemic controls underwent an upper gastrointestinal endoscopy, and gastric mucosal biopsies were obtained to detect the presence of Hp infection by histologic analysis and rapid urease test. Serum anti-Hp-specific IgG level was analysed by enzyme-linked immunosorbent assay. In the second part, Hp-positive AD patients received a triple eradication regimen (omeprazole, clarithromycin and amoxicillin), and all patients were followed up for 2 years, while under the same treatment with cholinesterase inhibitors. Hp was detected in 88% of AD patients and in 46.7% of controls (P < 0.001). Hp eradication was successful in 84.8% of treated patients. At the 2-year clinical endpoint, cognitive and functional status parameters improved in the subgroup of patients where Hp eradication was successful (P < 0.001 and P = 0.049 for MMSE and CAMCOG, respectively; P < 0.001 for FRSSD), but not in the other patients. Hp eradication may positively influence AD manifestations, suggesting a possible common link between Hp and AD.


Was Kandinsky a Synaesthete? Examining His Writings and Other Evidence.
Wassily Kandinsky is widely regarded as one of the most prominent examples of a synaesthetic artist. However, in the scientific literature there is disagreement on the genuineness of his synaesthesia. This paper investigates whether Kandinsky had inborn synaesthesia, while acknowledging that there are also types of induced synaesthesia which he may have cultivated. As these two types of synaesthesia are seen to work additively in some synaesthetes and not to be mutually exclusive, this is not seen as an argument against the view that he was a true inborn synaesthete. Whether Kandinsky was a synaesthete is examined through a detailed study of his primary writings (e.g., On the Spiritual in Art, Point and Line to Plane, and Reminiscences), in light of the modern diagnostic criteria. The experiences described in those writings indicate that his synaesthetic perceptions were genuine and inborn and not just a theoretical endeavour. Given the genetic dimension of synaesthesia, this view is further supported by the fact that Kandinsky's uncle Victor Kandinsky also described having synaesthetic experiences.


Remote Determination of Time-Dependent Stiffness of Surface-Degrading-Polymer Scaffolds Via Synchrotron-Based Imaging.
Surface-degrading polymers have been widely used to fabricate scaffolds with the mechanical properties appropriate for tissue regeneration/repair. During their surface degradation, the material properties of polymers remain approximately unchanged, but the scaffold geometry and thus mechanical properties vary with time. This paper presents a novel method to determine the time-dependent mechanical properties, particularly stiffness, of scaffolds from the geometric changes captured by synchrotron-based imaging, with the help of finite element analysis (FEA). Three-dimensional (3D) tissue scaffolds were fabricated from surface-degrading polymers, and during their degradation, the tissue scaffolds were imaged via the synchrotron-based imaging to characterize their changing geometry. On this basis, the stiffness behavior of scaffolds was estimated from the FEA, and the results obtained were compared to the direct measurements of scaffold stiffness from the load-displacement material testing. The comparison illustrates that the Young's moduli estimated from the FEA and characterized geometry are in agreement with the ones of direct measurements. The developed method of estimating the mechanical behavior was also demonstrated effective with a nondegrading scaffold that displays the nonlinear stress-strain behavior. The in vivo monitoring of Young's modulus by morphology characterization also suggests the feasibility of characterizing experimentally the difference between in vivo and in vitro surface degradation of tissue engineering constructs.


Supporting prescribing in Irish primary care: protocol for a non-randomised pilot study of a general practice pharmacist (GPP) intervention to optimise prescribing in primary care.
Prescribing for patients taking multiple medicines (i.e. polypharmacy) is challenging for general practitioners (GPs). Limited evidence suggests that the integration of pharmacists into the general practice team could improve the management of these patients. The aim of this study is to develop and test an intervention involving pharmacists, working within GP practices, to optimise prescribing in Ireland, which has a mixed public and private primary healthcare system. This non-randomised pilot study will use a mixed-methods approach. Four general practices will be purposively sampled and recruited. A pharmacist will join the practice team for 6 months. They will participate in the management of repeat prescribing and undertake medication reviews (which will address high-risk prescribing and potentially inappropriate prescribing, deprescribing and cost-effective and generic prescribing) with adult patients. Pharmacists will also provide prescribing advice regarding the use of preferred drugs, undertake clinical audits, join practice team meetings and facilitate practice-based education. Throughout the 6-month intervention period, anonymised practice-level medication (e.g. medication changes) and cost data will be collected. A nested Patient Reported Outcome Measure (PROM) study will be undertaken during months 4 and 5 of the 6-month intervention period to explore the impact of the intervention in older adults (aged ≥ 65 years). For this, a sub-set of 50 patients aged ≥ 65 years with significant polypharmacy (≥ 10 repeat medicines) will be recruited from each practice and invited to a medication review with the pharmacist. PROMs and healthcare utilisation data will be collected using patient questionnaires, and a 6-week follow-up review conducted. Acceptability of the intervention will be explored using pre- and post-intervention semi-structured interviews with key stakeholders. Quantitative and qualitative data analysis will be undertaken and an economic evaluation conducted. This non-randomised pilot study will provide evidence regarding the feasibility and potential effectiveness of general practice-based pharmacists in Ireland and provide data on whether a randomised controlled trial of this intervention is indicated. It will also provide a deeper understanding as to how a pharmacist working as part of the general practice team will affect organisational processes and professional relationships in a mixed public and private primary healthcare system.


Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.
The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.


Reduced pSmad2 immunodetection correlates with increased primary melanoma thickness.
Cutaneous melanoma is the most aggressive of cutaneous neoplasms. Identifying patients with an increased risk for the development of metastases is critical. This study investigates phospho-Smad2, a central factor of the transforming growth factor beta pathway, on formalin-fixed, paraffin-embedded tissues from 60 primary cutaneous melanomas (Breslow >1 mm), for its candidacy for being a prognostic marker in primary cutaneous melanoma. Phospho-Smad2 positivity was assessed for correlation with clinical parameters including Breslow index, melanoma type, survival, development of metastases, sentinel lymph node status and age. Phospho-Smad2 positivity was not associated with survival or development of metastases, suggesting that it would not be a useful prognostic marker. Despite this, we found phospho-Smad2 positivity to be correlated with low tumour thickness, indicating that as the primary tumour grows there is an increased inhibition of transforming growth factor beta signalling resulting in suppressed Smad2 phosphorylation. Additionally, phosphorylation of Smad2 in neighbouring melanoma cells and keratinocytes was interrelated, which is a further indication that Smad2 phosphorylation in primary melanoma is affected by local area microenvironmental factors. We hypothesize that the observed decrease in transforming growth factor beta signalling in thicker primary melanomas is due to the increased production of signalling inhibitors.