[Obesity and osteoporosis: effect of weight variation on bone mass].
Obesity and osteoporosis are both chronic conditions with multi-factor aetiologies and a considerable associated level of morbidity and mortality. They are endemic in economically developed countries. Various epidemiological studies have indicated an overweight condition to have a protective effect on the occurrence of osteoporotic fractures, but the data available on the effects of weight loss on the conservation of bone mass are scant and fragmented. The present review attempts to give a critical assessment of the published trials that have analyzed the evolution of bone mass during the administration of low calorie diets to obese females, as well as to identify those aspects that would deserve special attention in the planning of future research in this field.


First-trimester nasal bone evaluation for aneuploidy in the general population.
To evaluate the role of fetal nasal bone imaging at 10 3/7 to 13 6/7 weeks as a screening tool for aneuploidy, in a prospective multicenter trial. Unselected patients from the general population with viable singleton pregnancies at 10 3/7 to 13 6/7 weeks were recruited at 15 U.S. centers. All had screening with nuchal translucency (NT) ultrasound by specially trained sonographers. In the last 8 months of this trial, first trimester nasal bone evaluation was added to the screening protocol. Nasal bones were described as present, absent, or unable to determine. A total of 38,189 patients completed first trimester NT screening, of whom 6,324 also underwent nasal bone sonography. An acceptable nasal image was obtained in 4,801 cases (76%), with nasal bones described as present in 4,779 (99.5%), and absent in 22 (0.5%). There were 11 identified cases of trisomy-21 in the population of 6,324 patients. In 9 of the 11 cases (82%) the nasal bones were described as present, and 2 cases were described as unable to determine. The only other aneuploidies were 2 cases of trisomy-18, in 1 of which the nasal bones were described as absent, and in 1 present. Absence of nasal bones had sensitivity for aneuploidy of 7.7%, false-positive rate 0.3%, and positive predictive value 4.5%. First-trimester nasal bone evaluation was not a useful test for population screening for trisomy-21 and added little to first-trimester NT screening. The difficulty in performing first-trimester nasal bone sonography consistently, in the general population setting, will significantly limit the usefulness of this aneuploidy screening technique.


The effect of flower-like and non-flower-like visual properties on choice of unrewarding patterns by bumblebees.
How do distinct visual stimuli help bumblebees discover flowers before they have experienced any reward outside of their nest? Two visual floral properties, type of a pattern (concentric vs radial) and its position on unrewarding artificial flowers (central vs peripheral on corolla), were manipulated in two experiments. Both visual properties showed significant effects on floral choice. When pitted against each other, pattern was more important than position. Experiment 1 shows a significant effect of concentric pattern position, and experiment 2 shows a significant preference towards radial patterns regardless of their position. These results show that the presence of markings at the center of a flower are not so important as the presence of markings that will direct bees there.


The risk of Rh isoimmunization in ruptured tubal pregnancy.
In 9 (24%) out of 38 African women who had suffered a ruptured tubal pregnancy significant numbers of fetal erythrocytes (5 or more per 150,000 maternal cells) were found in the maternal circulation. This is a higher incidence than occurs after abortion and indicates that rupture of a tubal pregnancy is a potential source of Rh isoimmunization. The finding of fetal cells in the peritoneal cavity suggests that this is the main source of the fetal blood found in the maternal circulation. At operation on Rh-negative patients with ruptured tubal pregnancies, therefore, complete removal of the peritoneal blood should be attempted and the blood recovered should never be transfused into the patient, who should always receive prophylactic Rh immunoglobulin.


Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model.
Protection of the large intestine with its enormous amount of commensal bacteria is a challenge that became easier to understand when we recently could describe that colon has an inner attached mucus layer devoid of bacteria (Johansson et al. (2008) Proc. Natl. Acad. Sci. USA 105, 15064-15069). The bacteria are thus kept at a distance from the epithelial cells and lack of this layer, as in Muc2-null mice, allow bacteria to contact the epithelium. This causes colitis and later on colon cancer, similar to the human disease Ulcerative Colitis, a disease that still lacks a pathogenetic explanation. Dextran Sulfate (DSS) in the drinking water is the most widely used animal model for experimental colitis. In this model, the inflammation is observed after 3-5 days, but early events explaining why DSS causes this has not been described. When mucus formed on top of colon explant cultures were exposed to 3% DSS, the thickness of the inner mucus layer decreased and became permeable to 2 microm fluorescent beads after 15 min. Both DSS and Dextran readily penetrated the mucus, but Dextran had no effect on thickness or permeability. When DSS was given in the drinking water to mice and the colon was stained for bacteria and the Muc2 mucin, bacteria were shown to penetrate the inner mucus layer and reach the epithelial cells already within 12 hours, long before any infiltration of inflammatory cells. DSS thus causes quick alterations in the inner colon mucus layer that makes it permeable to bacteria. The bacteria that reach the epithelial cells probably trigger an inflammatory reaction. These observations suggest that altered properties or lack of the inner colon mucus layer may be an initial event in the development of colitis.


Clinical comparison of two different types of bifurcated graft for postoperative baPWV and ABI.
A newly-designed bifurcated graft with the distal end larger than the conventional type has been developed. The purpose of this study was to evaluate the early results of graft replacement using this new graft, and to compare whether the new graft is more advantageous than the conventional graft in terms of peripheral blood flow and arterial stiffness. Records of 36 patients who underwent bifurcated graft replacement for infrarenal abdominal aortic aneurysm (AAA), from May 2003 to September 2006 were reviewed after excluding peripheral arterial disease (ABI > 0.9). Subjects were divided into two groups: group C (N.=20), with implantation of the conventional type and group N (N.=16), with implantation of the new type. We investigated changes in brachial-ankle pulse wave velocity (baPWV) and ankle-brachial pressure index (ABI), measurements being performed preoperatively and postoperatively. baPWV in the postoperative group as a whole was significantly higher than in the preoperative group (P<0.05), while ABI in the postoperative group was lower than in the preoperative group (P<0.05). In group C, baPWV increased (P<0.05) and ABI decreased (P<0.05) after bifurcated graft replacement, whereas in group N, there were no significant differences in changes of baPWV and ABI. This study shows that the new graft reduces the development of arterial stiffness postoperatively compared with the conventional type. These results may predict the new type graft decrease in the risk of morbidity and mortality caused by atherosclerotic disease.


Do individual liquor permit systems help Indigenous communities to manage alcohol?
Liquor permits were once used throughout Scandinavia and North America for managing alcohol, but largely disappeared in the late 20th century. Today, they are used in some Indigenous communities in Nunavut, Canada and the Northern Territory, Australia. This paper examines the extent to which liquor permits: (i) contribute to reducing alcohol-related harms in Indigenous communities; and (ii) offer a viable mechanism for managing alcohol in Indigenous communities. The study draws on published and unpublished international literature on liquor permit systems in Indigenous communities, and on field visits to northern territory (NT) communities. Apart from one anecdotal report, the study found no evidence that liquor permit systems in Nunavut communities have reduced alcohol-related problems. In the NT, they have reduced alcohol-related harms in some communities. However, management of liquor permit systems generates significant administrative demands in communities. Effectiveness of liquor permit systems is a product of five factors: permits themselves; agencies and procedures for issuing and managing permits; agencies and procedures for supplying liquor; enforcement of permit conditions, and the presence of other agencies-legal and illegal-affecting supply and consumption of liquor. Liquor permits continue to be valued by some Indigenous communities for managing alcohol. This study suggests that they can do so provided: (i) agencies administering permits have adequate support; (ii) controls over non-legal purchasing and consumption of liquor are effective, and (iii) the permit system is viewed in the community as legitimate, equitable and transparent.


[In silico Analyses of Transcriptomes of the Marine Green Microalga Dunaliella tertiolecta: Identification of Sequences Encoding P-type ATPases].
De novo assembled transcriptomes of the marine microalga Dunaliella tertiolecta (Chlorophyta) were analyzed. Transcriptome assemblies were performed using short-read RNA-seq data deposited in the SRA database (DNA and RNA Sequence Read Archive, NCBI). A merged transcriptome was assembled using a pooled RNA-seq data set. The goal of the study was in silico identification of nucleotide sequences encoding P-type ATPases in D. tertiolecta transcriptomes. P-type ATPases play a considerable role in the adaptation of an organism to a variable environment, and this problem is particularly significant for microalgae inhabiting an environment with an unstable ionic composition. Particular emphasis was given to searching for a sequence coding Na^(+)-ATPase. This enzyme is expected to function in the plasma membrane of D. tertiolecta like in some marine algae, in particular, in the closely related alga Dunaliella maritima. An ensemble of 12 P-type ATPases consisting of members belonging to the five main subfamilies of the P-type ATPase family was revealed in the assembled transcriptomes. The genes of the following P-type ATPases were found: (1) heavy metal ATPases (subfamily PIB); (2) Ca^(2+)-ATPases of SERCA type (subfamily P2A); (3) H^(+)-ATPases (subfamily P3); (4) phospholipid-transporting ATPases (flippases) (subfamily P4); (5) cation-transporting ATPases of uncertain specificities (subfamily P5). The presence of functional Na^(+)-ATPases in marine algae is presently undoubted. However, contrary to expectations, we failed to find a nucleotide sequence encoding a protein that could unequivocally be considered a Na^(+)-ATPase. Further study is necessary to elucidate the roles of in silico revealed D. tertiolecta ATPases in Na^(+) transport.


Impact of perioperative blood transfusions on clinical outcomes in patients undergoing surgery for major urologic malignancies.
The association between allogeneic perioperative blood transfusion (PBT) and decreased survival among patients undergoing various oncological surgeries has been established in various malignant diseases, including colorectal, thoracic and hepatocellular cancer. However, when focusing on urologic tumors, the significance of PBT and its adverse effect remains debatable, mainly due to inconsistency between studies. Nevertheless, the rate of PBT remains high and may reach up to 62% in patients undergoing major urologic surgeries. Hence, the relatively high rate of PBT among related operations, along with the increasing prevalence of several urologic tumors, give this topic great significance in clinical practice. Indeed, recent retrospective studies, followed by systematic reviews in both prostate and bladder cancer surgery have supported the association that has been demonstrated in several malignancies, while other major urologic malignancies, including renal cell carcinoma and upper tract urothelial carcinoma, have also been addressed retrospectively. It is only a matter of time before the data will be sufficient for qualitative systematic review/qualitative evidence synthesis. In the current study, we performed a literature review to define the association between PBT and the oncological outcomes in patients who undergo surgery for major urologic malignancies. We believe that the current review of the literature will increase awareness of the importance and relevance of this issue, as well as highlight the need for evidence-based standards for blood transfusion as well as more controlled transfusion thresholds.


Construction of chitin/PVA composite hydrogels with jellyfish gel-like structure and their biocompatibility.
High strength chitin/poly(vinyl alcohol) (PVA) composite hydrogels (RCP) were constructed by adding PVA into chitin dissolved in a NaOH/urea aqueous solution, and then by cross-linking with epichlorohydrin (ECH) and freezing-thawing process. The RCP hydrogels were characterized by field emission scanning electron microscopy, FTIR, differential scanning calorimetry, solid-state (13)C NMR, wide-angle X-ray diffraction, and compressive test. The results revealed that the repeated freezing/thawing cycles induced the bicrosslinked networks consisted of chitin and PVA crystals in the composite gels. Interestingly, a jellyfish gel-like structure occurred in the RCP75 gel with 25 wt % PVA content in which the amorphous and crystalline PVA were immobilized tightly in the chitin matrix through hydrogen bonding interaction. The freezing/thawing cycles played an important role in the formation of the layered porous PVA networks and the tight combining of PVA with the pore wall of chitin. The mechanical properties of RCP75 were much higher than the other RCP gels, and the compressive strength was 20× higher than that of pure chitin gels, as a result of broadly dispersing stress caused by the orderly multilayered networks. Furthermore, the cell culture tests indicated that the chitin/PVA composite hydrogels exhibited excellent biocompatibility and safety, showing potential applications in the field of tissue engineering.


Heritabilities of intraocular pressure in the population of Korea: the Korean National Health and Nutrition Examination Survey 2008-2009.
Intraocular pressure (IOP) is the principal modifiable risk factor for the progression of primary open-angle glaucoma. Studies that have measured the IOP directly in large numbers of matched parent-offspring pairs are limited in Asian populations. To compare IOPs in parents and their offspring in Korea. Family-based cohort study examining data from the Korean National Health and Nutrition Examination Survey conducted between 2008 and 2009. Data were obtained from 9700 participants from Korea. Familial correlations for IOP were calculated in different types of relative pairs. Variance component methods were used to obtain heritability estimates. The individuals were stratified into 2 groups (those with and those without an IOP of ≥ 19 mm Hg; ie, high IOP group and nonhigh IOP group) based on the mean plus 2 SD IOP value of the entire study population. We evaluated the impact of parents' high IOP on offspring's high IOP. The relationship between parental systemic disease and high IOP in their offspring was also investigated. The mean (SD) IOPs in the right and left eyes were 13.90 (2.74) and 13.89 (2.74) mm Hg, respectively. Correlation coefficient estimates between parent-offspring pairs, sibling pairs, and spouse pairs for IOP were significant as 0.19, 0.31, and 0.29 (P < .001, P = .001, and P < .001, respectively). The total variance of the phenotype under study was explained by 2 sources of variation, additive genetic (36% [95% CI, 32%-40%]) and unique environment (64% [95% CI, 60%-68%]). The risks of high IOP conferred by parents' high IOP were found to be significant for participants whose parents had high IOP (odds ratio, 9.76 [95% CI, 2.16-44.12]). In this study, high IOP was not associated with parental diabetes mellitus, hypertension, obesity, or metabolic syndrome. Intraocular pressure showed a significant heritable tendency from parents to their offspring with a heritability estimate of 0.36 in Asian populations. The risk of high IOP was significantly increased in participants whose parents had high IOP. This has potential implications for the screening of family members of patients with ocular hypertension and glaucoma.


Kinetic mechanism and the rate-limiting step of Plasmodium vivax serine hydroxymethyltransferase.
Serine hydroxymethyltransferase (SHMT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes a hydroxymethyl group transfer from L-serine to tetrahydrofolate (H4folate) to yield glycine and 5,10-methylenetetrahydrofolate (CH2-H4folate). SHMT is crucial for deoxythymidylate biosynthesis and a target for antimalarial drug development. Our previous studies indicate that PvSHMT catalyzes the reaction via a ternary complex mechanism. To define the kinetic mechanism of this catalysis, we explored the PvSHMT reaction by employing various methodologies including ligand binding, transient, and steady-state kinetics as well as product analysis by rapid-quench and HPLC/MS techniques. The results indicate that PvSHMT can bind first to either L-serine or H4folate. The dissociation constants for the enzyme·L-serine and enzyme·H4folate complexes were determined as 0.18 ± 0.08 and 0.35 ± 0.06 mM, respectively. The amounts of glycine formed after single turnovers of different preformed binary complexes were similar, indicating that the reaction proceeds via a random-order binding mechanism. In addition, the rate constant of glycine formation measured by rapid-quench and HPLC/MS analysis is similar to the kcat value (1.09 ± 0.05 s(-1)) obtained from the steady-state kinetics, indicating that glycine formation is the rate-limiting step of SHMT catalysis. This information will serve as a basis for future investigation on species-specific inhibition of SHMT for antimalarial drug development.


Cost-effectiveness of vildagliptin for people with type 2 diabetes mellitus in Brazil; findings and implications.
Vildagliptin is an inhibitor of the enzyme dipeptidyl peptidase 4, indicated for the treatment of type 2 diabetes mellitus, combined or not with metformin. This study aims to evaluate the cost-effectiveness of vildagliptin in the Brazilian context. Areas covered: Using MEDLINE, Cochrane Library, Lilacs and CRD, six studies were selected for the economic models. This study utilised cost data in the Brazilian health system to provide the context. Expert commentary: Type 2 diabetes mellitus is an epidemic disease and represents a challenge for all health care systems. Although guidelines clearly define first-line treatment, there are several other promising treatments. Vildagliptin is one of them, resulting in a mean lifetime increase of 0.31 years compared to metformin alone and 1.19 more life years compared to other metformin combinations. Considering observational data, life years with dual vildagliptin-containing treatments were 0.37 more compared to other dual treatments. However, its high cost versus generic metformin and its unclear safety profile weakens its subsequent cost-effectiveness. Consequently, the incorporation of vildagliptin or its combination with metformin is currently not recommended for the Brazilian Health Care System. This may change as more data becomes available.


[Evaluation of the morphology of stapedial reflex in otosclerosis. Provoked otosclerotic stapedial reflex].
Stapedial reflex is used, amongst other pathologies, for the study of otosclerosis. In this retrospective study we have collected 188 cases of patients with otosclerosis whose diagnosis has been confirmed surgically and their first line relatives. We have performed a descriptive analysis of audiometric tests, tympanometries and ipsilateral stapedial reflexes in relation with the evolutive phase of the disease. Transmission hypoacusis has been seen in 54%, mixed hypoacusis in 29% and sensorineural hypoacusis 8% of cases. On and OFF stapedial reflexes have been seen in 18%, inverted reflexes in 46% and absent reflexes in 27% of cases. The original drawings of the different types of reflexes during the evolution of otosclerosis can be seen in the four figures shown in the study: normal reflexes; ON and OFF a, b and c types; inverted a and b; and absent reflexes. The clinical evolutive phase and the audiometric and impedance tests have been correlated. Through Chi-square (p < 0.001), we have obtained a statistical significance in relation to the use of stapedial reflexes. Also it has been suggested the use of provoked stapedial reflexes in patients with sub clinical otosclerosis in order to diagnose the disease. We conclude that the knowledge of the evolutive morphology os stapedial reflexes in otosclerosis helps diagnostic capacity.


Eph/ephrin signalling and function in oncogenesis: lessons from embryonic development.
Eph receptors and their membrane-bound ephrin ligands are developmental cell guidance cues that direct cell migration and orchestrate patterning processes by modulating adhesive or repulsive cell properties. During the past two decades, an exponentially growing interest in their function has resulted in a considerably advanced understanding of the cellular and molecular principles of Eph function in normal and oncogenic development. Ephs not only accurately guide the path of migrating cells, but also facilitate contact and communication between neighbouring cell populations, in particular at epithelial/mesenchymal boundaries. Precise cell positioning not only relies on accurately-graded expression of individual Eph/ephrin pairs, but on the sum of interactions within particular expression domains and their modulation through crosstalk with a range of other signalling systems. There is little doubt that Eph and ephrins provide exciting new targets for anti-cancer therapies, but in appreciation of the complexity of their signals and biological functions it is perhaps not surprising that the development of Eph-specific therapeutics is only emerging.


Oxidative Stress and Low Glutathione in Common Ear, Nose, and Throat Conditions: A Systematic Review.
Context • Oxidative stress and tissue-damaging, oxygen (O2)-related, free-radical formation is inherent in human metabolism, and the tissues of the ear, nose, and throat (ENT) have an increased exposure to injury from those substances. Because glutathione (GSH) is a major component in an antioxidant defense against oxidative damage in ENT tissues, a review of the impact of lowered GSH and oxidative stress in conditions associated with the upper respiratory tract is warranted. Objective • The review intended to summarize the role that oxidative stress and GSH play. Design • The research team performed a literature review from 1980 to the present that was based on the following keywords: oxidative stress, oxidation, antioxidant, and GSH in common ENT conditions. The review found the following conditions: (1) rhinitis, (2) allergic rhinitis, (3) chronic rhinosinusitis (CRS), (4) CRS with polyps, (5) otitis media with effusion, (6) chronic otitis media (COM), (7) COM and cholesteatoma, (8) tympanic membrane sclerosis, (9) tonsillitis, (10) Meniere's disease, (11) laryngeal conditions, and (12) chronic cough. Results • ENT conditions have been found to be associated with oxidative stress and with low GSH. A limited number of the reviewed studies discussed antioxidant use or repletion of GSH. Although only a few reports support the use of GSH or antioxidants as adjuncts in the management of ENT conditions, no reports of side effects were found related to their use. Conclusions • Many ENT conditions are associated with oxidative stress and decreased GSH, both locally in the affected tissues and systemically. The oxidative stress of those conditions may be related to depletion of GSH, which is increased by the higher levels of O2 in the upper respiratory tract. A small number of studies have reported clinical benefits from the use of an antioxidant or GSH support. The findings of benefits and the lack of reports of side effects suggest that the clinical use of antioxidants and support with GSH in ENT conditions may be considered as adjuncts to conventional management and that more research is warranted.


[Comparison among measures to prevent intrauterine adhesions after artificial abortion].
To investigate the clinical efficacy of oral medicine and sodium hyaluronate in prevention of intrauterine adhesions after artificial abortion. A total of 572 patients with early pregnancy termination through artificial abortion, who experienced two or more times of abortion, were retrospectively analyzed. Patients were randomly and voluntarily divided into 4 groups: an artificial cycle group, a drospirenone and ethinylestradiol tablets group, a sodium hyaluronate group, and a control group. The thickness of the endometrium, return time of menses, and the status of intrauterine adhesions were observed. The thickness of the endometrium in the artificial period group was greater than that in the control group (P<0.001). It was less in the drospirenone and ethinylestradiol tablets group comparing with that in the control group (P<0.001). There was no significant difference in the thickness of the endometrium between the sodium hyaluronate group and the control group (P=0.717). Return time of menses in the artificial menstrual cycle group and the drospirenone and ethinylestradiol tablets group was shorter than that in the control group (P<0.001). There was no significant difference in return time of menses between the sodium hyaluronate group and the control group (P=0.813). The incidence of intrauterine adhesions could be reduced by the 3 preventive measures (All P<0.01). Drugs for artificial cycle and drospirenone and ethinylestradiol tablets medication immediately after artificial abortion can effectively promote endometrial repair and reduce the incidence of intrauterine adhesions. However, for the patients with poor compliance, drospirenoneand ethinylestradiol tablets are the first choice for prevention of intrauterine adhesion.


Community organization moderates the effect of alcohol outlet density on violence.
There is growing evidence from multiple disciplines that alcohol outlet density is associated with community levels of assault. Based on the theoretical and empirical literatures on social organization and crime, we tested the hypothesis that the association between alcohol outlet density and neighbourhood violence rates is moderated by social organization. Using geocoded police data on assaults, geocoded data on the location of alcohol outlets, and controlling for several structural factors thought to be associated with violence rates, we tested this hypothesis employing negative binomial regression with our sample of 298 block groups in Cincinnati. Our results revealed direct effects of alcohol outlet density and social organization on assault density, and these effects held for different outlet types (i.e., off-premise, bars, restaurants) and levels of harm (i.e., simple and aggravated assaults). More importantly, we found that the strength of the outlet-assault association was significantly weaker in more socially organized communities. Subsequent analyses by level of organization revealed no effects of alcohol outlet density on aggravated assaults in organized block groups, but significant effects in disorganized block groups. We found no association between social (dis)organization and outlet density. These results clarify the community-level relationship between alcohol outlets and violence and have important implications for municipal-level alcohol policies.


Identification of novel susceptibility methylation loci for pancreatic cancer in a two-phase epigenome-wide association study.
The role of DNA methylation and its interplay with gene expression in the susceptibility to pancreatic cancer (PanC) remains largely unexplored. To fill in this gap, we conducted an integrative two-phase epigenome-wide association study (EWAS) of PanC using genomic DNA from 44 cases and 556 controls (20 local controls and 536 public controls in the Framingham Heart Study) in phase 1 and 23 cases and 22 controls in phase 2. We validated the findings using pre-diagnostic blood samples from 13 cases and 26 controls in the Women's Health Initiative (WHI) Study. We further examined gene expression in peripheral leukocytes of 47 cases and 31 controls involved in the methylation study using RNA sequencing and performed bidirectional Mendelian randomization (MR) analysis using existing single nucleotide polymorphism (SNP) data. In phase 1, we identified 2776 significantly differentially methylated CpG sites (DMPs) and 154 significantly differentially methylated regions (DMRs). In phase 2, we validated six DMPs (in or near AIM2, DGKA, STK39, and TNFSF8) and three DMRs (in or near nc886, LY6G5C, and HLA-DPB1). The DMR near nc886 was further validated in the WHI samples (P = 6.69 × 10-5). MR analysis suggested that the CpG sites cg00308130 and cg16684184 for nc886 and cg16875057 for STK39 were causally related to PanC susceptibility and that PanC influenced methylation of cg15354065 for DGKA. This first integrative EWAS of PanC provides novel insights into the role of DNA methylation and its interplay with SNPs and gene expression in the disease susceptibility.


Inverse Association Between Circulating Monocyte-Platelet Complexes and Inflammation in Ulcerative Colitis Patients.
Circulating monocytes from active ulcerative colitis (UC) patients produced high levels of tumor necrosis factor-alpha(TNFα) and interleukin(IL)-6 after Toll-like receptors (TLR) stimulation. Since platelets (PLT) can bind to leukocytes, thereby decreasing inflammatory cytokine production, UC patients may exhibit different levels of monocyte-platelet complexes depending on disease activity. We compared among healthy donors, active (onset flare and relapse), and inactive UC patients the presence of circulating monocyte-platelet complexes (CD14+PLT+) and membrane CD162 expression by flow cytometry. Lipopolysaccharide- binding protein, TNFα, and IL-10 were compared by ELISA. Binding of CD14+PLT+ to human umbilical vein endothelial cells (HUVECs) were analyzed by immunofluorescence. Onset flare UC patients had the lowest levels of CD14+PLT+. Membrane CD162, crucial for the PLT binding, was downregulated only on monocytes from onset flare UC patients. Membrane CD162 expression on CD14+ cells inversely correlated with lipopolysaccharide binding protein levels. As an expected consequence, more CD14+PLT+ than CD14+PLT- from onset flare UC patients bound to activated HUVECs. TNFα tended to negatively correlate with CD14+PLT+ in relapse and inactive UC patients, whereas IL-10 positively correlated with CD14+PLT+ in all UC patients (r = -0.43, P = 0.1 and r = 0.61, P = 0.01, respectively). The anti-inflammatory role of PLT binding to monocytes was confirmed in cocultures of PLT and monocytes. These cocultures increased the percentage of CD14+PLT+ and IL-10 production, and decreased TNFα production. These anti-inflammatory effects were abolished when we blocked the binding of PLT with neutralizing anti-CD62P antibody. Decreased CD162 expression associated with endotoxemia reduced the binding of PLT to monocytes through membrane CD162-CD62P, favoring the inflammatory response of onset flare UC patients.


Analysis of notch lacking the carboxyl terminus identified in Drosophila embryos.
The cell surface receptor Notch is required during development of Drosophila melanogaster for differentiation of numerous tissues. Notch is often required for specification of precursor cells by lateral inhibition and subsequently for differentiation of tissues from these precursor cells. We report here that certain embryonic cells and tissues that develop after lateral inhibition, like the connectives and commissures of the central nervous system, are enriched for a form of Notch not recognized by antibodies made against the intracellular region carboxy-terminal of the CDC10/Ankyrin repeats. Western blotting and immunoprecipitation analyses show that Notch molecules lacking this region are produced during embryogenesis and form protein complexes with the ligand Delta. Experiments with cultured cells indicate that Delta promotes accumulation of a Notch intracellular fragment lacking the carboxyl terminus. Furthermore, Notch lacking the carboxyl terminus functions as a receptor for Delta. These results suggest that Notch activities during development include generation and activity of a truncated receptor we designate NDeltaCterm.


Smith-Purcell radiation emission in aligned nanoparticles
Smith-Purcell (SP) radiation produced by interaction of fast electron beams running parallel to strings of nanoparticles is investigated. Results for the radiation emission probability and electron energy loss spectra using finite and infinite strings of Al and silica spheres are presented. Both of these quantities are obtained by solving Maxwell's equations exactly using a multipole expansion approach. The response of the spheres is described in terms of their local frequency-dependent dielectric functions. In silica, the emission probability is seen to coincide with the energy loss probability within the gap region, where the solid cannot absorb any energy. Large emission rates are predicted for Al, suggesting its possible application in tunable soft uv light generation. The dependence of the emission on the size of the spheres, the string period, and the electron energy is discussed in detail. Finite size effects are also studied for strings of 1-15 Al spheres.


[Physical developmental features in Magadan children and adolescents].
The age-related time course of changes in the anthropometric parameters was studied in children and adolescents aged 11-16 years who lived in Magadan. There were no great differences in the basic overall body measurements between the boys who were and not going in for sport. Among the adolescents, individuals who had a weak constitution were found to be predominant. Harmonic development was observed in 78.0-83.9% of the children and adolescents who were going in for sport and in 69.7-82.4% of those who were not. The proportion of boys who were dysharmonically developed was higher among those who were not going in for sport. Physical malformations were mainly associated with body mass deficit.


Application Site and Mosquito Age Influences Malathion- and Permethrin-Induced Mortality in Culex quinquefasciatus (Diptera: Culicidae).
Concentrations of malathion and permethrin typical in droplets generated from ultra-low-volume and low-volume applications used to control mosquito populations were evaluated for efficacy against multiple-aged Culex quinquefasciatus Say (Diptera: Culicidae), using a topical bioassay. Although insecticide droplets will impinge on many exoskeletal body regions and a range of ages of mosquitoes in a population, traditional mosquito topical bioassays focus pesticide application to the mesothoracic pleural or dorsal regions across an average mosquito age (e.g., 3-7 d). Our results document nonuniform insecticide sensitivity across body regions at ages not previously assessed in mosquitoes (teneral and 14-d old). We expect our findings to influence the topical bioassay process, illustrating the difference in mosquito body regions and ages that ultimately may explain insecticide effectiveness wherever droplets impinge upon the mosquito body during field control applications.


The use of autozygosity mapping and next-generation sequencing in understanding anterior segment defects caused by an abnormal development of the lens.
The formation of the anterior segment of the eye is an intricate process that is dependent to a large degree on the normal development of the lens. Despite intensive study of the role of well-described eye genes, many causes of lenticular and anterior segment anomalies remain elusive. The majority of genes implicated thus far act in an autosomal dominant manner. Autosomal recessive causes are less well described; their diagnosis has been hindered by technological limitations, extreme genetic heterogeneity, a lack of understanding of eye biology and the role of many genes within the genome. The opportunity for the discovery of extremely rare autosomal recessive causes of ocular abnormalities from the study of consanguineous families is large, particularly through the powerful combination of next-generation sequencing with autozygosity mapping. Having begun to overcome the genetic heterogeneity bottleneck, it is increasingly recognised that the interpretation of genetic variants and the association of novel genes with a particular phenotype remain challenging. Nonetheless, increasing understanding of the genetic and mutational basis of lens and anterior segment abnormalities will be of enormous value to our comprehension of eye disease(s). Further, it will improve our ability to accurately interpret putative disease-causing variants with the aim of providing more personalised patient care and avoiding lifelong visual loss in children.


Travellers returning from the island of Zanzibar colonized with MDR Escherichia coli strains: assessing the impact of local people and other sources.
Many travellers to low-income countries return home colonized at the intestinal level with extended-spectrum cephalosporin-resistant (ESC-R) and/or colistin-resistant (CST-R) Escherichia coli (Ec) strains. However, nothing is known about the local sources responsible for the transmission of these pathogens to the travellers. We compared the ESC-R- and CST-R-Ec strains found in the pre- (n = 23) and post-trip (n = 37) rectal swabs of 37 travellers from Switzerland to Zanzibar with those (i) contemporarily isolated from local people, poultry, retailed chicken meat (n = 31), and (ii) from other sources studied in the recent past (n = 47). WGS and core-genome analyses were implemented. Twenty-four travellers returned colonized with ESC-R- (n = 29) and/or CST-R- (n = 8) Ec strains. Almost all ESC-R-Ec were CTX-M-15 producers and belonged to heterogeneous STs/core-genome STs (cgSTs), while mcr-positive strains were not found. Based on the strains' STs/cgSTs, only 20 subjects were colonized with ESC-R- and/or CST-R-Ec that were not present in their gut before the journey. Single nucleotide variant (SNV) analysis showed that three of these 20 travellers carried ESC-R-Ec (ST3489, ST3580, ST361) identical (0-20 SNVs) to those found in local people, chicken meat, or poultry. Three further subjects carried ESC-R-Ec (ST394, ST648, ST5173) identical or highly related (15-55 SNVs) to those previously reported in local people, fish, or water. This is the first known study comparing the ESC-R- and/or CST-R-Ec strains obtained from travellers and local sources using solid molecular methods. We showed that for at least one-third of the returning travellers the acquired antibiotic-resistant Ec had a corresponding strain among resident people, food, animal and/or environmental sources.


[Transition of Children with Epilepsy to Adult Care: Current Status and Challenge].
Thirty percent of the patients consulting a pediatric neurologist have already reached adulthood as patients and their families do not like transfer to the adult clinics; moreover, there are no suitable clinics. Pediatric neurologists find it difficult to examine adult patients with childhood-onset epilepsy as they are unfamiliar with the psychiatric and psychological symptoms manifested in adulthood, and the common diseases of adulthood. On the other hand, adult neurologists have difficulty obtaining a complete picture of the patient's clinical history since childhood, and are unfamiliar with childhood-specific epilepsy syndrome. When it comes to transition, the patient's decision should be prioritized. Transition should be patient-centered, with cornerstones of flexibility, responsiveness, continuity, comprehensiveness, and coordination. For successful transition to occur, there must be psychosocial support, patient education, better medical system organization with inclusion of a transition process, such as transition clinic, increased number of epilepsy-specialized physicians/nurses, and resources such as checklists and programs to aid in transition.


Single-molecule study on polymer diffusion in a melt state: effect of chain topology.
We report a new methodology for studying diffusion of individual polymer chains in a melt state, with special emphasis on the effect of chain topology. A perylene diimide fluorophore was incorporated into the linear and cyclic poly(THF)s, and real-time diffusion behavior of individual chains in a melt of linear poly(THF) was measured by means of a single-molecule fluorescence imaging technique. The combination of mean squared displacement (MSD) and cumulative distribution function (CDF) analysis demonstrated the broad distribution of diffusion coefficient of both the linear and cyclic polymer chains in the melt state. This indicates the presence of spatiotemporal heterogeneity of the polymer diffusion which occurs at much larger time and length scales than those expected from the current polymer physics theory. We further demonstrated that the cyclic chains showed marginally slower diffusion in comparison with the linear counterparts, to suggest the effective suppression of the translocation through the threading-entanglement with the linear matrix chains. This coincides with the higher activation energy for the diffusion of the cyclic chains than of the linear chains. These results suggest that the single-molecule imaging technique provides a powerful tool to analyze complicated polymer dynamics and contributes to the molecular level understanding of the chain interaction.


Controlling the growth of a SiO2 coating on hydrophobic CsPbBr3 nanocrystals towards aqueous transfer and high luminescence.
Silica coating can effectively solve the stability issue of lead halide perovskite nanomaterials. However, it is difficult to achieve aqueous SiO2 coating on hydrophobic CsPbBr3 nanocrystals (NCs). In this paper, the hydrolysis process of tetramethoxysilane was controlled to get a homogeneous SiO2 coating or a NC/SiO2 Janus structure. In step 1, the Cs4PbBr6 NCs were silanized using partially hydrolyzed tetramethoxysilane (PH-TMOS). During this process, the Si-OH groups which came from PH-TMOS were absorbed onto the surface of the Cs4PbBr6 NCs with the removal of hydrophobic oleic acid (OA) ligands. In step 2, phase transformation from Cs4PbBr6 to CsPbBr3 occurred owing to the injection of water. Meanwhile, further hydrolysis of TMOS took place and generated cross-linked Si-O-Si. Because the silanization in step 1 created lots of growth sites, the condensation of SiO2 was not limited to the interface between water and hexane. After growing for 12 h, the fully covered CsPbBr3@SiO2 capsules were prepared. The anion exchange reactions of the CsPbBr3@SiO2 capsules were studied. Only one even and symmetric PL peak was apparent during the anion exchange process, which was different from the bare CsPbBr3 NCs. This result demonstrated that the SiO2 shell can act as a buffer layer to block the direct contact of CsPbBr3 with the excess PbBr2 precursor in solution. Compared with the CsPbBr3 NCs, CsPbBr3@SiO2 showed better stability in polar solvent and air. A bright green emission was also observed under UV light after 90 days. The successful preparation of CsPbBr3@SiO2 capsules with enhanced stability paves the way for the further development of lead halide perovskite nanomaterials.


Volume-Based Feeding in the Critically Ill Patient.
Critically ill patients placed on enteral nutrition (EN) are usually underfed. A volume-based feeding (VBF) protocol designed to adjust the infusion rate to make up for interruptions in delivery should provide a greater volume of EN than the more common fixed hourly rate-based feeding (RBF) method. This single-center, randomized (3:1; VBF/RBF) prospective study evaluated critically ill patients on mechanical ventilation expected to receive EN for ≥ 3 days. Once goal rate was achieved, the randomized feeding strategy was implemented. In the VBF group, physicians used a total goal volume of feeds to determine an hourly rate. For the RBF group, physicians determined a constant hourly rate of infusion to meet goal feeds. Sixty-three patients were enrolled in the study with a mean age of 52.6 years (60% male). Six patients were excluded after randomization because of early extubation. The VBF group (n = 37) received 92.9% of goal caloric requirements with a mean caloric deficit of -776.0 kcal compared with the RBF group (n = 20), which received 80.9% of goal calories (P = .01) and a caloric deficit of -1933.8 kcal (P = .01). Uninterrupted EN was delivered for 51.7% of all EN days in VFB patients compared with 54.5% in RBF patients. On days when feeding was interrupted, VFB patients overall received a mean 77.6% of goal calories (while RBF patients received 61.5% of goal calories, P = .001). No vomiting, regurgitation, or feeding intolerance occurred due to VBF. A VBF strategy is safe and improves delivery to better meet caloric requirements than the standard more commonly used rate-based strategy.


Chuanxiong (Rhizome of Ligusticum chuanxiong) Protects Ovariectomized Hyperlipidemic Rats from Bone Loss.
Oxidative stress (OS) is the common mechanism for age-related diseases. The co-occurrence of osteoporosis (OP) and cardiovascular disease (CVD) in postmenopausal women makes it warranted to find a holistic approach for treatment of multiple diseases or conditions. The rhizome of Ligusticum chuanxiong Hort. (CX), which has high anti-oxidant properties and is widely used for CVD treatment in China, might be the potential candidate. In the present study, CX ethanol extract (CXE) was applied to H2O2 induced MG63 cells to study its effects and mechanisms on osteoblastogenesis against OS. CXE was then administered to six-month-old Sprague Dawley sham or ovariectomized (OVX) rats fed either a low saturated fat-sucrose (LFS) or a high fat-sucrose (HFS) diet for 12 weeks, to confirm its anti-osteoporotic effects. The results demonstrated that CXE directly improved proliferation and differentiation in vitro in an H2O2-induced osteoblast cell model by attenuating cellular reactive oxygen species levels and inhibiting osteoblast apoptosis via PI3K/Akt signaling pathway. CXE significantly improved bone properties as revealed by the increase in trabecular bone mineral density and decrease in trabecular separation at proximal metaphysis of the tibia (PT) in HFS-fed OVX rats but not in LFS-fed OVX rats. CXE ameliorated dyslipidemia, greatly reduced lipid deposition and malondialdehyde levels, improved activities of superoxide dismutase, catalase and glutathione peroxidase in the livers of HFS-fed OVX rats. In conclusion, CXE could favor osteoblastogenesis against OS. The ability of CXE to reduce bone loss in HFS-fed OVX rats was associated with its abilities to correct dyslipidemia, and reduce lipid deposition and OS levels.


Mediastinal paragangliomas: the mayo clinic experience.
Extra-adrenal catecholamine-secreting tumors are referred to as paragangliomas. We reviewed our experience with mediastinal paragangliomas treated at Mayo Clinic over the last 30 years. Fourteen patients were identified who had resection of a mediastinal paraganglioma between 1973 and 2007. Perioperative data obtained from the medical record and follow-up information were reviewed. The median age of patients at operation was 39 years (range, 27 to 68 years), 71% were female, and all had a history of hypertension. Preoperative diagnosis of a catecholamine-secreting tumor was confirmed through elevated 24-hour urinary norepinephrine in 12 patients and tumor location was determined with metaiodobenzylguanidine scintigraphy, computed tomography or magnetic resonance imaging scans in the majority. The tumor was adjacent to the heart or great vessels in all patients and was resected through a median sternotomy (n = 10), or with posterolateral thoracotomy (n = 4). In 6 patients, cardiopulmonary bypass was used to facilitate dissection of the paraganglioma from the heart or great vessels. There was one intraoperative death in this series due to blood loss. Ten of the 11 patients were alive at follow-up (median follow-up: 2.3 years; range, 0 to 19.4 years). Symptoms of catecholamine excess were eliminated or greatly improved in all patients who had a functioning tumor preoperatively, but 6 of these patients were still being treated with antihypertensive medications. Functional paragangliomas can be diagnosed with measurement of fractionated catecholamines and metanephrines; mediastinal localization is determined with appropriate scanning techniques. These tumors can be treated successfully by surgical resection with modest surgical risk, often necessitating cardiopulmonary bypass, with good long-term survival. Hypertension may persist even after complete resection of the tumor.


Dry soils can intensify mesoscale convective systems.
Soil moisture can feed back on rainfall through the impact of surface fluxes on the environment in which convection develops. The vast majority of previous research has focused on the initiation of convection, but in many regions of the world, the majority of rain comes from remotely triggered mesoscale convective systems (MCSs). Here we conduct a systematic observational analysis of soil moisture feedbacks on propagating MCSs anywhere in the world and show a strong positive impact of drier soils on convection within mature MCSs. From thousands of storms captured in satellite imagery over the Sahel, we find that convective cores within MCSs are favored on the downstream side of dry patches ≥200 km across. The effect is particularly strong during the afternoon-evening transition when convection reaches its diurnal peak in intensity and frequency, with dry soils accounting for an additional one in five convective cores. Dry soil patterns intensify MCSs through a combination of convergence, increased instability, and wind shear, all factors that strengthen organized convection. These favorable conditions tend to occur in the vicinity of a surface-induced anomalous displacement of the Sahelian dry line/intertropical discontinuity, suggesting a strong link between dry line dynamics and soil moisture state. Our results have important implications for nowcasting of severe weather in the Sahel and potentially in other MCS hotspot regions of the world.


KVCT, MVCT, and hybrid CT image studies--treatment planning and dose delivery equivalence on helical tomotherapy.
To determine the equivalence of radiation therapy treatment planning and delivery for various imaging options on helical tomotherapy. Seven treatment plans using identical anatomy and planning parameters were created based on the following CT studies: Standard kilovoltage CT (kVCT); 2, 4, and 6 mm spacing megavoltage CT (MVCT); and 2, 4, and 6 mm hybrid MVCT/kVCT studies. In addition, two kVCT based plans were created to explore the effect of the choice of dose calculation grid for optimization. Calculated and measured dose distributions were compared via volumetric and dosimetric analysis at the planning stage, point dose measurements with ion chamber, along with EDR2 film data for gamma function analysis for distance to agreement of 3 mm and dose differences of 3%, 5%, and 7% using both the commercially available "cheese" phantom and the new QUASAR Verification (QVer) phantom. Plans created for each imaging option showed residual error increasing as image slice spacing increased and critical structure size decreased. With the exception of the low dose area in hybrid studies, point dose measurements were within the calculated/measured dose acceptance criteria of 5% on both the QVer and cheese phantoms. Gamma analysis for the original kVCT plan delivery showed an average of 98.5% +/- 0.5% and 98.8% +/- 0.3% of dose pixels passing kVCT study treatment and delivery quality assurance procedures, respectively. The QVer phantom allows for delivery quality assurance with simultaneous use of two films and more convenient gamma function assessment but shows some measurement discrepancy up to 10% compared to the cheese phantom. The kVCT, MVCT, and kVCT/MVCT hybrid studies showed considerable agreement at both planning and delivery stages. The choice of calculation grid is more important when dealing with smaller anatomical structures.


Embedding 3D models of biological specimens in PDF publications.
By providing two examples, the option for embedding 3D models in electronic versions of life science publications is presented. These examples, presumably representing the first such models published, are developmental stages of an evertebrate (Patella caerulea, Mollusca) and a vertebrate species (Psetta maxima, Teleostei) obtained from histological section series reconstruction processed with the software package Amira. These surface rendering models are particularly suitable for a PDF file because they can easily be transformed to a file format required and components may be conveniently combined and hierarchically arranged. All methodological steps starting from specimen preparation until embedding of resulting models in PDF files with emphasis on conversion of Amira data to the appropriate 3D file format are explained. Usability of 3D models in PDF documents is exemplified and advantages over 2D illustrations are discussed, including better explanation capabilities for spatial arrangements, higher information contents, and limiting options for disguising results by authors. Possibilities for additional applications reaching far beyond the examples presented are suggested. Problems such as long-term compatibility of file format and hardware plus software, editing and embedding of files, file size and differences in information contents between printed and electronic version will likely be overcome by technical development and increasing tendency toward electronic at the cost of printed publications. Since 3D visualization plays an increasing role in manifold disciplines of science and appropriate tools for the popular PDF format are readily available, we propose routine application of this way of illustration in electronic life science papers.


[Enterosorption in experimental acute kidney failure].
The paper provides the results of 32 experiments on 22 mongrel male dogs with a view to measuring creatinine levels in the lumen of various intestinal segments before and after bilateral nephrectomy and evaluating the effects the enterosorbent brand SKN administered into isolated portions of the intestinal tube on alteration of intraluminal concentrations of creatinine, serum creatinine, and "middle-sized" molecules. Four parts of the intestine were identified: (1) proximal; (2) middle and (3) distal portions of the small intestine, and (4) the large intestine up to the anal sphincter. Two days following bilateral nephrectomy, creatinine levels were increased in the proximal, middle, distal portions of the small bowel and in the large bowel by 18, 11, 5, and 1.4 times, respectively, as compared to the baseline creatinine concentration in the intestinal parts mentioned. The administration of the enterosorbent into the different intestinal parts revealed that with its 6-hour exposure, the most potent effect (lower concentrations of creatinine and "middle-sized" molecules in serum) was observed in the proximal portions of the small bowel. This phenomenon is likely to be attributable to greater vascularization and the maximal creatinine and "middle-sized" molecule concentration in these intestinal portions. With this, it was shown that the higher baseline concentrations of serum creatinine and "middle-sized" molecules were, the more actively they absorbed on the charcoal enterosorbent brand SKN in the intestine.


Loa loa and Mansonella perstans microfilaremia in the department of Lékoumou, Republic of Congo.
Loiasis is endemic in the northern and western part of the Republic of Congo. Between 2004 and 2010, surveys were conducted, using the RAPLOA method, in all departments of the Republic of Congo to assess the distribution of loiasis. Prior to 2004, only two parasitological surveys on loiasis had been conducted in Congo and mainly in the Department of Lékoumou, in the southwestern of the country. In 2019, we conducted a parasitological survey in this same department, more than 30 years after the first surveys. The study was conducted in 21 villages. Loa loa and Mansonella perstans microfilaremia levels were quantified using 50 µl calibrated blood smears. A total of 2444 individuals were examined. The median age of the screened individuals was 43 (interquartile range: 30-57, range: 18-91) years old. The overall prevalences of L. loa and M. perstans microfilaremia were 20.0% [95% confidence intervals (CI) 18.0-21.6%] and 1.0% (95% CI 0.6-1.4%) respectively. The proportion of individuals with a microfilarial density of L. loa > 8000 mf/ml and > 30,000 mf/ml were 5.1% (95% CI 4.3-6.1%) and 1.1% (95% CI 0.8-1.7%), respectively. The overall community microfilarial load was 3.4 mf/ml. Prevalences and intensities of L. loa infection remained generally stable between the late 1980s and 2019 in the Lékoumou Department. In contrast, parasitological indicators for M. perstans have declined sharply in the intervening years for an unknown reason.


Vitamin B12-loaded chitosan-based nanoparticle-embedded polymeric nanofibers for sublingual and transdermal applications: Two alternative application routes for vitamin B12.
Alzheimer's disease (AD) is a neurodegeneration type that is biologically recognizable via β-amyloid plaques and tau neurofibril tangles. Global estimation for the total count of individuals enduring AD will rise up to 131 million by 2050. Investigations suggested the existence of a direct proportion between the likelihood of AD occurrence and vitamin B12 (VB12) hypovitaminosis. Approved VB12 administrations, intramuscular and oral, each has serious defects broaching the demand for alternative routes. This work developed VB12-loaded chitosan/tripolyphosphate/polyvinyl alcohol (CS/TPP/PVA) nanoparticles (NPs) embedded in polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone/polycaprolactone (PVP/PCL) nanofibrous (NFs) produced by pressurized gyration (PG) for sublingual and transdermal routes, respectively. Biomaterials were investigated morphologically, chemically, and thermally. Moreover, degradation, disintegration, release behavior, and release kinetics were analyzed. The effectiveness and safety of nanomaterials were assessed and proven with the alamarBlue test on the Aβ1-42-induced SH-SY5Y model. The final evaluation suggested the feasibility, safety, and effectiveness of produced systems. Consequently, two alternative VB12 application routes were developed with high effectivity and low toxicity with the power of nanotechnology.


Reversible inactivation of typhus Rickettsiae. I. Inactivation by freezing.
Rickettsiae that have been frozen and thawed in isotonic salt solutions show greatly decreased toxicity for mice, hemolytic activity, respiration, and infectivity for eggs. All these properties can be partially restored by incubation of the rickettsiae in the presence of DPN and coenzyme A for 2 hours at 34 degrees C. The extent of both inactivation and of subsequent reactivation is markedly affected by the presence of low concentrations of sucrose during the process of freezing and thawing. It has been shown that DPN is present in rickettsial suspensions and that in preparations that have not been frozen, the DPN sediments with the rickettsiae. After freezing in isotonic salt solution the DPN becomes non-sedimentable.


A new (singleton) rainfrog of the Pristimantis myersi Group (Amphibia: Craugastoridae) from the northern Andes of Ecuador.
Reserva Las Gralarias is one of the best-studied localities of the Ecuadorian Andes in terms of its batrachofauna. However, as expected in any community, some species are rare and, therefore, their discovery and description are problematic. Herein, based on a single specimen, we describe Pristimantis gralarias sp nov. Even though we are aware of the problems associated to singleton species (i.e., unknown intraspecific variation, limited ecological information), our efforts to finding additional specimens have been unsuccessful. Thus, given the importance of species descriptions in threatened areas (e.g. Andes), and that the new taxon is supported by both morphological and genetic data, we consider that the description is justified. Pristimantis gralarias sp nov is easily distinguished from all other members of the P. myersi group by its long and slender fingers and toes, with discs that are not expanded laterally (or are only slightly expanded). Furthermore, the new species is characterized by having a black venter with minute white spots and a red groin. A molecular phylogeny corroborates the placement of the new species in the P. myersi group and its distinctiveness in relation to other species. Finally, we discuss on the limitations and advantages associated to species descriptions based on one or few specimens.


High Burden of Antimicrobial Resistance among Bacteria Causing Pyogenic Wound Infections at a Tertiary Care Hospital in Kathmandu, Nepal.
Pyogenic wound infections are one of the most common clinical entities caused and aggravated by the invasion of pathogenic organisms. Prompt and aggressive antimicrobial therapy is needed to reduce the burden and complications associated with these infections. In this study, we intended to investigate the common pathogens and their antimicrobial susceptibility patterns from the pyogenic wound infections at a tertiary care hospital in Kathmandu, Nepal. A laboratory based cross-sectional study was carried out among the pyogenic clinical specimens of the patients visiting Manmohan Memorial Teaching Hospital, Kathmandu, Nepal. Processing of clinical specimens and isolation and identification of bacterial pathogens were carried out using standard microbiological methods. Antimicrobial susceptibilities and resistant profiles were determined by following the standard guidelines of Clinical and Laboratory Standards Institute (CLSI). About 65% of the clinical specimens were positive for the bacterial growth and Gram positive bacteria (57.4%) were the leading pathogens among pyogenic wound infections. Staphylococcus aureus (412, 49.28%), Escherichia coli (136, 16.27%), Klebsiella spp. (88, 10.53%), and Pseudomonas spp. (44, 5.26%) were the common pathogens isolated. High level of drug resistance was observed among both Gram positive bacteria (51.9%) and Gram negative bacteria (48.7%). Gram positive isolates were resistant to ampicillin, ciprofloxacin, cotrimoxazole, erythromycin, and cloxacillin. Gram negative isolates were resistant to cephalosporins but were well susceptible to amikacin and imipenem. Pyogenic wound infections are common in our hospital and majority of them were associated with multidrug resistant bacteria. The detailed workup of the prevalent pathogens present in infected wounds and their resistance pattern is clearly pertinent to choosing the adequate treatment.


Positive psychological well-being and mortality: a quantitative review of prospective observational studies.
To review systematically prospective, observational, cohort studies of the association between positive well-being and mortality using meta-analytic methods. Recent years have witnessed increased interest in the relationship between positive psychological well-being and physical health. We searched general bibliographic databases: Medline, PsycINFO, Web of Science, and PubMed up to January 2008. Two reviewers independently extracted data on study characteristics, quality, and estimates of associations. There were 35 studies (26 articles) investigating mortality in initially healthy populations and 35 studies (28 articles) of disease populations. The meta-analyses showed that positive psychological well-being was associated with reduced mortality in both the healthy population (combined hazard ratio (HR) = 0.82; 95% Confidence Interval (CI) = 0.76-0.89; p < .001) and the disease population (combined HR = 0.98; CI = 0.95-1.00; p = .030) studies. There were indications of publication bias in this literature, although the fail-safe numbers were 2444 and 1397 for healthy and disease population studies, respectively. Intriguingly, meta-analysis of studies that controlled for negative affect showed that the protective effects of positive psychological well-being were independent of negative affect. Both positive affect (e.g., emotional well-being, positive mood, joy, happiness, vigor, energy) and positive trait-like dispositions (e.g., life satisfaction, hopefulness, optimism, sense of humor) were associated with reduced mortality in healthy population studies. Positive psychological well-being was significantly associated with reduced cardiovascular mortality in healthy population studies, and with reduced death rates in patients with renal failure and with human immunodeficiency virus-infection. The current review suggests that positive psychological well-being has a favorable effect on survival in both healthy and diseased populations.


Quantitative evaluation of human delta opioid receptor desensitization using the operational model of drug action.
Agonist-mediated desensitization of the opioid receptors is thought to function as a protective mechanism against sustained opioid signaling and therefore may prevent the development of opioid tolerance. However, the exact molecular mechanism of opioid receptor desensitization remains unresolved because of difficulties in measuring and interpreting receptor desensitization. In the present study, we investigated deltorphin II-mediated rapid desensitization of the human delta opioid receptors (hDOR) by measuring guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding and inhibition of cAMP accumulation. We developed a mathematical analysis based on the operational model of agonist action (Black et al., 1985) to calculate the proportion of desensitized receptors. This approach permits a correct analysis of the complex process of functional desensitization by taking into account receptor-effector coupling and the time dependence of agonist pretreatment. Finally, we compared hDOR desensitization with receptor phosphorylation at Ser363, the translocation of beta-arrestin2, and hDOR internalization. We found that in Chinese hamster ovary cells expressing the hDOR, deltorphin II treatment leads to phosphorylation of Ser363, translocation of beta-arrestin2 to the plasma membrane, receptor internalization, and uncoupling from G proteins. It is noteworthy that mutation of the primary phosphorylation site Ser363 to alanine had virtually no effect on agonist-induced beta-arrestin2 translocation and receptor internalization yet significantly attenuated receptor desensitization. These results strongly indicate that phosphorylation of Ser363 is the primary mechanism of hDOR desensitization.


Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice.
Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.


Exploring genome wide bisulfite sequencing for DNA methylation analysis in livestock: a technical assessment.
Recent advances made in "omics" technologies are contributing to a revolution in livestock selection and breeding practices. Epigenetic mechanisms, including DNA methylation are important determinants for the control of gene expression in mammals. DNA methylation research will help our understanding of how environmental factors contribute to phenotypic variation of complex production and health traits. High-throughput sequencing is a vital tool for the comprehensive analysis of DNA methylation, and bisulfite-based strategies coupled with DNA sequencing allows for quantitative, site-specific methylation analysis at the genome level or genome wide. Reduced representation bisulfite sequencing (RRBS) and more recently whole genome bisulfite sequencing (WGBS) have proven to be effective techniques for studying DNA methylation in both humans and mice. Here we report the development of RRBS and WGBS for use in sheep, the first application of this technology in livestock species. Important technical issues associated with these methodologies including fragment size selection and sequence depth are examined and discussed.


HLA antigen expression in autoimmune endocrinopathies.
The HLA allelic frequency was determined in three groups of autoimmune endocrinopathies: A) 30 patients with autoimmune thyroiditis, B) 20 patients with polyglandular activation of autoimmunity, and C) 10 patients with the autoimmune polyglandular syndrome type II. The groups were defined by the clinical state and serological parameters. Healthy blood donors of Caucasian population from the US database of HLA frequencies served as the controls. In group A, a higher occurrence of HLA-A24 (21.7 %) was found as compared to group B (5.0 %) and to the controls (8.5 %), of HLA-B27 (15.0 %) and of HLA-DR-11 (20 %) as compared to the controls (4.2 % and 8.5 %). In group B, a higher occurrence of HLA-A3 (25.0 %) was found as compared to group A (10 %) and to the controls (11.8 %), and of HLA-B8 (22.5 %) as compared to group A (8.3 %) and to the controls (8.6 %). In this group the occurrence of HLA-DR3 (30.0 %) was higher as compared to group A (10.0 %) and to the controls (9.8 %) and of HLA-B8 (30.0 %) as compared to group A (8.3 %) and to the controls (8.6 %). Genetic markers indicate a similarity of groups B and C. Patients in these groups could be at different stages of the same disease, however, some distinctions between them lead us to consider the possibility whether different epigenetic factors could extend the difference between these groups in the course of clinical development.


[Policies encouraging price competition in the generic drug market: Lessons from the European experience].
To describe alternative policies aimed at encouraging price competition in generic drug markets in countries with strict price regulation, and to present some case studies drawn from the European experience. Systematic literature review of articles and technical reports published after 1999. The shortcomings in consumer price competition observed in some European generic markets, including Spain, may be reduced through three types of public reimbursement or financing reforms: policies aimed at improving the design of current maximum reimbursement level policies; policies aimed at monitoring competitive prices in order to reimburse real acquisition cost to pharmacies; and, more radical and market-oriented policies such as competitive tendering of public drug purchases. The experience of recent reforms adopted in Germany, Belgium, Holland, Norway, and Sweden offers a useful guide for highly price-regulated European countries, such as Spain, currently characterized by limited consumer price competition and the high discounts offered to pharmacy purchases. Direct price regulation and/or the generic reference pricing systems used to reduce generic drug prices in many European countries can be successfully reformed by adopting measures more closely aimed at encouraging consumer price competition in generic drug markets.


Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis.
Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of α1- and α2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-β-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis.


Association of dietary elements and lower urinary tract symptoms.
The purpose of the study was to establish whether dietary elements are related to lower urinary tract symptoms (LUTS) and thus to diseases causing LUTS. This population-based study was carried out in 1994; a questionnaire was mailed to all men born in 1924, 1934 or 1944 living in Tampere or 11 rural or semi-rural municipalities in the same county, altogether 3143 men. Of this population, 68% were ultimately included in the study. A modified version of the DAN-PSS-1 questionnaire (10 of the questions) was used to assess urinary symptoms and problems arising from them. A symptom index was formed by multiplying the symptom and problem scores for hesitancy, incomplete emptying, urge, urge incontinence, nocturia and daytime frequency, and totalling the products. The men were also asked to report on their medical history, how often they ate vegetables and meat, whether they used butter, margarine or vegetable oil in food, how much alcohol and coffee they consumed, their smoking history and their weight and height. The risk of LUTS was estimated according to the frequency of meat and vegetable intake and the kind of fat used. The confounder-adjusted risk of LUTS was 0.68 (95% CI 0.54-0.86) among men consuming vegetables daily compared with men consuming vegetables less frequently. Compared with men who eat meat less frequently, the confounder-adjusted risk of LUTS was 2.08 (95% CI 1.00-4.10) among men consuming meat weekly, and 2.56 (95% CI 1.30-5.02) among men consuming meat daily. The confounder-adjusted risk of LUTS was 0.73 (95% CI 0.58-0.93) among men who consumed butter compared to those who did not. Dietary elements may also have an important role in the development of diseases causing LUTS. Direct effects of food components may likewise influence the occurrence of LUTS.


Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability.
Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model. An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of eIF-5A2 in aging. Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p < 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice. These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.


Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data.
To determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressants used alone and in combination with a benzodiazepines (BZ). Population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births (British Columbia, Canada, N=119,547) during a 39-month period (1998-2001). The incidence and risk differences (RD) for major congenital anomalies (CA) and congenital heart disease (CHD), including ventricular and atrial septal defects (VSD, ASD), from infants of mothers treated with an SRI alone, a benzodiazepine (BZ) alone, or SRI+BZ in combinationcompared to outcomesno exposure. Risk for a CA or CHD did increase following combined SRI+BZ exposure compared with no exposure. However, using a weighted regression model, controlling for maternal illness characteristics, combination therapy risk remained significantly associated only with CHD. The risk for an ASD was higher following SRI monotherapy compared with no exposure, after adjustment for maternal covariates. Dose/day was not associated with increased risk. Infants exposed to prenatal SRIs in combination with BZs had a higher a incidence of CHD compared to no exposure, even after controlling for maternal illness characteristics. SRI monotherapy was not associated with an increased risk for major CA, but was associated with an increased incidence of ASD. Risk was not associated with first trimester medication dose/day.


Comparison of diagnostic routines for suspected Alzheimer's disease patients in US-American and German primary care.
Aim: Thorough diagnostics are a prerequisite for the optimal treatment of Alzheimer's disease (AD). Biomarker-based diagnostics are standard in academia, data on practitioners' diagnostic workups is scarce. Materials & methods: Surveys in German and US healthcare providers (HCP) were conducted regarding diagnostics in presumed AD patients. A subsample of 153 German and 88 US professionals was analyzed in detail. Results: Fewer German physicians conduct AD diagnostics themselves compared with US colleagues (67% vs 99%; p < 0.0001). German doctors more often order diagnostics at other institutions (65% vs 45%; p < 0.005). No significant differences were found regarding the type of diagnostics ordered at other institutions. Conclusion: Diagnostic routines for suspected AD patients differ between German and US-American healthcare providers.


Lung transplant pathology. A comparative study of pulmonary acute rejection and cytomegaloviral infection.
This article describes a comparative study performed to determine the histologic features of pulmonary rejection and cytomegaloviral (CMV) infection following lung transplantation. Rejection was defined clinically by findings of new pulmonary symptoms or radiographic changes or decreased oxygenation in the absence of documented infection in patients who were treated for rejection and improved. These patients also had negative CMV cultures. CMV infection was studied in a group of non-lung and non-bone marrow transplant patients and was defined by the presence of characteristic nuclear inclusions in lung biopsies. Ten rejection biopsies and nine CMV biopsies were examined. No histologic feature was unique to rejection, however; perivascular lymphocytic infiltrates occurred more frequently and more intensely in rejection than in CMV infection (p = 0.0029). Endothelialitis also occurred more frequently in rejection (p = 0.0331), but it was always seen in association with perivascular lymphocytic inflammation. In rejection, the inflammatory infiltrate was primarily perivascular, with extension into the interstitium in several cases. In contrast, CMV infection was characterized predominantly by interstitial inflammation with involvement of associated vessels. We conclude that although overlapping features are present in both processes, pulmonary rejection can be distinguished from CMV infection on the basis of histology.


Menstrual and reproductive factors and lung cancer risk: A pooled analysis from the international lung cancer consortium.
Many clinical features of lung cancer are different in women and men. Sex steroid hormones exert effects in nonreproductive organs, such as the lungs. The association between menstrual and childbearing factors and the risk of lung cancer among women is still debated. We performed a pooled analysis of eight studies contributing to the International Lung Cancer Consortium (4,386 cases and 4,177 controls). Pooled associations between menstrual or reproductive factors and lung cancer were estimated using multivariable unconditional logistic regression. Subgroup analyses were done for menopause status, smoking habits and histology. We found no strong support for an association of age at menarche and at menopause with lung cancer, but peri/postmenopausal women were at higher risk compared to premenopausal (OR 1.47, 95% CI 1.11-1.93). Premenopausal women showed increased risks associated with parity (OR 1.74, 95% CI 1.03-2.93) and number of children (OR 2.88, 95% CI 1.21-6.93 for more than 3 children; p for trend 0.01) and decreased with breastfeeding (OR 0.54, 95% CI 0.30-0.98). In contrast, peri/postmenopausal subjects had ORs around unity for the same exposures. No major effect modification was exerted by smoking status or cancer histology. Menstrual and reproductive factors may play a role in the genesis of lung cancer, yet the mechanisms are unclear, and smoking remains the most important modifiable risk factor. More investigations in large well-designed studies are needed to confirm these findings and to clarify the underlying mechanisms of gender differences in lung cancer risk.


@neurIST - chronic disease management through integration of heterogeneous data and computer-interpretable guideline services.
This paper presents an overview of computerised decision support for clinical practice. The concept of computer-interpretable guidelines is introduced in the context of the @neurIST project, which aims at supporting the research and treatment of asymptomatic unruptured cerebral aneurysms by bringing together heterogeneous data, computing and complex processing services. The architecture is generic enough to adapt it to the treatment of other diseases beyond cerebral aneurysms. The paper reviews the generic requirements of the @neurIST system and presents the innovative work in distributing executable clinical guidelines.


The use of pressure-controlled inverse ratio ventilation in the surgical intensive care unit.
A key element in the treatment of Adult Respiratory Distress Syndrome (ARDS) is improvement in oxygen delivery to match metabolic demands. Conventional modes of ventilation have decreased mortality (50%) very little. We have done a retrospective analysis of 30 surgical patients who were treated with pressure-controlled inverse ratio ventilation. Mortality was 10%. Arterial oxygenation improved from 40.8 +/- 12.2 mm Hg to 138 +/- 47.2 mm Hg, while PCO2 decreased from 37.8 +/- 7.6 mm Hg to 31.1 +/- 5.9 mm Hg. Simultaneously, with the use of pressure-controlled inverse ratio ventilation, minute ventilation could be decreased by 30%, which may be secondary to increased O2 delivery to the tissue. Our data indicate that pressure-controlled inverse ratio ventilation may be beneficial to surgical patients with ARDS.


In vitro mechanical analysis of complete-arch mandibular implant-supported fixed prostheses abutment screws after cyclic loading.
Clinicians question when to evaluate for worn or loose implant-supported retainer screws to prevent possible clinical complications. The purpose of this study was to compare differences among initial and postdynamically loaded detorque values and identify physical structural changes of prosthetic retaining screws in a simulated implant-supported mandibular complete fixed prosthesis. Nine groups and nonloaded controls comprising a 5-implant-supported, milled titanium framework were fabricated and assembled (screw torque 35 Ncm). Dynamic loading (20 to 220 N) was applied to simulate 2 years of oral function. After testing, screw detorque values were measured (ΔT, initial-detorque value). A scanning electron microscopic analysis of screw threads was used to assess physical changes. Data were analyzed by 2-way ANOVA to determine the influence of loading and implant position on ΔT (α=.05). ΔT values of loaded and nonloaded groups were compared separately at each implant position and showed a significant difference only for the implant in the central position (P=.002). All positions were compared in terms of ΔT values separately for loaded and nonloaded conditions. A significantly higher ΔT was found in 1 cantilever area of the loaded group, whereas a significantly lower ΔT value was found in the central position in the nonloaded group. No statistically significant differences were found in physical changes between loading and nonloading or among implant positions. When delivering a multiimplant supported prosthesis, the application of dynamic loading and the sequence in which implant screws are tightened could influence the subsequent detorque value of a screw; they have no effect on the physical appearance of screws after extended function.


Discovery of lead quinone cathode materials for Li-ion batteries.
Organic cathode materials are attractive candidates for the development of high-performance Li-ion batteries (LIBs). The chemical space of candidate molecules is too vast to be explored solely by experiments; however, it can be systematically explored by a high-throughput computational search that incorporates a spectrum of screening techniques. Here, we present a time- and resource-efficient computational scheme that incorporates machine learning and semi-empirical quantum mechanical methods to study the chemical space of approximately 200 000 quinone-based molecules for use as cathode materials in LIBs. By performing an automated search on a commercial vendor database, computing battery-relevant properties such as redox potential, gravimetric charge capacity, gravimetric energy density, and synthetic complexity score, and evaluating the structural integrity upon the lithiation process, a total of 349 molecules were identified as potentially high-performing cathode materials for LIBs. The chemical space of the screened candidates was visualized using dimensionality reduction methods with the aim of further downselecting the best candidates for experimental validation. One such directly purchasable candidate, 1,4,9,10-anthracenetetraone, was analyzed through cyclic voltammetry experiments. The measured redox potentials of the two lithiation steps, , of 3.3 and 2.4 V, were in good agreement with the predicted redox potentials, , of 3.2 and 2.3 V vs. Li/Li+, respectively. Lastly, to lay out the principles for rational design of quinone-based cathode materials beyond the current work, we constructed and discussed the quantitative structure property relationships of quinones based on the data generated from the calculations.


The initial experience of InterSurgeon: an online platform to facilitate global neurosurgical partnerships.
Despite general enthusiasm for international collaboration within the organized neurosurgical community, establishing international partnerships remains challenging. The current study analyzes the initial experience of the InterSurgeon website in partnering surgeons from across the world to increase surgical collaboration. One year after the launch of the InterSurgeon website, data were collected to quantify the number of website visits, average session duration, total numbers of matches, and number of offers and requests added to the website each month. Additionally, a 15-question survey was designed and distributed to all registered members of the website. There are currently 321 surgeon and institutional members of InterSurgeon representing 69 different countries and all global regions. At the time of the survey there were 277 members, of whom 76 responded to the survey, yielding a response rate of 27.4% (76/277). Twenty-five participants (32.9%) confirmed having either received a match email (12/76, 15.8%) or initiated contact with another user via the website (13/76, 17.1%). As expected, the majority of the collaborations were either between a high-income country (HIC) and a low-income country (LIC) (5/18, 27.8%) or between an HIC and a middle-income country (MIC) (9/18, 50%). Interestingly, there were 2 MIC-to-MIC collaborations (2/18, 11.1%) as well as 1 MIC-to-LIC (1/18, 5.6%) and 1 LIC-to-LIC partnership. At the time of response, 6 (33.3%) of the matches had at least resulted in initial contact via email or telephone. One of the partnerships had involved face-to-face interaction via video conference. A total of 4 respondents had traveled internationally to visit their partner's institution. Within its first year of launch, the InterSurgeon membership has grown significantly. The partnerships that have already been formed involve not only international visits between HICs and low- to middle-income countries (LMICs), but also telecollaboration and inter-LMIC connections that allow for greater exchange of knowledge and expertise. As membership and site features grow to include other surgical and anesthesia specialties, membership growth and utilization is expected to increase rapidly over time according to social network dynamics.


Bipolar disorder and tuberous sclerosis complex: is it a mere coincidence?
Tuberous sclerosis complex (TSC) is associated with significant psychiatric comorbidity mainly in the form of autistic disorders, hyperkinetic disorders, depression, and anxiety disorders. There are very few reports of bipolar disorder in TSC. The authors present the case of a patient with TSC having bipolar disorder manifesting as manic as well as depressive episodes. The diagnosis of TSC was based on the presence of facial angiofibromas, enamel pits, and shagreen patches on clinical examination, and the presence of cortical tubers and calcified subependymal nodules on neuroimaging. The patient presented during the manic phase of the illness and responded well to treatment with carbamazepine and haloperidol and became symptom free within 1 month. The patient's neuropsychological assessment revealed a borderline level of intellectual functioning and deficits in attention and concentration, recent memory, delayed and immediate recall, and visual retention. To our knowledge, this is the first report of TSC with bipolar disorder having both manic as well as depressive episodes. The nature of association between TSC and bipolar disorder, and its clinical implications are discussed.


Imaging anatomy and pathology of extraocular muscles in adults.
The extraocular muscles (EOM) are involved in a variety of disease processes with characteristic findings on imaging. EOM anatomy is described, followed by a review of adult EOM pathology. The imaging characteristics are explained with examples. The pattern of EOM disease on imaging, in corroboration with clinical findings, can often lead the radiologist towards a specific diagnosis.


Residues within the myristoylation motif determine intracellular targeting of the neuronal Ca2+ sensor protein KChIP1 to post-ER transport vesicles and traffic of Kv4 K+ channels.
KChIPs (K+ channel interacting proteins) regulate the function of A-type Kv4 potassium channels by modifying channel properties and by increasing their cell surface expression. We have explored factors affecting the localisation of Kv4.2 and the targeting of KChIP1 and other NCS proteins by using GFP-variant fusion proteins expressed in HeLa cells. ECFP-Kv4.2 expressed alone was not retained in the ER but reached the Golgi complex. In cells co-expressing ECFP-Kv4.2 and KChIP1-EYFP, the two proteins were co-localised and were mainly present on the plasma membrane. When KChIP1-EYFP was expressed alone it was instead targeted to punctate structures. This was distinct from the localisation of the NCS proteins NCS-1 and hippocalcin, which were targeted to the trans-Golgi network (TGN) and plasma membrane. The membrane localisation of each NCS protein required myristoylation and minimal myristoylation motifs of hippocalcin or KChIP1 were sufficient to target fusion proteins to either TGN/plasma membrane or to punctate structures. The existence of targeting information within the N-terminal motifs was confirmed by mutagenesis of residues corresponding to three conserved basic amino acids in hippocalcin and NCS-1 at positions 3, 7 and 9. Residues at these positions determined intracellular targeting to the different organelles. Myristoylation and correct targeting of KChIP1 was required for the efficient traffic of ECFP-Kv4.2 to the plasma membrane. Expression of KChIP1(1-11)-EYFP resulted in the formation of enlarged structures that were positive for ERGIC-53 and beta-COP. ECFP-Kv4.2 was also accumulated in these structures suggesting that KChIP1(1-11)-EYFP inhibited traffic out of the ERGIC. We suggest that KChIP1 is targeted by its myristoylation motif to post-ER transport vesicles where it could interact with and regulate the traffic of Kv4 channels to the plasma membrane under the influence of localised Ca2+ signals.


Perspectives on training in obstetrics and gynaecology during the COVID-19 pandemic: Thematic analysis of trainee responses from a pan-European survey.
Coronavirus disease 19 (COVID-19) has affected many aspects of the lives of medical professionals. Postgraduate training has also been affected and mitigation plans are still ongoing. To understand the perspectives of trainees in obstetrics and gynaecology (ObGyn) during the pandemic. A cross-sectional exploratory survey conducted electronically from 20th of April 2020 to 1st July 2020. The original questionnaire comprised of 40 questions and a free-text option. The free-text questions covered five main domains: effect of the pandemic on training, worries about training, acquisition of skills during the pandemic, training period and extensions and responsibilities outside training during the pandemic. The responses to these questions in the survey were analysed using pragmatic thematic analysis. Trainees felt there was lack of training as well as training opportunities. Some took the pandemic as an opportunity to gain new skills. Trainees were also worried about time in training and uncertainty about extensions. Lastly, many had concerns pertaining to patient care, an inability to contribute to departmental organisation, and dissatisfaction with the implemented policies. The difficulties in Obstetrics and gynaecology training due to the pandemic need to be mitigated. When planning for reshaping the training programmes to accommodate for the discrepancies caused, trainers need to consider the perspectives of trainees and actively involve them in the decision making, designing and executing future plans. Efforts are currently underway to address the training time lost during the pandemic in Europe. Recognising the paramount importance of providing exceptional care for women and children across the continent, it becomes imperative to consider the valuable perspectives and insights offered by those who represent the future generation of specialists in the field.