Pediatric Sepsis Definition-A Systematic Review Protocol by the Pediatric Sepsis Definition Taskforce.
Sepsis is responsible for a substantial proportion of global childhood morbidity and mortality. However, evidence demonstrates major inaccuracies in the use of the term "sepsis" in clinical practice, coding, and research. Current and previous definitions of sepsis have been developed using expert consensus but the specific criteria used to identify children with sepsis have not been rigorously evaluated. Therefore, as part of the Society of Critical Care Medicine's Pediatric Sepsis Definition Taskforce, we will conduct a systematic review to synthesize evidence on individual factors, clinical criteria, or illness severity scores that may be used to identify children with infection who have or are at high risk of developing sepsis-associated organ dysfunction and separately those factors, criteria, and scores that may be used to identify children with sepsis who are at high risk of progressing to multiple organ dysfunction or death. We will identify eligible studies by searching the following databases: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. We will include all randomized trials and cohort studies published between January 1, 2004, and March 16, 2020. Data extraction will include information related to study characteristics, population characteristics, clinical criteria, and outcomes. We will calculate sensitivity and specificity of each criterion for predicting sepsis and conduct a meta-analysis if the data allow. We will also provide pooled estimates of overall hospital mortality. The potential risk factors, clinical criteria, and illness severity scores from this review which identify patients with infection who are at high risk of developing sepsis-associated organ dysfunction and/or progressing to multiple organ dysfunction or death will be used to inform the next steps of the Pediatric Sepsis Definition Taskforce.


Identification of genes and molecular pathways involved in the progression of premalignant oral epithelia.
An early interventional effort in oral premalignancy requires novel molecular targets and diagnostic biomarkers to delay or reverse incidences of malignant progression. Microarray-based transcriptional profiling in disease states provides global insight into the causal biomolecular processes and novel pathways involved. In this study, we investigated transcript profiles in precancerous oral lesions to identify nearly 1,700 genes as significantly overexpressed or underexpressed and a primarily affected metabolic pathway that may be responsible for irreversible transition to progressive stages of oral cancer. For the first time, we show a convergence of several genes and pathways known for their oncogenic capabilities, in progression of premalignant oral epithelial tissues. This study consequently provides a molecular basis for persistent proinflammatory conditions in oral premalignant tissues. We found that lipocalin-type prostaglandin D(2) synthase (PTGDS), a key enzyme in the arachidonic acid metabolism pathway, as repressed in premalignant stages. We show the protective role of these enzyme-derived metabolites in inhibiting cell proliferation using an in vitro oral cancer progression model. We have also confirmed the overexpression of two invasion-related biomarkers, psoriasin (PSOR1) and versican (CSPG2), in oral premalignant and malignant archival tissues. Our results clearly indicate that pharmacologic intervention with anti-inflammatory prostaglandin D(2)-like analogues may help prevent or delay oral epithelial carcinogenesis because of metabolic restoration of a negative feedback regulatory loop through its several cognate receptors or target molecules. Further studies directed toward a multitude of possible protective mechanisms of this lipocalin-type enzyme or its products in oral cancer progression are warranted.


Single Neuron Optimization as a Basis for Accurate Biophysical Modeling: The Case of Cerebellar Granule Cells.
In realistic neuronal modeling, once the ionic channel complement has been defined, the maximum ionic conductance (Gi-max) values need to be tuned in order to match the firing pattern revealed by electrophysiological recordings. Recently, selection/mutation genetic algorithms have been proposed to efficiently and automatically tune these parameters. Nonetheless, since similar firing patterns can be achieved through different combinations of Gi-max values, it is not clear how well these algorithms approximate the corresponding properties of real cells. Here we have evaluated the issue by exploiting a unique opportunity offered by the cerebellar granule cell (GrC), which is electrotonically compact and has therefore allowed the direct experimental measurement of ionic currents. Previous models were constructed using empirical tuning of Gi-max values to match the original data set. Here, by using repetitive discharge patterns as a template, the optimization procedure yielded models that closely approximated the experimental Gi-max values. These models, in addition to repetitive firing, captured additional features, including inward rectification, near-threshold oscillations, and resonance, which were not used as features. Thus, parameter optimization using genetic algorithms provided an efficient modeling strategy for reconstructing the biophysical properties of neurons and for the subsequent reconstruction of large-scale neuronal network models.


Fear of recurrence following head and neck cancer in the outpatient clinic.
Fear of recurrence (FOR) following head and neck cancer is one of the most frequent concerns of patients and is associated with psychological distress. The aims of this study were, first, to report the clinical characteristics of patients selected for FOR concerns on a patient concerns inventory (PCI) and, second, to compare the degree of FOR using a FOR questionnaire of those patients expressing FOR concerns on the PCI with those who did not. Two cohorts were used. The first comprised consecutive oncology patients attending clinics from August 2007 for 9 months (N = 123). These patients completed the PCI only. The second comprised patients attending the same clinic for over 4 months from October 2008 (N = 68), and this group completed both the PCI and the FOR questionnaire. FOR was the most frequently selected issue on the PCI (42%). There were no obvious differences in selecting FOR by patient characteristics. Those who scored 'a lot' or 'all the time' for questions 1-6 in the FOR questionnaire and responses (on a 10-point scale) of 7-10 for question 7 were deemed as having 'significant' FOR. In those raising the issue of FOR on the PCI, 79% (15/19) had significant problems compared to 24% (12/49) if they did not. FOR is a common concern and because it is not possible to identify patients based on clinical parameters, it is important to screen for FOR to direct patients to appropriate support and intervention.


Physician knowledge of the Glasgow Coma Scale.
Appropriate triage is critical to optimizing outcome from battle related injuries. The Glasgow Coma Scale (GCS) is the primary means by which combat casualties, who have suffered head injury, are triaged. For the GCS to be reliable in this critical role, it must be applied accurately. To determine the level of knowledge of the GCS among military physicians with exposure and/or training in the scale we administered a prospective, voluntary, and anonymous survey to physicians of all levels of training at military medical centers with significant patient referral base. The main outcome measures were correct identification of title and categories of the GCS along with appropriate scoring of each category. Overall performance on the survey was marginal. Many were able to identify what "GCS" stands for, but far fewer were able to identify the titles of the specific categories, let alone identify the specific scoring of each category. When evaluated based on medical specialties, those in surgical specialties outperformed those in the medical specialties. When comparing the different levels of training, residents and fellows performed better than attending staff or interns. Finally, those with Advanced Trauma Life Support (ATLS) certification performed significantly better than those without the training. Physician knowledge of the GCS, as demonstrated in this study, is poor, even in a population of individuals with specific training in the use of the scale. It is concluded that, to optimize outcome from combat related head injury, methods for improving accurate quantitation of neurologic state need to be explored.


Dispersal and Diving Adjustments of the Green Turtle Chelonia mydas in Response to Dynamic Environmental Conditions during Post-Nesting Migration.
In response to seasonality and spatial segregation of resources, sea turtles undertake long journeys between their nesting sites and foraging grounds. While satellite tracking has made it possible to outline their migration routes, we still have little knowledge of how they select their foraging grounds and adapt their migration to dynamic environmental conditions. Here, we analyzed the trajectories and diving behavior of 19 adult green turtles (Chelonia mydas) during their post-nesting migration from French Guiana and Suriname to their foraging grounds off the coast of Brazil. First Passage Time analysis was used to identify foraging areas located off Ceará state of Brazil, where the associated habitat corresponds to favorable conditions for seagrass growth, i.e. clear and shallow waters. The dispersal and diving patterns of the turtles revealed several behavioral adaptations to the strong hydrodynamic processes induced by both the North Brazil current and the Amazon River plume. All green turtles migrated south-eastward after the nesting season, confirming that they coped with the strong counter North Brazil current by using a tight corridor close to the shore. The time spent within the Amazon plume also altered the location of their feeding habitats as the longer individuals stayed within the plume, the sooner they initiated foraging. The green turtles performed deeper and shorter dives while crossing the mouth of the Amazon, a strategy which would help turtles avoid the most turbulent upper surface layers of the plume. These adjustments reveal the remarkable plasticity of this green turtle population when reducing energy costs induced by migration.


Association between age at disease onset of anti-neutrophil cytoplasmic antibody-associated vasculitis and clinical presentation and short-term outcomes.
ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03]. Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.


Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy.
Our goal was to determine the risk of stroke or non-cerebral embolism associated with paroxysmal compared with sustained atrial fibrillation (AF). The risk of stroke and non-cerebral embolism and the efficacy of oral anticoagulation (OAC) in paroxysmal AF as compared with sustained AF are not precisely known. The ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) was a trial comparing OAC to combined antiplatelet therapy with aspirin and clopidogrel for prevention of vascular events in 6,706 AF patients. The incidence of thromboembolic events and major bleeds were compared in patients with paroxysmal AF (n = 1,202) and persistent or permanent AF (n = 5,495). Patients with paroxysmal AF were younger, had a shorter AF history, more hypertension, and less valvular disease, heart failure, and diabetes mellitus than patients with sustained AF. At baseline, patients with paroxysmal AF had a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke [doubled]) risk score of 1.79 +/- 1.03 compared with 2.04 +/- 1.12 in patients with sustained AF (p < 0.00001). The annualized risk of stroke or non-central nervous system (CNS) systemic embolism was 2.0 in paroxysmal AF compared with 2.2 in sustained AF (relative risk 0.87, 95% confidence interval [CI] 0.59 to 1.30, p = 0.496). After adjusting for confounding baseline variables, the relative risk was 0.94 (95% CI 0.63 to 1.40, p = 0.755). The incidence of stroke and non-CNS embolism was lower for patients treated with OAC irrespective of type of AF. There were more bleedings of any type in patients receiving clopidogrel plus aspirin, irrespective of the type of AF. Patients with paroxysmal AF treated with aspirin plus clopidogrel or OAC have a similar risk for thromboembolic events than patients with sustained AF. This risk can be significantly lowered with OAC. (The ACTIVE W trial; http://www.clinicaltrials.gov/ct/show/NCT00243178;NCT00243178).


Ki-67 Labeling Indices in 'Classic' versus 'Blastoid' Mantle Cell Lymphomas--Proposed Cutoff Values for Routine Diagnostic Workup.
Mantle-cell lymphoma (MCL) is a unique entity of peripheral B-cell lymphoma that has a discrete morphologic, immunologic, and genetic phenotype, with more common 'classic' and less frequent 'blastoid' and 'pleomorphic' variants, associated with an aggressive clinical course. The aim of this study was to analyze proliferation (Ki-67) indices of 'classic' (c-MCL) and 'blastoid' (b-MCL) variants of a cohort of MCL and to suggest cut off values for the Ki-67 proliferation index in these two subsets. MCL cases diagnosed over 4 1/2 years at Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi were retrieved and reviewed. Ki-67 labelling was scored and analysed. A total of 90 of cases of MCL were scrutinized. Mean age±SD was 60.2±12.5 years and the male to female ratio was 4:1, with 67 (75%) cases of c-MCL and 23 (25%) cases of b-MCL. Most samples were lymph node biopsies (n=68), whereas the remainder were from various extranodal sites The mean Ki-67 proliferation index was 29.5%±14.4% in classic variants and 64.4±15.2% for the blastoid variant, the difference being statistically significant (p=0.029). It was concluded that differential cut-off values of Ki-67 labeling may be used in more objective way to reliably classify MCL into classic or blastoid variants by diagnostic pathologists. We propose a <40 proliferative index to be suggestive of c-MCL and one of >50 for the blastoid variant.


[A survey of self-medication practices and related factors in the general population: the Ohasama study].
Encouraging self-medication is expected to reduce healthcare costs. To assess the current situation of self-medication practices in the general population, we conducted a questionnaire survey regarding the use of over-the-counter (OTC) medications or dietary supplements in 1008 participants (37% men; mean age, 64±13 years) from Ohasama, a rural Japanese community. A total of 519 (52%) participants used OTC medications or dietary supplements, with common cold medication (36%) and supplements (28%) such as shark cartilage products representing the most common choices. Stepwise logistic regression showed female gender, a higher frequency of visits from a household medicine kit distributor, dyslipidemia, and lower home systolic blood pressure levels as predictors for the use of such materials (chi-square values: 25.3, 12.6, 7.0, and 4.6, respectively; all p<0.03). Stratifying the participants according to the use of antihypertensive treatment showed a negative association between systolic blood pressure and the use of OTC medications or supplements only in participants being treated for hypertension. These results suggest that although the adoption rate of self-medication in Japan can be increased in rural areas, it may remain lower in urban areas. The present study clarifies the factors associated with the use of OTC medications or dietary supplements and indicates that appropriate self-medication practices might improve the control of hypertension, particularly in patients undergoing antihypertensive treatment.


Goitrogenic and estrogenic activity of soy isoflavones.
Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate.


[Rupture of the Achilles tendon--fibrin gluing or suture?].
The rise of recreational sports activities and the incidence of ruptures of the Achilles tendons has increased simultaneously. Recently the use of fibrin sealing for surgical therapy of ruptured Achilles tendons has emerged as an alternative technique. Between 1982 and 1989 62 consecutive patients were operated for unilateral Achilles tendon rupture. Following causes for ruptures are known: 36 indirect traumas in sport (74%), 9 direct blunt injuries at occupational work (18%), 3 traffic-accidents (11%) and 1 rupture after operation of a Haglund exostosis. 25 patients (56%) were treated by suture technique and 20 patients (44%) with fibrin sealant. The mean long term follow-up of 49 months is known of 49 patients. There were 3 (12%) postoperative infections in the suture group and none in the fibrin group. After suturing the Achilles tendon 3 (12%) reruptures occurred 8-10 weeks after tendon repair and 1 (5%) rerupture after fibrin sealing. All reruptures are caused by a new adequate trauma. The time of return to social and recreational activities was 9 months in the suture group and 7 months in the fibrin group. The functional and cosmetic results after use of fibrin was significant better, and the long-term results were very satisfactory. We prefer fibrin sealing for the treatment of acute ruptures of Achilles tendons.


Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment.
Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. However, the molecular mechanisms and the role as a pathogenicity factor remains unclear. Using single virus particle tracking, we show that the mobility of chondroitin sulfate-bound HSV-1 virions is decreased in absence of the mucin-like region. This decrease in mobility correlates with an increase in HSV-1-chondroitin sulfate binding forces as observed using atomic force microscopy-based force spectroscopy. Our data suggest that the mucin-like region modulates virus-glycosaminoglycan interactions by regulating the affinity, type, and number of glycoproteins involved in the virus-glycosaminoglycan interaction. This study therefore presents new evidence for a role of the mucin-like region in balancing the interaction of HSV-1 with glycosaminoglycans and provides further insights into the molecular mechanisms used by the virus to ensure both successful cell entry and release from the infected cell.


Predictors and moderators of internet- and group-based cognitive behaviour therapy for panic disorder.
Internet-based cognitive behaviour therapy (ICBT) can be equally effective as traditional face-to-face cognitive behaviour therapy (CBT) for treating panic disorder (PD). However, little is known about the predictors and moderators of outcome of ICBT when delivered in psychiatric outpatient settings. This study investigated a selection of outcome predictors and moderators of ICBT for panic disorder based on data from a randomised controlled trial where therapist-guided ICBT was compared with group CBT (GCBT) for panic disorder. Participants (N = 104) received 10 weeks of ICBT or GCBT and were assessed before and after treatment, and after six months. Multiple regression analyses were used to test for significant predictors of treatment outcome. Predictors of positive treatment response for both modalities were having low levels of symptom severity and work impairment. In addition, anxiety sensitivity was found to have a small negative relationship with treatment outcome, suggesting that anxiety sensitivity may slightly enhance treatment response. Treatment modality had a moderating effect on the relationship between domestic impairment and outcome and on the relationship between initial age of onset of panic symptoms and treatment outcome, favouring ICBT for patients having had an early onset of PD symptoms and for patients having a high domestic functional impairment. These results suggest that both ICBT and GCBT are effective treatment modalities for PD and that it is possible to predict a significant proportion of the long-term outcome variance based on clinical variables.


The association of anticonvulsant use with fractures in spinal cord injury.
The aim of this study was to determine whether anticonvulsants, including the benzodiazepine subclass, are associated with an increased risk for lower extremity fractures in male patients with spinal cord injury. All male patients with a history of a traumatic spinal cord injury of 2 yrs' duration or longer in the Veterans Affairs Spinal Cord Disease Registry from 2002 to 2007 were included. Incident lower extremity fractures during this period and anticonvulsant use were identified. The association of anticonvulsant use, overall, by type (enzyme inducing, non-enzyme inducing), by number (monotherapy vs. polytherapy), by benzodiazepine subclass, and by individual medication used was determined. In this cohort, 892 veterans sustained a fracture, and 6555 did not. Compared with nonusers of anticonvulsants, there was a significant positive relationship with fractures by overall use of anticonvulsants (HR, 1.17 [95% CI, 1.01-1.36]), by users of the benzodiazepine subclass (HR, 1.28 [95% CI, 1.11-1.47]), and by polytherapy compared with monotherapy (HR, 1.20 [95% CI, 1.00-1.42]) but not by anticonvulsant type (HR, 0.92 [95% CI, 0.58-1.47]). Temazepam (HR, 1.28 [95% CI, 1.01-1.62]), alprazolam (HR, 1.54 [95% CI, 1.04-2.29]), and diazepam (HR, 1.23 [95% CI, 1.06-1.41]) were significantly positively associated with fractures. Attention to fracture prevention is important when anticonvulsants are prescribed in spinal cord injury, particularly when more than one anticonvulsant is used.


Careful treatment planning enables safe ablation of liver tumors adjacent to major blood vessels by percutaneous irreversible electroporation (IRE).
Irreversible electroporation (IRE) is a tissue ablation method, which relies on the phenomenon of electroporation. When cells are exposed to a sufficiently electric field, the plasma membrane is disrupted and cells undergo an apoptotic or necrotic cell death. Although heating effects are known IRE is considered as non-thermal ablation technique and is currently applied to treat tumors in locations where thermal ablation techniques are contraindicated. The manufacturer of the only commercially available pulse generator for IRE recommends a voltage-to-distance ratio of 1500 to 1700 V/cm for treating tumors in the liver. However, major blood vessels can influence the electric field distribution. We present a method for treatment planning of IRE which takes the influence of blood vessels on the electric field into account; this is illustrated on a treatment of 48-year-old patient with a metastasis near the remaining hepatic vein after a right side hemi-hepatectomy. Output of the numerical treatment planning method shows that a 19.9 cm3 irreversible electroporation lesion was generated and the whole tumor was covered with at least 900 V/cm. This compares well with the volume of the hypodense lesion seen in contrast enhanced CT images taken after the IRE treatment. A significant temperature raise occurs near the electrodes. However, the hepatic vein remains open after the treatment without evidence of tumor recurrence after 6 months. Treatment planning using accurate computer models was recognized as important for electrochemotherapy and irreversible electroporation. An important finding of this study was, that the surface of the electrodes heat up significantly. Therefore the clinical user should generally avoid placing the electrodes less than 4 mm away from risk structures when following recommendations of the manufacturer.


TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype.
Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-β signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.


Thermal properties of bulk polyimides: insights from computer modeling versus experiment.
Due to the great importance for many industrial applications it is crucial from the point of view of theoretical description to reproduce thermal properties of thermoplastic polyimides as accurate as possible in order to establish "chemical structure-physical properties" relationships of new materials. In this paper we employ differential scanning calorimetry, dilatometry, and atomistic molecular dynamics (MD) simulations to explore whether the state-of-the-art computer modeling can serve as a precise tool for probing thermal properties of polyimides with highly polar groups. For this purpose the polyimide R-BAPS based on dianhydride 1,3-bis(3',4-dicarboxyphenoxy)benzene (dianhydride R) and diamine 4,4'-bis(4''-aminophenoxy)biphenyl sulphone) (diamine BAPS) was synthesized and extensively studied. Overall, our findings show that the widely used glass-transition temperature Tg evaluated from MD simulations should be employed with great caution for verification of the polyimide computational models against experimental data: in addition to the well-known impact of the cooling rate on the glass-transition temperature, correct definition of Tg requires cooling that starts from very high temperatures (no less than 800 K for considered polyimides) and accurate evaluation of the appropriate cooling rate, otherwise the errors in the measured values of Tg become undefined. In contrast to the glass-transition temperature, the volumetric coefficient of thermal expansion (CTE) does not depend on the cooling rate in the low-temperature domain (T < Tg) so that comparison of computational and experimental values of CTE provides a much safer way for proper validation of the theoretical model when electrostatic interactions are taken into account explicitly. Remarkably, this conclusion is most likely of generic nature: we show that it also holds for the commercial polyimide EXTEM, another polyimide with a similar chemical structure.


Identification of a new gene encoding EPSPs with high glyphosate resistance from the metagenomic library.
Glyphosate, a powerful nonselective herbicide, acts as an inhibitor of the activity of the enzyme 5-enoylpyruvylshikimate-3-phosphate synthase (EPSPS) encoded by the aroA gene involved in aromatic amino acid biosynthesis. An Escherichia coli mutant AKM4188 was constructed by insertion a kanamycin cassette within the aroA coding sequence. The mutant strain is an aromatic amino acids auxotroph and fails to grow on M9 minimal media due to the inactive aroA. A DNA metagenomic library was constructed with samples from a glyphosate-polluted area and was screened by using the mutant AKM4188 as recipient. Three plasmid clones, which restored growth to the aroA mutant in M9 minimal media supplemented with chloramphenicol, kanamycin, and 50 mM: glyphosate, were obtained from the DNA metagenomic library. One of them, which conferred glyphosate tolerance up to 150 mM: , was further characterized. The cloned fragment encoded a polypeptide, designated RD, sharing high similarity with other Class II EPSPS proteins. A His-tagged RD fusion protein was produced into E. coli to characterize the enzymatic properties of the RD EPSP protein.


A computational approach for identifying microRNA-target interactions using high-throughput CLIP and PAR-CLIP sequencing.
MicroRNAs (miRNAs) play a critical role in down-regulating gene expression. By coupling with Argonaute family proteins, miRNAs bind to target sites on mRNAs and employ translational repression. A large amount of miRNA-target interactions (MTIs) have been identified by the crosslinking and immunoprecipitation (CLIP) and the photoactivatable-ribonucleoside-enhanced CLIP (PAR-CLIP) along with the next-generation sequencing (NGS). PAR-CLIP shows high efficiency of RNA co-immunoprecipitation, but it also lead to T to C conversion in miRNA-RNA-protein crosslinking regions. This artificial error obviously reduces the mappability of reads. However, a specific tool to analyze CLIP and PAR-CLIP data that takes T to C conversion into account is still in need. We herein propose the first CLIP and PAR-CLIP sequencing analysis platform specifically for miRNA target analysis, namely miRTarCLIP. From scratch, it automatically removes adaptor sequences from raw reads, filters low quality reads, reverts C to T, aligns reads to 3'UTRs, scans for read clusters, identifies high confidence miRNA target sites, and provides annotations from external databases. With multi-threading techniques and our novel C to T reversion procedure, miRTarCLIP greatly reduces the running time comparing to conventional approaches. In addition, miRTarCLIP serves with a web-based interface to provide better user experiences in browsing and searching targets of interested miRNAs. To demonstrate the superior functionality of miRTarCLIP, we applied miRTarCLIP to two public available CLIP and PAR-CLIP sequencing datasets. miRTarCLIP not only shows comparable results to that of other existing tools in a much faster speed, but also reveals interesting features among these putative target sites. Specifically, we used miRTarCLIP to disclose that T to C conversion within position 1-7 and that within position 8-14 of miRNA target sites are significantly different (p value = 0.02), and even more significant when focusing on sites targeted by top 102 highly expressed miRNAs only (p value = 0.01). These results comply with previous findings and further suggest that combining miRNA expression and PAR-CLIP data can improve accuracy of the miRNA target prediction. To sum up, we devised a systematic approach for mining miRNA-target sites from CLIP-seq and PAR-CLIP sequencing data, and integrated the workflow with a graphical web-based browser, which provides a user friendly interface and detailed annotations of MTIs. We also showed through real-life examples that miRTarCLIP is a powerful tool for understanding miRNAs. Our integrated tool can be accessed online freely at http://miRTarCLIP.mbc.nctu.edu.tw.


The use of impedance aggregometry to evaluate platelet function after the administration of DDAVP in healthy dogs treated with aspirin or clopidogrel.
To evaluate the effect of 1-Desamino-8-d-arginine vasopressin (DDAVP; desmopressin acetate) on platelet aggregation in healthy dogs receiving aspirin or clopidogrel. 7 healthy staff-owned dogs. In this randomized double-blinded crossover study, impedance aggregometry was performed on samples of lithium-heparinized whole blood samples from dogs before (T0) treatment with aspirin (1 mg/kg, PO, q 24 h for 4 days; ASP group) or clopidogrel (1 mg/kg, PO, q 24 h for 4 days; CLP group) and then before (T1) and after (T2) treatment with DDAVP (0.3 μg/kg, IV, once). There was a 14-day washout period before the crossover component. Aggregometry was performed with 4 different assays, each of which involved a different agonist reagent to stimulate platelet function: ADP, thrombin receptor activating peptide-6, arachidonic acid, or collagen type 1. Median results for platelet aggregometry with agonist reagents ADP, arachidonic acid, or thrombin receptor activating peptide-6 significantly decreased between T0 and T1 for the CLP group; however, no meaningful difference in platelet aggregation was detected in the ASP group. Results for platelet aggregometry did not differ substantially between T1 and T2 regardless of treatment group or assay. Findings suggested that administration of DDAVP may have no effect on platelet aggregation (measured with platelet aggregometry) in healthy dogs treated with clopidogrel. Because no inhibition of platelet aggregation was detected for dogs in the ASP group, no conclusion could be made regarding the effects of DDAVP administered to dogs treated with aspirin.


Knowledge of blood transfusion among nurses.
To measure nurses' knowledge of blood transfusion in the United Arab Emirates. Blood transfusion is a fundamental aspect of nursing practice and nurses' knowledge of it is essential for safe practice. Yet little is known about their blood transfusion practice and the knowledge that underpins it. The few studies that have investigated this topic previously have shown deficiencies in both knowledge and practice. To date, no such study has been carried out in the Middle East. A descriptive, cross-sectional study. A random sample of 248 nurses from two general hospitals in the Emirate of Abu Dhabi. The response rate was 94AE3%. A knowledge questionnaire comprising six sections and 49 items was developed for this study. Data were analysed using descriptive and inferential statistics. The overall knowledge scores of nurses were generally low ranging from 27-56 of a possible score of 70. Data analysis revealed knowledge deficits in several key aspects of blood transfusion. There were statistically significant relationship between nurses' knowledge and the work setting, the country where they trained and type of qualifications. This survey highlighted knowledge deficits which could be detrimental to patient safety. These results have implications for nursing education, policy and practice. Nurses have the responsibility to update their knowledge of and skills in carrying out blood transfusion. The tool developed in this study may be useful for educators and managers to identify gaps in knowledge and inform decisions to address them.


Bonobos voluntarily hand food to others but not toys or tools.
A key feature of human prosociality is direct transfers, the most active form of sharing in which donors voluntarily hand over resources in their possession Direct transfers buffer hunter-gatherers against foraging shortfalls. The emergence and elaboration of this behaviour thus likely played a key role in human evolution by promoting cooperative interdependence and ensuring that humans' growing energetic needs (e.g. for increasing brain size) were more reliably met. According to the strong prosociality hypothesis, among great apes only humans exhibit sufficiently strong prosocial motivations to directly transfer food. The versatile prosociality hypothesis suggests instead that while other apes may make transfers in constrained settings, only humans share flexibly across food and non-food contexts. In controlled experiments, chimpanzees typically transfer objects but not food, supporting both hypotheses. In this paper, we show in two experiments that bonobos directly transfer food but not non-food items. These findings show that, in some contexts, bonobos exhibit a human-like motivation for direct food transfer. However, humans share across a far wider range of contexts, lending support to the versatile prosociality hypothesis. Our species' unusual prosocial flexibility is likely built on a prosocial foundation we share through common descent with the other apes.


Parallel view-dependent level-of-detail control.
We present a scheme for view-dependent level-of-detail control that is implemented entirely on programmable graphics hardware. Our scheme selectively refines and coarsens an arbitrary triangle mesh at the granularity of individual vertices to create meshes that are highly adapted to dynamic view parameters. Such fine-grain control has previously been demonstrated using sequential CPU algorithms. However, these algorithms involve pointer-based structures with intricate dependencies that cannot be handled efficiently within the restricted framework of GPU parallelism. We show that by introducing new data structures and dependency rules, one can realize fine-grain progressive mesh updates as a sequence of parallel streaming passes over the mesh elements. A major design challenge is that the GPU processes stream elements in isolation. The mesh update algorithm has time complexity proportional to the selectively refined mesh, and moreover, can be amortized across several frames. The result is a single standard index buffer that can be used directly for rendering. The static data structure is remarkably compact, requiring only 57 percent more memory than an indexed triangle list. We demonstrate real-time exploration of complex models with normals and textures, as well as shadowing and semitransparent surface rendering applications that make direct use of the resulting dynamic index buffer.


Guidelines: The dos, don'ts and don't knows of remediation in medical education.
Two developing forces have achieved prominence in medical education: the advent of competency-based assessments and a growing commitment to expand access to medicine for a broader range of learners with a wider array of preparation. Remediation is intended to support all learners to achieve sufficient competence. Therefore, it is timely to provide practical guidelines for remediation in medical education that clarify best practices, practices to avoid, and areas requiring further research, in order to guide work with both individual struggling learners and development of training program policies. Collectively, we generated an initial list of Do's, Don'ts, and Don't Knows for remediation in medical education, which was then iteratively refined through discussions and additional evidence-gathering. The final guidelines were then graded for the strength of the evidence by consensus. We present 26 guidelines: two groupings of Do's (systems-level interventions and recommendations for individual learners), along with short lists of Don'ts and Don't Knows, and our interpretation of the strength of current evidence for each guideline. Remediation is a high-stakes, highly complex process involving learners, faculty, systems, and societal factors. Our synthesis resulted in a list of guidelines that summarize the current state of educational theory and empirical evidence that can improve remediation processes at individual and institutional levels. Important unanswered questions remain; ongoing research can further improve remediation practices to ensure the appropriate support for learners, institutions, and society.


Spanish-speaking patients' engagement in interactive voice response (IVR) support calls for chronic disease self-management: data from three countries.
We measured Spanish-speaking patients' engagement in Interactive Voice Response (IVR) calls using data from self-management support studies in Honduras, Mexico and the US. A total of 268 patients with diabetes or hypertension participated in 6-12 weeks of weekly IVR follow-up. Participants had an average of 6.1 years of education, and 73% of them were women. After 2443 person-weeks of follow-up, patients had completed 1494 IVR assessments. The call completion rates were higher in the US (75%) than in Honduras (59%) or Mexico (61%; P < 0.001). Patients participating with an informal caregiver were more likely to complete calls (adjusted odds ratio 1.5; P = 0.03) while patients reporting fair or poor health at enrolment were less likely (adjusted odds ratio 0.59; P = 0.02). Satisfaction rates were high, with 98% of patients reporting that the system was easy to use, and 86% reporting that the calls helped them a great deal in managing their health problems. IVR self-management support is feasible among Spanish-speaking patients with chronic disease, including those living in less-developed countries. Involving informal caregivers may increase patient engagement.


Regional Changes in Density and Microarchitecture in the Ultradistal Tibia of Female Recruits After U.S. Army Basic Combat Training.
Musculoskeletal injuries, such as stress fracture, are responsible for over 10-million lost-duty days among U.S. Army Soldiers. During Basic Combat Training (BCT), an 8- to 10-week program that transforms civilians into Soldiers, women are four times more likely than men to sustain a stress fracture. In this work, we performed high-resolution peripheral quantitative computed tomography scans on the ultradistal tibia of 90 female recruits [age = 21.5 ± 3.3 (mean ± standard deviation) years] before the start of BCT and after 8 weeks into BCT. Then, we divided the scanned bone volume into four sectors-lateral, posterior, medial, and anterior-and computed the bone density and microarchitectural parameters in each of the four sectors pre- and post-BCT. We used linear mixed models to estimate the mean difference for bone density and microarchitectural parameters, while controlling for age, race, and pre-BCT body mass index. Our results revealed that the total volumetric bone mineral density, trabecular volumetric bone mineral density, and trabecular thickness increased (p < 0.05) in each of the four sectors. In addition, cortical thickness and trabecular bone volume/total volume increased in both medial and posterior sectors (p < 0.05). Overall, six and five out of nine parameters improved in the medial and posterior sectors, respectively, after BCT. In conclusion, the heightened physical activity during BCT led to the most beneficial bone adaptation in the medial and posterior sectors of the ultradistal tibia, which is indicative of higher loading in these sectors during activities performed in the course of BCT.


Promoting Physical and Psychological Rehabilitation Activities and Evaluating Potential Links Among Cancer-Related Fatigue, Fear of Recurrence, Quality of Life, and Physiological Indicators in Cancer Survivors.
Cancer-related fatigue and fear of recurrence (FOR) are the most common symptoms in cancer survivors and severely affect quality of life (QOL). This study aims to promote and evaluate the effectiveness of physical and psychological rehabilitation activities for cancer survivors. A longitudinal study with an interventional research design was conducted. A total of 80 participants were randomly assigned to experimental groups E1 (Qigong exercise [QE]) or E2 (stress management [SM]) or the control group. The E1 and E2 groups received QE and SM, respectively, as interventions once a week for 12 weeks, and effects were assessed. Cancer-related fatigue, FOR, QOL, and heart rate variability (HRV) were evaluated at baseline (T0), after 12 weeks (T1), and at the 3-month follow-up (T2). QE and SM effectively strengthened the physical and psychological functions of cancer survivors at the T1 phase. Although differences in FOR and QOL were not statistically significant, the scores were decreased and increased, respectively. Although the effects during the T2 phase were not as significant as those during T1, the score progress was maintained. The effects on HRV were significantly different among the E1, E2, and control groups at T1, which shows that the performance of both experimental groups was better than that of the control group. Physical and psychological rehabilitation activities should be practiced periodically and should be led by professional staff. Long-term educational resources and care should also be provided. HRV can be used to efficiently monitor the status of the mind-body balance and is a more suitable index than questionnaires for physical and psychological function evaluation in cancer survivors.


Bugs and drugs: oncolytic virotherapy in combination with chemotherapy.
Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular OV, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future.


Ligand-induced conformational change in the alpha7 nicotinic receptor ligand binding domain.
Molecular dynamics simulations of a homology model of the ligand binding domain of the alpha7 nicotinic receptor are conducted with a range of bound ligands to induce different conformational states. Four simulations of 15 ns each are run with no ligand, antagonist d-tubocurarine (dTC), agonist acetylcholine (ACh), and agonist ACh with potentiator Ca(2+), to give insight into the conformations of the active and inactive states of the receptor and suggest the mechanism for conformational change. The main structural factor distinguishing the active and inactive states is that a more open, symmetric arrangement of the five subunits arises for the two agonist simulations, whereas a more closed and asymmetric arrangement results for the apo and dTC cases. Most of the difference arises in the lower portion of the ligand binding domain near its connection to the adjacent transmembrane domain. The transfer of the more open state to the transmembrane domain could then promote ion flow through the channel. Variation in how subunits pack together with no ligand bound appears to give rise to asymmetry in the apo case. The presence of dTC expands the receptor but induces rotations in alternate directions in adjacent subunits that lead to an asymmetric arrangement as in the apo case. Ca(2+) appears to promote a slightly greater expansion in the subunits than ACh alone by stabilizing the C-loop and ACh positions. Although the simulations are unlikely to be long enough to view the full conformational changes between open and closed states, a collection of different motions at a range of length scales are observed that are likely to participate in the conformational change.


Understanding the lingering consequences of what we treat and what we do.
Granja and colleagues have helped us by showing that long-term follow-up is feasible and by trying to tease out whether select intensive care unit patient populations are at particular risk of adverse outcomes. This work gives us clues for future investigations which will hopefully interrogate further the potential mechanisms of action that underlie poor long-term outcomes. In the meantime, we can hope that this quality of follow-up will move from the research arena to become a part of routine clinical care.


Linear growth following complicated severe malnutrition: 1-year follow-up cohort of Kenyan children.
Stunting is the most common manifestation of childhood undernutrition worldwide. Children presenting with severe acute malnutrition (SAM) are often also severely stunted. We evaluated linear growth and its determinants after medically complicated SAM. We performed secondary analysis of clinical trial data (NCT00934492) from HIV-uninfected Kenyan children aged 2-59 months hospitalised with SAM. Outcome was change in height/length-for-age z-score (HAZ) between enrolment and 12 months later. Exposures were demographic, clinical, anthropometric characteristics and illness episodes during follow-up. Among 1169 children with HAZ values at month 12 (66% of those in original trial), median (IQR) age 11 (7-17) months and mean (SD) HAZ -2.87 (1.6) at enrolment, there was no change in mean HAZ between enrolment and month 12: -0.006Z (95% CI -0.07 to 0.05Z). While 262 (23%) children experienced minimal HAZ change (within ±0.25 HAZ), 472 (40%) lost >0.25 and 435 (37%) gained >0.25 HAZ. After adjusting for regression to the mean, inpatient or outpatient episodes of diarrhoea and inpatient severe pneumonia during follow-up were associated with HAZ loss. Premature birth and not being cared by the biological parent were associated with HAZ gain. Increases in mid-upper arm circumference and weight-for-age were associated with HAZ gain and protected against HAZ loss. Increase in weight-for-height was not associated with HAZ gain but protected against HAZ loss. No threshold of weight gain preceding linear catch-up growth was observed. Interventions to improve dietary quality and prevent illness over a longer period may provide opportunities to improve linear growth.


Florfenicol concentrations in ovine tear fluid following intramuscular and subcutaneous administration and comparison with the minimum inhibitory concentrations against mycoplasmal strains potentially involved in infectious keratoconjunctivitis.
To measure florfenicol concentrations in ovine tear fluid after IM and SC administration and determine minimum inhibitory concentrations (MICs) of florfenicol against field isolates of Mycoplasma organisms potentially involved in infectious keratoconjunctivitis. 9 healthy adult Lacaune ewes. Animals received an IM and SC administration of florfenicol (20 mg/kg) in a 2-way crossover design. Samples of blood and tear fluid were collected before and for 24 hours after administration. Concentrations of florfenicol in plasma and tear fluid were measured via high-performance liquid chromatography. The MIC of florfenicol for various Mycoplasma strains cultured from sheep and goats was determined via an agar dilution method. Mean florfenicol concentration in tear fluid for the 24-hour period was significantly higher after IM administration (0.70 μg/mL) than after SC administration (0.22 μg/mL) and was maintained for a longer duration. The lacrimal fluid-to-plasma concentration ratio was not different between the 2 routes of administration, with mean values of 40.2% and 32.5% after IM and SC administration, respectively. The MIC for Mycoplasma agalactiae, Mycoplasma conjunctivae, and Mycoplasma mycoides isolates ranged from 0.5 to 8 μg of florfenicol/mL. Two strains of M agalactiae could be considered resistant to florfenicol. Florfenicol readily penetrated the preocular tear fluid of sheep after IM and SC administration. For both routes of administration, doses > 20 mg/kg would be necessary to achieve tear fluid concentrations of florfenicol greater than the MICs for most strains of Mycoplasma organisms.


A New Method for the Characterization of Electrically Conducting Liquid Bridges.
An electrical conductance technique is employed in investigating the behavior of constant volume liquid bridges when their length is altered. The liquid bridges are edge-pinned between two vertical, identical rods with a variable separation distance. Rods of different radius, material, and edge geometry are examined as they play a role in the response of the system. It is shown that liquid bridge volume and rod radius are the parameters that mainly influence the conductance signal. A mathematical framework is developed for the identification of the geometrical characteristics of liquid bridges explicitly from conductance data. The role of gravity is discussed in both the experiments and the theoretical analysis. The theoretical predictions obtained show a close agreement with measurements. Copyright 2000 Academic Press.


Selective antagonism of hormone-induced vasoconstriction by synthetic atrial natriuretic factor in the rat microcirculation.
Synthetic atrial natriuretic factor (ANF) was either added to suffusate solutions (30 nM) or infused into the jugular vein (0.1 nanomol/min/100 g) of anesthetized rats. Steady-state blood flow was calculated from arteriolar diameter and red blood cell velocity measurements using video microscopy in the intestinal or skeletal muscle microcirculation. Arterioles demonstrated spontaneous vasomotor tone by dilating to topical adenosine, but topical or intravenous ANF did not cause vasodilation. Either angiotensin, norepinephrine, or vasopressin was added to the suffusates in the presence or absence of a cyclooxygenase inhibitor (30 microM, meclofenamate or indomethacin) because each agonist is known to stimulate vasoactive prostanoid synthesis. In the intestine, angiotensin (500 nM) caused 40 +/- 2% blood flow decreases during intravenous saline but only 23 +/- 6% during intravenous ANF. Angiotensin (162 nM) and a cyclooxygenase inhibitor caused 19 +/- 4% blood flow decreases but only 8 +/- 5% decreases with cyclooxygenase inhibitor and topical ANF. In contrast, norepinephrine (2-5 microM) caused vasoconstriction that was not altered by topical or intravenous ANF, either alone or in combination with cyclooxygenase inhibitors. In the spinotrapezius muscle, angiotensin (1-2 nM) plus a cyclooxygenase inhibitor caused 40-60% blood flow decreases but only 20-30% decreases during intravenous or topical ANF. Topical or intravenous ANF did not alter the vasoconstriction evoked by arginine vasopressin (0.5-1.0 nM) or by norepinephrine (40-230 nM). Thus, supraphysiologic concentrations of ANF produced no direct vasodilation in the intestinal or skeletal muscle microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)


Meta-analysis of the clinical efficacy and safety of oblique lateral interbody fusion and transforaminal interbody fusion in the treatment of degenerative lumbar spondylolisthesis.
The aim of this study was to comprehensively evaluate the efficacy of oblique lateral interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF) in the treatment of degenerative lumbar spondylolisthesis by meta-analysis. A computer-based search of PubMed, Cochrane Library, Embase, Web of Science Core Collection databases, the China National Knowledge Infrastructure, China Biology Medicine, and Wanfang Digital Periodicals was conducted from the time of inception of each database to December 2021. The review process was conducted according to the PRISMA guidelines and registered in the PROSPERO database. Meta-analysis was performed using RevMan 5.4 software provided by the Cochrane Library. Thirteen studies were included in the statistical analysis. One randomized controlled study and 12 cohort studies with 954 patients were included. In terms of operation time, intraoperative blood loss, Oswestry disability index score, intervertebral height, and complications, the OLIF group was better than the TLIF group, and the difference was statistically significant (P < 0.05). There was no significant difference between the two groups in terms of visual analogue scale score, lumbar lordosis or fused segment lordosis (P > 0.05). Both OLIF and TLIF are effective surgical modalities in the treatment of degenerative lumbar spondylolisthesis. They achieve similar therapeutic effects, but OLIF is superior to TLIF in restoring intervertebral height. At the same time, OLIF has the advantages of short operation time and less intraoperative blood loss.


Polychlorinated dibenzo-p-dioxins and the human immune system: 4 studies on two Spanish families with increased body burdens of highly chlorinated PCDDs.
The consequences of exposure of people to highly chlorinated polychlorodibenzo-p-dioxins (PCDDs) are much less known than those of TCDD. We report on levels of PCDDs (and PCDFs) in 13 members of two families poisoned by contaminated cooking oil. Originally, all persons displayed chloracne as an early symptom. Persisting hexa- and higher chlorinated PCDDs could be analysed many years after exposure. Highest values found in blood lipids were: OCDD 660,000 pg/g; HpCDD 58,000 pg/g; HxCDDs: 3500 pg/g. None of the participants exhibited increased TCDD levels at the time of study. During a period of 6 years, HpCDD and OCDD disappeared from the blood lipids much faster in persons exposed as children or young adults, than from lipids of their parents. Surface receptors on blood lymphocytes of the members of the two families and the proliferative capacity of these blood cells in the presence of typical stimulants were analysed. Even in family members with the highest body burdens of hexa- to octachlorinated PCDDs we could not detect pronounced changes from a reference population with respect to the immunological markers. Minor deviations of levels of some receptors in a few, but not all, highly exposed persons suggested a similar trend to those reported in previous studies of persons with body burdens of > or =3000 pg TCDD/g blood lipids. An increase in the number of total blood lymphocytes in some subjects exposed as children may have similarity with highly TCDD-exposed children in Seveso.


Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores.
To address concerns regarding the tumorigenic potential of undifferentiated human pluripotent stem cells (hPSC) that may remain after in vitro differentiation and ultimately limit the broad use of hPSC-derivatives for therapeutics, we recently described a method to selectively eliminate tumorigenic hPSC from their progeny by inhibiting nicotinamide phosphoribosyltransferase (NAMPT). Limited exposure to NAMPT inhibitors selectively removes hPSC from hPSC-derived cardiomyocytes (hPSC-CM) and spares a wide range of differentiated cell types; yet, it remains unclear when and how cells acquire resistance to NAMPT inhibition during differentiation. In this study, we examined the effects of NAMPT inhibition among multiple time points of cardiomyocyte differentiation. Overall, these studies show that in vitro cardiomyogenic commitment and continued culturing provides resistance to NAMPT inhibition and cell survival is associated with the ability to maintain cellular ATP pools despite depletion of NAD levels. Unlike cells at earlier stages of differentiation, day 28 hPSC-CM can survive longer periods of NAMPT inhibition and maintain ATP generation by glycolysis and/or mitochondrial respiration. This is distinct from terminally differentiated fibroblasts, which maintain mitochondrial respiration during NAMPT inhibition. Overall, these results provide new mechanistic insight into how regulation of cellular NAD and energy pools change with hPSC-CM differentiation and further inform how NAMPT inhibition strategies could be implemented within the context of cardiomyocyte differentiation. Stem Cells Translational Medicine 2017;6:1191-1201.


Stenotic transverse sinus predisposes to poststenting hyperperfusion syndrome as evidenced by quantitative analysis of peritherapeutic cerebral circulation time.
Hyperperfusion syndrome is a devastating complication of carotid stent placement. The shortening of cerebral circulation time after stent placement is seen as a good indicator of the development of hyperperfusion syndrome. The purpose of our study was to evaluate whether patients with ipsilateral transverse sinus stenosis are prone to having shortened cerebral circulation time after stent placement, subsequently leading to the possible development of hyperperfusion syndrome. Forty-nine patients with >70% unilateral carotid stenosis undergoing stent placement were recruited for analysis. Group A consisted of patients with a stenotic ipsilateral transverse sinus >50% greater than the diameter of the contralateral transverse sinus; the remaining patients were in group B. Quantitative DSA was used to calculate cerebral circulation time. Cerebral circulation time was defined as the time difference between the relative time to maximal intensity of ROIs in the proximal internal carotid artery and the internal jugular vein. ΔCCT was defined as cerebral circulation time before stent placement minus cerebral circulation time after stent placement. ΔCCT, white matter hyperintensity signals, and sulcal effacement in MR imaging were compared between the 2 groups. ΔCCT was significantly shorter in group A (0.65 ± 1.3) than in group B (-0.12 ± 1.4). Three patients had white matter hyperintensity signals in group A, and 1 developed hyperperfusion syndrome. Group B showed no MR imaging signs of hyperperfusion syndrome. Ipsilateral hypoplastic transverse sinus was associated with prolonged cerebral circulation time before stent placement and greatly shortened cerebral circulation time after stent placement. Inadequate venous drainage might play a role in impaired cerebral autoregulation and might influence the development of poststenting hyperperfusion syndrome.


Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium.
Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.


A survey for spotted fever group rickettsiae and ehrlichiae in Amblyomma variegatum from St. Kitts and Nevis.
Eighty-nine Amblyomma variegatum ticks were collected from the islands of St. Kitts and Nevis in the Caribbean and preserved in 70% ethanol or local rum. After being washed in sterile water, their DNA was extracted and analyzed by a polymerase chain reaction (PCR) for DNA of spotted fever group rickettsiae and ehrlichiae. None of the tested ticks was positive in a PCR assay using the primers 16S EHRD and 16S EHRR for the 16S rRNA gene of Ehrlichia spp.. Forty-one percent of the A. variegatum (36 of 89 of which 34 [47%] of 72 were adult males, 2 (13%) of 16 were adult females, and 0 (0%) of 1 were nymphs) were positive in a PCR assay using the primer pair 190-70 and 190-701 for the outer membrane protein A (ompA) gene of spotted fever group rickettsiae. All PCR amplification products obtained had 100% sequence homology with Rickettsia africae, the agent of African tick-bite fever.


Do parabens have the ability to interfere with steroidogenesis?
The effects of ethyl and butyl paraben on steroidogenesis were evaluated in rats exposed in utero. Pregnant Wistar rats were dosed from gestational day (GD) 7 to GD 21, followed by examination of the dams, and the fetuses. Additionally, both parabens were tested in vitro in the H295R steroidogenesis assay and in the T-screen assay, the later to test for their ability to act as thyroid hormone receptor agonist or antagonist. In the in utero exposure toxicity study, neither ethyl nor butyl paraben showed any treatment-related effects on testosterone production, anogenital distance, or testicular histopathology. However, butyl paraben caused a significant decrease in the mRNA expression level of estradiol receptor-beta in fetal ovaries, and also significantly decreased the mRNA expression of steroidogenic acute regulatory protein and peripheral benzodiazepine receptor in the adrenal glands. In vitro butyl paraben increased the proliferation of the GH3 cells in the T-Screen assay, thereby acting as a weak thyroid hormone receptor agonist. In the adrenal H295R steroidogenesis assay both ethyl and butyl paraben caused a significant increase in the progesterone formation. Overall, the results indicate that butyl paraben might have the ability to act as endocrine disruptor by interfering with the transport of cholesterol to the mitochondrion, thereby interfering with steroidogenesis, but also that the two tested parabens do not show clear endocrine disrupting capabilities in our short-term in vivo experiment.


Infection trains the host for microbiota-enhanced resistance to pathogens.
The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Mechanistically, taurine potentiates the microbiota's production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens. As such, pharmaceutical sequestration of sulfide perturbs the microbiota's composition and promotes pathogen invasion. Together, this work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train the microbiota, promoting its resistance to subsequent infection.


Serotypes and genotypes of invasive pneumococci in the central part of Slovenia.
To investigate epidemiology of invasive pneumococcal disease (IPD) in the central part of Slovenia in a population with no routine pneumococcal vaccination, we carried out serotyping of isolates by sequential multiplex polymerase chain reaction (PCR) and genotyping by repetitive sequence-based PCR (rep-PCR) and some by multilocus sequence typing. IPD was confirmed in 134 (26.5 %) of 510 acutely ill patients, either by a positive blood culture or real-time PCR (rt-PCR). In 94 patients, isolates were available for typing (24 from blood and 70 from nasopharynx). They belonged to 12 different serotypes; the most prevalent were 14 (27.6 % isolates), 9V, 3 (12.7 % each), 7F (9.5 %), 19A, and 1 (7.4 % each) followed by 4, 6A/B, 19F, 23F, 18C, and 33F. Genotyping yielded 34 rep-PCR genotypes and 13 subtypes; six were found in serotype 14, one in 9V, four each in 3, 19A, and 6A/B, three each in 7F and 1, and two each in 4, 19F, 23F, and 18C. Serotype 9V was the most homogenous and 14 and 19A were heterogenous and had two divergent clonal groups each. The most common genotypes belonged to virulent widespread clones, like ST162, ST9, ST15, ST156, ST191, and ST1377; however, sporadic clones were also observed.


Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up.
Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up. To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA). Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic. Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies. After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies--51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, -4.5; 95% CI, -6.0 to -2.9; P < .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, -7.1; 95% CI, -8.4 to -5.8; P < .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P < .001) compared with antiadalimumab antibody-negative ones (n = 28 [14%]). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (< 3.2; HR, 3.6; 95% CI, 1.8-7.2; P < .001) compared with antiadalimumab antibody-negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody-negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 < 2.6; HR, 7.1; 95% CI, 2.1-23.4; P < .001) compared with antiadalimumab antibody-negative ones. Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.


Outcome analysis of cirrhotic patients undergoing chest tube placement.
Patients with cirrhosis can acquire pulmonary conditions that may or may not be related to their illness. Although posing a greater risk for complications, chest tubes are sometimes placed as treatment for hepatic hydrothorax and other pulmonary conditions. The aim of this study was to analyze the outcomes of chest tube placement in cirrhotic patients. A retrospective analysis was performed of 59 adults with cirrhosis undergoing chest tube placement. Variables that were investigated included reason for chest tube placement, complications developing while having the tube in place, and outcome. The 59 subjects were classified as having Child-Turcotte-Pugh (CTP) class A cirrhosis (n = 3), CTP class B cirrhosis (n = 31), and CTP class C cirrhosis (n = 25). Indications for having a chest tube placed were hepatic hydrothorax (n = 24), pneumothorax (n = 9), empyema (n = 8), video-assisted thoracoscopy (VAT) [n = 7], non-VAT (n = 5), and hemothorax (n = 3). The CTP class A subjects had their chest tubes removed without further complications early in the course, and were excluded from further statistical analysis. Twenty-five subjects (42%) had significant pleural effusions requiring chest tube placement. Among the CTP class B and class C subjects, the median duration with chest tube in place was 5.0 days (range, 1 to 53 days). Serum total bilirubin levels, presence of portosystemic encephalopathy, and CTP C classification were predictors of mortality. Mortalities were seen in 5 of 31 CTP class B subjects (16%), and 10 of 25 CTP class C subjects (40%). The tubes were successfully removed in a total of 39 subjects (66%) with no further procedure. Forty-seven subjects (80%) acquired one or more of the following complications: renal dysfunction, electrolyte imbalances, and infection. When placed for all indications, chest tubes may be successfully removed in the majority of cirrhotic patients. However, a third of all patients still die with the chest tube still in place. Failure to remove the chest tube increases mortality in patients with increasing severity of liver disease.


Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.
Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.


Addressing knowledge gaps and prevention for tuberculosis-infected Indian adults: a vital part of elimination.
India plans to eliminate tuberculosis (TB) by 2025, and has identified screening and prevention as key activities. Household contacts (HHCs) of index TB cases are a high-risk population that would benefit from rapid implementation of these strategies. However, best practices for TB prevention and knowledge gaps among HHCs have not been studied. We evaluated TB knowledge and understanding of prevention among tuberculin skin-test (TST) positive HHCs. While extensive information is available in other high-burden settings regarding TB knowledge gaps, identifying how Indian adult contacts view their transmission risk and prevention options may inform novel screening algorithms and education efforts that will be part of the new elimination plan. We approached adult HHC to administer a questionnaire on TB knowledge and understanding of infection. Over 1 year, 100 HHC were enrolled at a tertiary hospital in Pune, India. The study population was 61% (n = 61) female, with a mean age of 36.6 years (range 18-67, SD = 12). Education levels were high, with 78 (78%) having at least a high school education, and 23 (24%) had at least some college education. Four (4%) of our participants were HIV-infected. General TB knowledge among HHC was low, with a majority of participants believing that you can get TB from sharing dishes (70%) or touching something that has been coughed on (52%). Understanding of infection was also low, with 42% believing that being skin-test positive means you have disease. To assess readiness for preventive therapy, we asked participants whether they are at a higher risk of progressing to active disease because of their LTBI status. Fifty-four (55%) felt that they are at higher risk. Only 8% had heard of preventive therapy. Our TB knowledge survey among HHCs with evidence of recent exposure found that knowledge is poor and families are confused about transmission in the household. It is imperative that the Indian program develop tools and incentives that can be used to educate TB cases and their families on what infected HHCs can do to prevent disease, including preventive therapy.


Electrophysiological properties of neurosensory progenitors derived from human embryonic stem cells.
In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, stem cell-derived neurons may provide a potential source of replacement cells. The success of such a therapy relies upon producing a population of functional neurons from stem cells, to enable precise encoding of sound information to the brainstem. Using our established differentiation assay to produce sensory neurons from human stem cells, patch-clamp recordings indicated that all neurons examined generated action potentials and displayed both transient sodium and sustained potassium currents. Stem cell-derived neurons reliably entrained to stimuli up to 20 pulses per second (pps), with 50% entrainment at 50 pps. A comparison with cultured primary auditory neurons indicated similar firing precision during low-frequency stimuli, but significant differences after 50 pps due to differences in action potential latency and width. The firing properties of stem cell-derived neurons were also considered relative to time in culture (31-56 days) and revealed no change in resting membrane potential, threshold or firing latency over time. Thus, while stem cell-derived neurons did not entrain to high frequency stimulation as effectively as mammalian auditory neurons, their electrical phenotype was stable in culture and consistent with that reported for embryonic auditory neurons.


The prevalence of depression in axial spondyloarthritis and its association with disease activity: a systematic review and meta-analysis.
Depression is common among patients with axial spondyloarthritis (axSpA), but reports of its prevalence are highly variable. We performed a systematic review to (i) describe the prevalence of depression in axSpA, (ii) compare its prevalence between axSpA, ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA) cohorts, and (iii) compare disease activity and functional impairment between those with and without depression. We searched Medline, PubMed, Web of Science, PsycINFO, CINAHL Plus, the Cochrane library and conference abstracts of the European League Against Rheumatism, British Society for Rheumatology and American College of Rheumatology using a predefined protocol in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed using quality-effects model. Fifteen original articles and one abstract were included for analysis; 14 studies described AS cohorts and two nr-axSpA. Three screening criteria and one diagnostic criterion were used to define depression. Prevalence ranged from 11 to 64% depending on criteria and thresholds used. Pooled prevalence of at least moderate depression was 15% using the Hospital Anxiety and Depression Scale (HADS) threshold of ≥ 11. The prevalence of depression was similar between axSpA, AS and nr-axSpA cohorts. Patients with depression had significantly worse disease activity, including higher BASDAI by 1.4 units (95% CI 1.0 to 1.9), ASDAS by 0.5 units (95% CI 0.3 to 0.7) and ESR by 3.5 mm/h (95% CI 0.6 to 6.4). They also had greater functional impairment with higher BASFI and BASMI by 1.2 units (95% CI 0.6 to 1.8) and 0.6 units (95% CI 0.3 to 0.8), respectively. Mean age of each study cohort inversely correlated with depression prevalence. Depression is common among axSpA patients and is associated with more severe disease activity and functional impairment. Identifying and managing depression should form part of their holistic care. Further longitudinal studies are needed to explore the impact of depression on treatment outcomes and axSpA treatment on symptoms of depression.


β-Glucan and dark chocolate: a randomized crossover study on short-term satiety and energy intake.
The aims of this study were to adapt a traditional recipe into a healthier form by adding 3 g of oat β-glucan, substituting milk chocolate to dark chocolate with 70% cocoa, and to examine the effect of these alterations on short-term satiety and energy intake. Study subjects (n = 25) were tested in a randomized, crossover design with four products closely matched for energy content. Four different versions of a traditional recipe including milk chocolate-control (CON), oat β-glucan (B-GLU), dark chocolate (DARK) or oat β-glucan and dark chocolate (B-GLU + DARK) were given to subjects on different test days. After subjects were asked to report visual analog scale (VAS) scores on sensory outcomes and related satiety for four hours ad libitum, lunch was served and energy intake of individuals was measured. VAS scores indicated that none of the test foods exerted an improved effect on satiety feelings. However, energy intake of individuals during ad libitum lunch was significantly lower in dark chocolate groups (CON: 849.46 ± 47.45 kcal versus DARK: 677.69 ± 48.45 kcal and B-GLU + DARK: 691.08 ± 47.45 kcal, p = 0.014). The study demonstrated that substituting dark chocolate for milk chocolate is more effective in inducing satiety during subsequent food intake in healthy subjects.


Down-Regulation of Cannabinoid Type 1 (CB1) Receptor and its Downstream Signaling Pathways in Metastatic Colorectal Cancer.
Changes in the regulation of endocannabinoid production, together with an altered expression of their receptors are hallmarks of cancer, including colorectal cancer (CRC). Although several studies have been conducted to understand the biological role of the CB1 receptor in cancer, little is known about its involvement in the metastatic process of CRC. The aim of this study was to investigate the possible link between CB1 receptor expression and the presence of metastasis in patients with CRC, investigating the main signaling pathways elicited downstream of CB1 receptor in colon cancer. Fifty-nine consecutive patients, with histologically proven colorectal cancer, were enrolled in the study, of which 30 patients with synchronous metastasis, at first diagnosis and 29 without metastasis. A low expression of CB1 receptor were detected in primary tumor tissue of CRC patients with metastasis and consequently, we observed an alteration of CB1 receptor downstream signaling. These signaling routes were also altered in intestinal normal mucosa, suggesting that, normal mucosa surrounding the tumor provides a realistic picture of the molecules involved in tissue malignant transformation. These observations contribute to the idea that drugs able to induce CB1 receptor expression can be helpful in order to set new anticancer therapeutic strategies.


Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases.
Mucins are large multifunctional glycoproteins whose primary functions are to protect and lubricate the surfaces of epithelial tissues lining ducts and lumens within the human body. Several lines of evidence also support the involvement of mucins in more complex biological processes such as epithelial cell renewal and differentiation, cell signaling, and cell adhesion. Recent studies have uncovered the role of select mucins in the pathogenesis of cancer, underscoring the importance of a detailed knowledge about mucin biology. Under normal physiological conditions, the production of mucins is optimally maintained by a host of elaborate and coordinated regulatory mechanisms, thereby affording a well-defined pattern of tissue-, time-, and developmental state-specific distribution. However, mucin homeostasis may be disrupted by the action of environmental and/or intrinsic factors that affect cellular integrity. This results in an altered cell behavior that often culminates into a variety of pathological conditions. Deregulated mucin production has indeed been associated with numerous types of cancers and inflammatory disorders. It is, therefore, crucial to comprehend the underlying basis of molecular mechanisms controlling mucin production in order to design and implement adequate therapeutic strategies for combating these diseases. Herein, we discuss some physiologically relevant regulatory aspects of mucin production, with a particular emphasis on aberrations that pertain to pathological situations. Our views of the achievements, the conceptual and technical limitations, as well as the future challenges associated with studies of mucin regulation are exposed.


Sexual and cardiovascular correlates of male unfaithfulness.
Definitions of unfaithfulness and its consequences vary across different cultures, religions, and legal jurisdictions; however, having extramarital affairs is associated in most societies with a stigma. Therefore, the study of this sensitive topic is extremely complex, and its prevalence is often underestimated. To offer a summary of available data in literature about unfaithfulness. An extensive Medline search was performed including the following words "unfaithfulness,""extramarital affairs,""infidelity,""men." The search, up to December 4, 2011, was restricted to English-language articles. We reported literature data on the prevalence of unfaithfulness and on related psychobiological, sexual, and risk factors. Some surveys reported that 1.5-4% of married men had extramarital coitus in any given year, others that 23.2% of men have cheated during their current relationship. Different studies reported a lifetime prevalence of unfaithfulness between 15% and 50%. With respect to factors related to unfaithfulness, several authors reported that men with extramarital affairs more frequently have a dysfunctional primary relationship, in both relational and sexual terms. In addition, parenthood, as well as conflicts within the family, seem to be associated with a higher risk of having an affair. Furthermore, unfaithful men display a higher androgenization, larger testis volume, lower prevalence of hypoactive sexual desire, and better sexual functioning. Only few studies have evaluated the correlation between infidelity and cardiovascular risk, reporting that having an extramarital affair could have a negative impact on cardiac morbidity and mortality. Several interpersonal, sexual, and biological factors are associated with having extramarital affairs. Unfaithfulness in men seems to be associated with a higher risk of major cardiovascular events.


Increased Surface Albedo in the Northern Hemisphere: Did satellites warn of the weather troubles of 1972 and 1973?
Routine mapping of snow and ice fields in the northern hemisphere was started by NOAA in 1967. Large year-to-year variations of the snow and pack-ice covers were observed. The annual mean coverage increased by 12 percent during 1971 and has remained high. The index R, which shows the approximate amount of energy reflected from the surface by snow and ice under the mean cloudiness, increased correspondingly. Thus, if the cloud cover over the snow fields did not increase substantially, the anomalous weather patterns of 1972 and 1973 could have been connected with the deficit in surface heat exchange which originated in the northern hemisphere the year before. During the past 7 years the largest changes occurred in the fall and in the continental interiors of Asia and America (8). Two synoptic parameters which could readily provide information on the development of snow and ice cover in the northern hemisphere are (i) the total area momentarily covered and (ii) the running annual mean of snow and ice coverage for the preceding 1-year period. By 20 September 1973 the annual mean coverage was 37.3 x 10(6) km(2), 11 to 12 percent higher than at the same time during 1968 through 1970. Snow cover-fall, the season when 15 x 10(6) to 55 x 10(6) km(2) of the northern hemisphere is covered with snow and ice, started on 20 September 1973, compared to 17 September 1972 and 5 or 10 October during 1967 through 1970. The links between the atmosphere, the oceans, and the land surfaces must be better understood before the role of snow and ice can be thoroughly explained and exploited for long-range weather forecasting. But it is clear that snow, hitherto almost overlooked in synoptic meteorological reports, must be important in the mechanism of weather changes.


Metastatic breast cancer: understanding current management options.
To review the standard treatment options for metastatic breast cancer, present recently approved chemotherapeutic and hormonal approaches, and describe novel biologic therapies, particularly the use of monoclonal antibodies. Published articles, abstracts, and conference proceedings. Standard treatment options available to women with metastatic breast cancer include surgery, radiation therapy, hormonal therapy, chemotherapy, and palliative approaches. New chemotherapeutic approaches for the management of metastatic breast cancer include the recently approved agents paclitaxel, docetaxel, and capecitabine. New hormonal agents such as toremifene, letrozole, and exemestane also have been approved. Finally, an agent from a new class of agents--biologic response modifiers (BRMs)--now. Is available. Trastuzumab, a monoclonal antibody (one class of BRMs), is a new and promising approach available to a subpopulation of women with metastatic breast cancer. Although standard treatment options for the management of metastatic breast cancer may prolong survival for some, they have not resulted in a cure for the majority of women. Recent advances in the understanding of cancer cellular biology have led to newer approaches such as monoclonal antibodies and other BRMs that may offer hope of extended survival and improved quality of life for certain women. This field is growing quickly, and new targets for breast cancer therapy are being studied. Nurses who become familiar with newer treatment options available for the management of metastatic breast cancer, including new chemotherapeutic and hormonal approaches and monoclonal antibody therapy, are better able to provide information and support for their patients. Clinicians must understand the criteria for patient selection for newer agents, particularly trastuzumab. In addition, recognizing adverse effects and knowing the management strategies for treatment-related toxicities help to ensure positive patient outcomes.


The clinical spectrum of Castleman's disease.
Castleman's disease (CD) is a rare, poorly understood lymphoproliferative disease. The spectrum of symptoms and course of disease are broad, but there is no large study describing the natural history of this disease. Basic clinic and laboratory data from the records of 113 patients with CD evaluated at the Mayo Clinic and University of Nebraska were abstracted. The impact of these variables on overall survival (OS) from time of diagnosis was evaluated. Sixty patients had multicentric disease. Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome. For all patients, 2, 5, and 10-year OS was 92%, 76%, 59%, respectively. Most of the factors identified as risk factors for death on univariate analysis cosegregated with diagnostic criteria for POEMS syndrome, which supported the concept of four categories of CD, which are (along with their 5-year OS): (1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%). We have demonstrated that CD represents a spectrum of disease that can be differentiated by simple prognostic factors that provide a framework for further study.


Needs, acceptability, and value of humanitarian medical assistance in remote Peruvian Amazon riverine communities.
Much debate exists regarding the need, acceptability, and value of humanitarian medical assistance. We conducted a cross-sectional study on 457 children under 5 years from four remote riverine communities in the Peruvian Amazon and collected anthropometric measures, blood samples (1-4 years), and stool samples. Focus groups and key informant interviews assessed perspectives regarding medical aid delivered by foreigners. The prevalence of stunting, anemia, and intestinal parasites was 20%, 37%, and 62%, respectively. Infection with multiple parasites, usually geohelminths, was detected in 41% of children. The prevalence of intestinal parasites both individual and polyparasitism increased with age. Participants from smaller communities less exposed to foreigners expressed lack of trust and fear of them. However, participants from all communities were positive about foreigners visiting to provide health support. Prevalent health needs such as parasitic infections and anemia may be addressed by short-term medical interventions. There is a perceived openness to and acceptability of medical assistance delivered by foreign personnel.