Polyomavirus nephropathy: morphology, pathophysiology, and clinical management.
Viral nephropathies, particularly those caused by polyomaviruses of the BK-virus strain, are serious complications following renal transplantation. The review will highlight the morphological, pathophysiological and clinical aspects of BK-virus nephropathy. New patient management strategies are discussed. Immunosuppression with tacrolimus and mycophenolate-mofetil promotes the activation of latent BK-virus in the urinary tract and increases the odds ratio for developing BK-virus nephropathy significantly. A productive infection with BK-viruses shows viral replication in tubular epithelial cells and acute tubular injury. BK-virus nephropathy can be further complicated by concurrent acute rejection episodes contributing to graft demise. Risk assessment after transplantation and patient management during ongoing viral nephropathy have undergone revision by the introduction of real time quantitative polymerase chain reaction techniques measuring BK-virus genome load fluctuations in the serum. Treatment strategies for BK-virus nephropathy include not only low-dose immunosuppression but also drugs with antiviral effects: cidofovir and leflunomide. Transient anti-rejection therapy, including anti-lymphocytic preparations, is a therapeutic option in cases of BK-virus nephropathy and concurrent acute rejection. Recent advances in patient management strategies have resulted in markedly improved graft survival. In cases of graft loss due to BK-virus nephropathy, re-transplantation should be considered. BK-virus nephropathy is a significant complication following renal transplantation. Recent advances have improved our understanding of the morphological changes, potential risk factors and patient management strategies would be optimized. The availability of quantitative viral load measurements now offers the opportunity for a more accurate and timely clinical intervention.


Pneumococcal conjugate vaccines: emerging clinical information and its implications.
Since 2000, when the first pneumococcal conjugate vaccine was introduced into routine use in the USA, it has had a substantial impact on invasive pneumococcal disease both in the immunized and nonimmunized population. It has also been shown to reduce pneumonia and otitis in young children and has reduced antibiotic nonsusceptible pneumococcal infections. In the USA, three primary doses and a booster dose are recommended (a so-called '3 + 1 schedule'). Some countries have or will soon introduce routine immunization with fewer doses, with either two primary doses and a booster dose ('2 + 1 schedule') or no booster dose ('3 + 0 schedule'). Some serotypes produce less antibody in a two-dose compared with a three-dose primary series. The booster dose may also be important in reducing nasopharyngeal carriage, hence absence of a booster dose may reduce indirect protection. It remains to be seen whether these schedule changes will reduce vaccine effectiveness within the population. Important future developments include extending the number of serotypes included in the vaccine and the possible extension of use into adults in whom indirect protection has been useful, but not as extensive as might be possible with direct immunization.


Maxillary and sella turcica morphology in newborns with cleft lip and palate.
The first aim was to examine maxillary developmental fields by analyzing bone size parameters within the maxillary bone complex in newborns with unilateral cleft lip (UCL) and unilateral cleft lip and palate (UCLP). The second aim was to evaluate sella turcica morphology in unilateral cleft lip and unilateral cleft lip and palate. Axial and profile radiographs from 40 newborns (boy-girl, 1:1) in each group (20 unilateral cleft lip and 20 unilateral cleft lip and palate) were randomly selected among radiographs taken for optimizing treatment planning. Analysis of maxillary bone size was performed on axial radiographs and size parameters were measured. Furthermore, analysis of sella turcica morphology was performed on profile radiographs. The results were divided into groups with normal morphology and severe deviations in the morphology. The maxillary areas were significantly shorter and broader in unilateral cleft lip and palate than in unilateral cleft lip. A profound asymmetry in the maxillary areas was seen in unilateral cleft lip and palate, but not in unilateral cleft lip. In both cleft types, approximately half of the individuals had deviations in sella turcica morphology. The most severe deviations occurred in newborns with unilateral cleft lip and palate. In newborns with unilateral cleft lip and palate, the maxillary areas are significantly shorter, broader, and more asymmetric than in newborns with unilateral cleft lip. The present study showed that bone structures are a suitable parameter for characterizing the craniofacial developmental fields. Additionally, a high incidence of deviations in sella turcica morphology might indicate that this area is affected in individuals with clefts.


Pharmacodynamics of Aloe vera and acemannan in therapeutic applications for skin, digestion, and immunomodulation.
Scientific studies of Aloe vera have tentatively explained therapeutic claims from a mechanistic perspective. Furthermore, in vitro outcomes demonstrate that the breakage of acemannan chains into smaller fragments enhances biological effects. These fragments can intravenously boost vaccine efficacy or entrain the immune system to attack cancer cells by mannose receptor agonism of macrophage or dendritic cells. With oral consumption, epithelialisation also occurs at injured sites in the small intestine or colon. The main advantage of dietary acemannan is the attenuation of the digestive process, increasing satiety, and slowing the release of sugars from starches. In the colon, acemannan is digested by microbes into short-chain fatty acids that are absorbed and augment the sensation of satiety and confer a host of other health benefits. In topical applications, an acemannan/chitosan combination accelerates the closure of wounds by promoting granular tissue formation, which creates a barrier between macrophages or neutrophils and the wound dressing. This causes M2 polarisation, reversal of inflammation, and acceleration of the re-epithelialisation process. This review summarises and explains the current pharmacodynamic paradigm in the context of acemannan in topical, oral, and intravenous applications. However, due to contradictory results in the literature, further research is required to provide scientific evidence to confirm or nullify these claims.


POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature.
The t(8;21)(q22;q22) translocation, present in approximately 5% of adult acute myeloid leukemia (AML) cases, produces the AML1/ETO (AE) fusion protein. Dysregulation of the Pit/Oct/Unc (POU) domain-containing transcription factor POU4F1 is a recurring abnormality in t(8;21) AML. In this study, we showed that POU4F1 overexpression is highly correlated with, but not caused by, AE. We observed that AE markedly increases the self-renewal capacity of myeloid progenitors from murine bone marrow or fetal liver and drives the expansion of these cells in liquid culture. POU4F1 is neither necessary nor sufficient for these AE-dependent properties, suggesting that it contributes to leukemia through novel mechanisms. To identify targets of POU4F1, we performed gene expression profiling in primary mouse cells with genetically defined levels of POU4F1 and identified 140 differentially expressed genes. This expression signature was significantly enriched in human t(8;21) AML samples and was sufficient to cluster t(8;21) AML samples in an unsupervised hierarchical analysis. Among the most highly differentially expressed genes, half are known AML1/ETO targets, implying that the unique transcriptional signature of t(8;21) AML is, in part, attributable to POU4F1 and not AML1/ETO itself. These genes provide novel candidates for understanding the biology and developing therapeutic approaches for t(8;21) AML.


Analysis of DNA replication in Saccharomyces cerevisiae by two-dimensional and pulsed-field gel electrophoresis.
Two methods to analyze DNA replication in budding yeast are described here. One is two-dimensional (2D) gel electrophoresis, which has been used to analyze replication intermediates in yeast. The other method is pulsed-field gel electrophoresis (PFGE) that monitors the replication status of a chromosome. These are convenient and easy, and they do not require specialized equipment.


The role of release bursts in the perception of [s]-stop clusters.
The role of the release burst as a cue to the perception of stop consonants following [s] was investigated in a series of studies. Experiment 1 demonstrated that silent closure duration and burst duration can be traded as cues for the "say"-"stay" distinction. Experiment 2 revealed a similar trading relation between closure duration and burst amplitude. Experiments 3 and 4 suggested, perhaps surprisingly, that absolute, not relative, burst amplitude is important. Experiment 5 demonstrated that listener's sensitivity to bursts in a labeling task is at least equal to their sensitivity in a burst detection task. Experiments 6 and 7 replicated the trading relation between closure duration and burst amplitude for labial stops in the "slit"-"split" and "slash"-"splash" distinctions, although burst amplification, in contrast to attenuation, had no effect. All experiments revealed that listeners are remarkably sensitive to the presence of even very weak release bursts.


[The roles of Helicobacter pylori and pattern of gastritis in the pathogenesis of reflux esophagitis].
Comparing the infection rates and density of Helicobacter pylori (H. pylori) and the patterns of gastritis in reflux esophagitis (RE) and non-erosive reflux disease (NERD) patients to investigate the role of H. pylori in the pathogenesis of RE. Two hundred and twenty-three out-patients with typical gastroesophageal reflux symptoms who consecutively visited the hospital underwent ambulatory 24-hour pH monitoring and gastroscopy, and biopsy of the gastric mucosa. RE and NERD were diagnosed based on the presentation of endoscopy. Gastritis was divided into four different patterns: chronic non-atrophic antritis (CNAA); chronic non-atrophic pan-gastritis (CNAG); chronic atrophic antritis (CAA); and chronic atrophic pan-gastritis (CAG). H. pylori infection was evaluated by Warthin-Starry staining. DeMeester score > or = 15 was considered as pathological acid reflux. Sixty-two patients (27.8%) were found to have RE, 161 (72.2%) were found to have NERD. Totally, 67 patients had H. pylori infection (30.0%). There was no significant difference in H. pylori infection rate between the RE and NERD groups (25.8% vs. 31.5%, P > 0.05). 45 of the 223 patients were diagnosed as with CNAA (20.2%), 88 (39.5%) with CNAG, 65 (29.2%) with CAA, and 25 (11.2%) with CAG. The CAG rates in the RE and NERD groups were 6.5% and 13.0% respectively (P > 0.05). There were no differences in abnormal pH monitoring rate and DeMeester score among the different patterns of gastritis. In the sixty-seven H. pylori-positive GERD patients, the 24 h pH monitoring positive rate of the moderate-severe H. pylori colonization density group was 46.4%, significantly higher than that of the mild H. pylori colonization density group (73.5%, P < 0.05); and the mean intra-gastric pH value during 24 hours of the moderate-severe H. pylori colonization density group was 2.3 +/- 0.8, significantly higher than that of the mild H. pylori colonization density group (2.0 +/- 1.1, P < 0.05). H. pylori infection is associated with the pattern of gastritis, but shows no relationship to the incidence of RE. High density of H. pylori colonization in gastric corpus may reduce the esophageal acid exposure. Diffuse atrophic gastritis may protect the patients from RE.


Thermodynamic and structural properties of repulsive hard-core Yukawa fluid: integral equation theory, perturbation theory and Monte Carlo simulations.
The thermodynamic and structural properties of purely repulsive hard-core Yukawa particles in the fluid state are determined through Monte Carlo simulation and modeled using perturbation theory and integral equation theory in the mean spherical approximation (MSA). Systems of particles with Yukawa screening lengths of 1.8, 3.0, and 5.0 are examined with results compared to variations of MSA and perturbation theory. Thermodynamic properties were predicted well by both theories in the fluid region up to the fluid-solid phase boundary. Further, we found that a simplified exponential version of the MSA is the most accurate at predicting radial distribution function at contact. Radial distribution function of repulsive hard-core Yukawa particles are also reported. The results show that methods based on MSA and perturbation theory that are typically applied to the attractive hard-core Yukawa potential can also be extended to the purely repulsive hard-core Yukawa potential.


Molecular Characterization of Fasciola hepatica in Sheep Based on DNA Sequences of Ribosomal ITS-1.
World Health Organization (WHO) considers Fascioliasis as a neglected tropical disease that requires global efforts for disease control. Data from the genetic characterization of Fasciola population shed light on the spread of infections among animals which could help in the development of effective parasite control. The aim of the present work was to genetically characterize Fasciola adult worms isolated from sheep in Saudi Arabia by sequence analysis of ITS-1 region. A total of 12,653 slaughtered sheep in Jeddah city, Saudi Arabia were examined for the presence of Fasciola spp. adult worms. The ITS-1 region of all parasites was amplified and sequenced. Overall, 12 variants DNA sequences were obtained. The variance of isolates ranged from 0.00771 to 0.34405. BLAST search showed that all obtained sequences were Fasciola hepatica and had >99.3% similarity with F. hepatica isolates from Spain and USA (from different hosts other than sheep). Phylogenetic analysis showed that Fasciola isolates were closely related to isolates from different countries. The current study showed that F. hepatica was the only spp. isolated from sheep in Jeddah. Further studies from different localities in Saudi Arabia are needed to help in the development of disease control.


Solid-state 13C NMR studies on organic-inorganic hybrid zeolites.
A novel type of organic-inorganic hybrid zeolite with organic lattice (ZOL) is studied in detail by solid-state (13)C magic angle spinning nuclear magnetic resonance (MAS NMR). The (13)C MAS NMR measurements employing several pulse sequences quantitatively demonstrate that methylene groups are really incorporated in the framework, although they are partially cleaved into methyl groups. The organic species in ZOL materials are open for adsorbates, which is evidenced by the (13)C MAS NMR measurements for an n-hexane-adsorbing ZOL material. This finding strongly suggests that organic moieties are incorporated as a zeolite framework, indicating that ZOL is not a physical mixture of a carbon-containing amorphous aggregate and a conventional zeolite but a true organic-inorganic hybrid zeolite.


[Julien Bogousslavsky].
Julien Bogousslavsky is undoubtedly one of the giants of modern neurology. He is best known for creating the Lausanne Stroke Registry and for publishing a considerable number of works on the symptoms and signs caused by cerebrovascular disturbance. Bogousslavsky's research interests extend to the broader field of human cerebral activity, including higher brain function disturbance and even psychiatric symptoms. In this article, his works are introduced according to the following three themes: (1) neurological symptoms and signs caused by a specific lesion in the brain, (2) neurological symptoms and signs caused by a specific cerebrovascular lesion, and (3) psychiatric and/or neuropsychological symptoms caused by organic brain damage.


Spiritual well-being of Italian advanced cancer patients in the home palliative care setting.
This study evaluates the spiritual well-being (SpWB) in very advanced cancer patients assisted by the home palliative care program of ANT Foundation, a no-profit Italian organisation. SpWB was assessed by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp12), including Meaning, Peace, and Faith subscales. The quality-of-life (QoL) was evaluated by using the Functional Assessment of Cancer Therapy-General scale. Questionnaires were distributed to 1,055 patients and 683 were compiled and evaluable for analysis. The mean scores of FACIT-Sp12 as well as of QoL were notably lower than reference values for cancer survivors. The FACIT-Sp12 score was higher in patients with less impaired Karnofsky Performance Status, fully participating in religious rituals and living in central Italy. A high Pearson's correlation was found between QoL and FACIT-Sp12 (r = .60), Peace (r = .71) and Meaning (r = .52), while it was marginal for Faith (r = .27). The hierarchical regression analysis showed that FACIT-Sp12 is a significant predictor of QoL. The study suggests that Italian patients with advanced cancer assisted by expert multi-professional teams in the home palliative care setting have a low level of SpWB thereby highlighting the need for the integration of spiritual support as part of comprehensive cancer care.


Teeth Bleaching Efficacy During Clear Aligner Orthodontic Treatment.
Clear aligner treatment has become popular for many orthodontic cases that ordinarily would have required traditional orthodontic brackets and wires. One of the motivating reasons for patients to use clear aligner therapy is to improve their esthetic appearance, which typically is the same motivation for teeth bleaching, thus a combination of the two treatments may be desirable. The case report presented demonstrates bleaching concurrent with clear aligner (Invisalign®) treatment. A concern about bleaching during such treatment is that the areas on the tooth under the composite attachments, or buttons, used to retain the clear aligner trays may remain unbleached. However, due to the small molecular size of the bleaching material agent and its ability to permeate the tooth, the area under the attachment will be bleached as well. With this understanding, a practitioner can treat patients more efficiently by being able to complete bleaching treatment simultaneously with clear aligner treatment.


Human pattern-evoked electroretinogram.
We have recorded electroretinographic (ERG) responses to grating patterns whose spatial, temporal, and contrast parameters were varied. The resultant evoked potential is dependent on spatial frequency and it exhibits a spatial band-pass characteristic. The peak frequency is dependent on retinal eccentricity. These findings are independent of temporal frequency, contrast, or mean luminance in the photopic range. These results suggest that the pattern ERG originates from a postreceptoral site.


Mechanisms of social synchrony between circadian activity rhythms in cohabiting marmosets.
In marmosets, social synchrony between circadian profiles of activity is stronger in animals that cohabit in a family. The activity of three breeding pairs was recorded by actiwatches to investigate the mechanisms involved in the synchrony between the circadian activity profiles during cohabitation in marmoset reproductive pairs. The dyads were submitted to LD 12:12 (21 days) and LL: 1) cohabitation (24 days), 2) removal of the cage mate (20 days), 3) reintroduction of the mate into the cage of the 1st situation (30 days) and 4) removal of the cage mate (7 days). Next, they were rejoined and maintained in LD 12:12 (11 days). In conditions involving cohabitation of pair, the general and maximum correlation indexes between circadian profiles were higher in cage mates compared to animals of the same or different sex with which they maintain only acoustic and olfactive contact. This strong synchrony between rhythms was accompanied by a stable phase relationship at the activity onset and offset, with identical circadian periods between mates. When the pairs were separated, there was a break in stability in the phase relationships between activity profiles with different circadian periods and a greater phase angle difference between rhythms of cage mates. During separation, two females and one male progressively anticipated the activity onset and offset in a phase similar to that in previous conditions, expressing entrainment to the mate. During the first reintroduction, two pairs exhibited signs of masking in rhythm. Although modulation in the rhythm of some animals has been observed through acoustic cues from animals outside the colony, we suggest that cohabitation favors strong synchrony between the circadian activity profiles of marmoset reproductive pairs involving synchronization by entrainment and masking. Further studies in the absence of external social cues are necessary to clarify the role of these mechanisms on social synchronization in marmosets.


Risk factors and classification of reintervention following deep venous stenting for acute iliofemoral deep vein thrombosis.
Acute iliofemoral deep vein thrombosis (DVT) is associated with the development of post-thrombotic syndrome (PTS). Thrombolysis and deep venous stenting can restore vessel outflow and can reduce the incidence of PTS. However, for a proportion of patients, subsequent stenosis or reocclusion will necessitate further intervention. In the present study, we aimed to identify the risk factors, examine the outcomes (reintervention success and PTS), and develop a classification system for reintervention. A retrospective single-center cohort study of patients who had undergone successful lysis for iliofemoral DVT from 2013 to 2017. The patients' records and imaging studies were examined for demographics, risk factors, extent of thrombus and vessel clearance, stenting, flow, reintervention, anticoagulation compliance, Villalta score, and secondary patency. From our findings, a system of classification for patients for whom procedures have failed was developed, constituting technical, hematologic, flow related, or multiple factors. Of 143 limbs (133 patients), 48 (33.6%) had required reintervention, of which 25 had presented with reocclusion (17.4%). The median time to reintervention was 45 days. The need for reintervention was associated with inferior vena cava thrombus (risk ratio [RR], 2.16; P < .01), stenting across the inguinal ligament (RR, 2.08; P < .01), and anticoagulation noncompliance (RR, 7.09; P < .01). Successful reintervention was achieved in 31 limbs (64.6%): 23 of 23 (100%) treated before occlusion vs 8 of 25 (36.4%) treated after occlusion (RR, 32.31; P < .01). A greater incidence of any PTS was observed for patients requiring reintervention (median Villalta score, 3 [interquartile range, 1-5]; vs 1 [interquartile range, 1-4]; RR, 2.28; P = .029). Cases without complete vessel occlusion (reintervention and control) had a lower rate of any PTS (14.0% vs 42.9%; RR, 3.06; P < .01) and moderate to severe PTS (3.0% vs 14.3%; RR, 4.76; P = .046) Technical issues were observed in 54.2% of reintervention cases and 6.3% of cases not requiring reintervention (P < .01). Hematologic issues were identified in 33.3% of reintervention cases and 1.1% of cases not requiring reintervention (P < .01). Flow-related issues were observed in 43.8% of the reintervention cases and no cases not requiring reintervention (P < .01). Of the reintervention cases, 27.1% were multifactorial and were associated with a lower rate of vessel salvage; however, this did not translate into a significant difference in secondary patency on survival analysis (RR, 1.70; P = .429). A large proportion of patients required reintervention because of potentially preventable factors. Anticoagulation compliance, thrombus burden, and poor flow are important risk factors to consider in patient selection. Reintervention increased the risk of PTS and was more often successful when achieved before vessel occlusion.


Virologic and immunologic effectiveness of tipranavir/ritonavir (TPV/r)- versus darunavir/ritonavir (DRV/r)-based regimens in clinical practice.
Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). Multicenter, retrospective cohort study. The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm( 3) (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm(3) (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression.


Antifungal activity of oils macerates of North Sardinia plants against Candida species isolated from clinical patients with candidiasis.
Antibiotic resistance is one of the bigger problem of public health: the rise of multi-drug resistant organisms causes a challenge in the treatment of infective diseases. Anti-Candida resistance to conventional antifungal agents has increased in the last period. Our research was intended to evaluate antimicrobial activity of oil macerate (OM) of Helichrysum microphyllum Cambess. subsp. tyrrhenicum Bacch., Brullo & Giusso and OM of Hypericum perforatum subsp. angustifolium against several clinical strains. The study included 30 patients with candidiasis who had not received any antifungal treatment before they were enrolled. A collection of 30 clinical isolates belonging to 5 different species of Candida spp. was selected for this study. The data obtained showed an interesting activity of both Oil Macerate especially against C. krusei and C. parapsilosis. On the contrary, H. microphyllum Oil Macerate has had a better activity than the H.perforatum especially in relation to C. glabrata and C. krusei.


Feasibility of translaminar screw placement in Korean population: morphometric analysis of cervical spine.
To analyze the feasibility of unilateral and bilateral translaminar screw placement in Koran population, and compare the acceptance rate using previously reported data in American population. The translaminar lengths, thickness, heights, and sagittal-diagonal measurements were performed. The feasibility analysis was performed using unilateral and bilateral 3.5 mm cervical screw placement on the CT scans within 0.5 mm of safety margin. We also performed radiographic analysis of the morphometric dimensions and the feasibility of unilateral and bilateral translaminar screw placement at C3-C7. Korean population had similar or significantly shorter translaminar lengths and thickness (lengths and thickness in C7 among males; lengths in C6-C7 and thickness in C4 among females) than American population, but had similar or significantly longer translaminar heights and sagittal-diagonal measurements (heights in C3-C7 and sagittal-diagonal measurements in C3-C6 among males; heights in C7 and sagittal-diagonal measurements in C3-C7 among females). Unilaterally, translaminar screw acceptance rates in C3-C7 were similar between Korean and American male population, but the rates in C4-C6 were significantly smaller between Korean and American female population. Bilaterally, translaminar screw acceptance rates in C3 and C5-C6 were significantly larger between Korean and American male population, but the rates in C3-C7 were similar between Korean and American female population. The feasibility of unilateral and bilateral translaminar screw placement is different depending on different ethnics. Subaxial cervical unilateral translaminar screw placement among Korean male population and bilateral placement at C4-C7 among Korean female population are more acceptable than American population.


Feasibility of targeting canine soft tissue sarcoma with MR-guided high-intensity focused ultrasound.
Magnetic resonance imaging-guided high-intensity-focused ultrasound (MR-HIFU) is a non-invasive treatment modality that precisely focuses ultrasound energy within a tumour and can be customised to result in a wide range of local bioeffects. The purpose of this study was to determine the feasibility of using MR-HIFU to treat soft tissue sarcoma (STS) in dogs. Medical records of dogs admitted to the Virginia-Maryland College of Veterinary Medicine from 1 January 2012 to 31 December 2016 were searched for a diagnosis of sarcoma with available cross-sectional imaging of the tumour (MRI or CT). Fifty-three (53) dogs were eligible for inclusion. Tumor tissue (in bone as well as in soft tissue) was considered targetable unless: (1) the ultrasound path was completely obstructed by bone or gas and (2) the MR-HIFU target was within the spinal cord or less than 1 cm from the margin of the spinal cord. Tumors were categorised as <50% targetable, ≥50% targetable or non-targetable. Eighty-one percent of STS (81.1%, 43/53) were targetable. The head/spine tumour sites had the highest proportion of non-targetable tumours (36%, 9/25). The majority of truncal and axillary tumours were ≥50% targetable (88.9%, 16/18) ,and all extremity tumours were considered ≥50% targetable (100%, 5/5). The majority of STS were targetable. This is the first study to evaluate MR-HIFU targetability of canine STS. HIFU has potential as a therapeutic modality for treating STS in dogs, and this veterinary application is a possible model for treatment of naturally occurring STS in humans.


A study on the compliance of a right coronary artery and its impact on wall shear stress.
A computational model incorporating physiological motion and uniform transient wall deformation of a branchless right coronary artery (RCA) was developed to assess the influence of artery compliance on wall shear stress (WSS). Arterial geometry and deformation were derived from modern medical imaging techniques, whereas the blood flow was solved numerically employing a moving-grid approach using a well-validated in-house finite element code. The simulation results indicate that artery compliance affects the WSS in the RCA heterogeneously, with the distal region mostly experiencing these effects. Under physiological inflow conditions, coronary compliance contributed to phase changes in the WSS time history, without affecting the temporal gradient of the local WSS nor the bounds of the WSS magnitude. Compliance does not cause considerable changes to the topology of WSS vector patterns nor to the localization of WSS minima along the RCA. We conclude that compliance is not an important factor affecting local hemodynamics in the proximal region of the RCA while the influence of compliance in the distal region needs to be evaluated in conjunction with the outflow to the myocardium through the major branches of the RCA.


In vitro antiproliferative and antiangiogenic effects of Flavin7.
Flavin7 (F7) is a nutritional supplement often taken by cancer patients in Central Europe during chemo- and radiation therapy. In this study, investigation of the antiproliferative and antiangiogenic activities of this supplement were performed. Flavin7 showed antiproliferative activity in Jurkat as well as in HeLa cells. It significantly reduced the growth of both cancer cell lines at the doses of 200 microg/ml to 20 microg/ml (p<0.001 and p<0.01, respectively). In F7-treated Jurkat cells we found a significant increase in the fraction of cells with sub-G(0)/G(1) DNA content, which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by annexin V staining and DNA fragmentation. Furthermore, F7 at the doses of 100 microg/ml to 4 microg/ml inhibited endothelial cell migration and capillary tube formation what indicates its potential antiangiogenic properties. Flavin7 also inhibited the activity of matrix metalloproteinases (MMPs), preferentially MMP-9, at the doses of 100 microg/ml to 4 microg/ml. Our data suggest that F7 possesses marked antiproliferative and antiangiogenic properties in vitro. Further research is needed to elucidate also its in vivo activities.


Management of facial spasm with Clostridium botulinum toxin, type A (Oculinum)
One hundred five patients received 391 graded injections of Clostridium botulinum type A toxin (Oculinum) to treat uncontrollable facial muscle spasm. Patients had essential blepharospasm (n = 61), hemifacial spasm (n = 24), or aberrant regeneration of the seventh cranial nerve (n = 20). Muscle spasms were reduced within two days of the first injection of toxin and, in most cases, the drug effect lasted three to four months. Control of facial muscle spasm was achieved in all patients. Complications related to treatment included transient blepharoptosis (n = 7), diplopia (n = 2), and altered facial expression (n = 11). Systemic side effects were not observed. Select chemodenervation of facial muscles with graded injections of botulinum toxin is a useful adjunct to control blepharospasm, hemifacial spasm, and facial spasm due to aberrant regeneration of the facial nerve.


Inflammatory Bowel Disease and Small Bowel Cancer Risk, Clinical Characteristics, and Histopathology: A Population-Based Study.
Inflammatory bowel disease (IBD) may increase risk of small bowel cancer (SBC). However, little is known of the characteristics and features of IBD-SBC, due to a low number of cases worldwide. We performed a population-based study of IBD and SBC to calculate risk and increase our understanding of clinical characteristics and histopathological and molecular features. The study population consisted of all individuals aged 16 years or older living in Denmark during 1978-2010. Through linkage between national registers and subsequent scrutiny of medical records and pathology descriptions, we identified 40 cases of IBD-SBC. Risk was calculated by standardized incidence ratio (SIR) (observed/expected); patient characteristics were derived from medical files, and surgery specimens were obtained from hospitals nationwide for histopathological and molecular analyses. During 241,620 person-years of follow-up, 23 patients with Crohn's disease developed small bowel adenocarcinoma (SIR, 14.38; 95% confidence interval, 8.78-22.20) and 9 developed neuroendocrine tumors (SIR, 6.83; 95% confidence interval, 3.13-12.97). No significantly increased risk of SBC was found among patients with ulcerative colitis. Most patients with SBC had moderate-to-severe Crohn's disease with small bowel and upper gastrointestinal involvement. Assessment of surgical specimens of small bowel adenocarcinomas revealed a clear transition from inflammation to dysplasia and cancer, whereas no tumors had evidence of microsatellite instability. In a population-based study of patients in Denmark with IBD and SBC, we found risk of adenocarcinomas and neuroendocrine tumors to be increased among persons with Crohn's disease. Most patients with IBD-SBC had extensive IBD of moderate-to-severe activity. Adenocarcinomas appeared to develop via an inflammation-dysplasia-carcinoma pathway, but differed from IBD-related colorectal adenocarcinomas in their molecular features.


Polarization-independent fast optical shutter with high transmission.
In this work, we designed a fast cholesteric shutter by switching the director between homeotropic and transient planar states. It is polarization independent, has sub-millisecond response time, high transmission in homeotropic state, and is highly reflective in the transient planar state. We also developed a driving waveform to achieve a long dark state of the device. The device has potential to be applied in the optics and display industries, for applications that could include augmented reality, head-up displays, transparent OLED displays, and smart windows.


Egg clutch dehydration induces early hatching in red-eyed treefrogs, Agalychnis callidryas.
Terrestrial eggs have evolved repeatedly in tropical anurans exposing embryos to the new threat of dehydration. Red-eyed treefrogs, Agalychnis callidryas, lay eggs on plants over water. Maternally provided water allows shaded eggs in humid sites to develop to hatching without rainfall, but unshaded eggs and those in less humid sites can die from dehydration. Hatching responses of amphibian eggs to dry conditions are known from two lineages with independent origins of terrestrial eggs. Here, we experimentally tested for dehydration-induced early hatching in another lineage (Agalychnis callidryas, Phyllomedusidae), representing a third independent origin of terrestrial eggs. We also investigated how dehydration affected egg and clutch structure, and egg mortality. We collected clutches from a pond in Gamboa, Panama, and randomly allocated them to wet or dry treatments at age 1 day. Embryos hatched earlier from dry clutches than from wet clutches, accelerating hatching by ∼11%. Clutch thickness and egg diameter were affected by dehydration, diverging between treatments over time. Meanwhile, mortality in dry clutches was six-fold higher than in control clutches. With this study, early hatching responses to escape mortality from egg dehydration are now known from three anuran lineages with independent origins of terrestrial eggs, suggesting they may be widespread. Further studies are needed to understand how terrestrial amphibian eggs can respond to, or will be affected by, rapid changes in climate over the next decades.


Docetaxel, capecitabine and carboplatin in metastatic esophagogastric cancer: a phase II study.
A Phase I investigation of docetaxel, carboplatin, and capecitabine at our institution demonstrated the safety and tolerability of this regimen in patients with metastatic esophagogastric cancer. The objectives of this Phase II study were to determine the response rate, toxicity, and survival for patients with metastatic esophagogastric cancer treated with this regimen. Chemotherapy naïve patients with metastatic esophageal or gastric cancer received a regimen comprised of docetaxel 40 mg/m(2), days 1 and 8, carboplatin AUC = 2, Days 1 and 8, and capecitabine 2000 mg/m(2), Days 1-10 in 21-Day cycles. Patients were treated until disease progression or unacceptable toxicity. Twenty-five patients were treated with a median of 4 cycles of chemotherapy. Twelve of 25 patients (48 percent) had a Grade 3/4 toxicity. There were no Grade 4 nonhematologic toxicities, and 1 patient (4 percent) had neutropenic fever. There were 3 complete responses, and 9 partial responses, for an overall response rate of 48 percent. The median survival was 8 months (95% confidence interval, 5.5-13 months), and the 1-year survival was 36 percent. Weekly docetaxel and carboplatin with capecitabine was an easily administered outpatient regimen. The response rate and 1-year survival were similar to more complex regimens. Future trials may investigate the substitution of carboplatin with more active agents.


Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone.
The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors that play important roles in multiple disease conditions. The activation of PPARs by specific ligands is associated with growth suppression of several different types of human cancer, but the molecular mechanism responsible for this growth suppressive effect remains elusive. The aim of this study was to determine the distribution of PPARgamma protein/mRNA expression in uterine leiomyomas and to identify the PPARgamma induced signaling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPARgamma, in view of identifying targets that could possibly affect the viability and proliferation of uterine leiomyoma cells. Dose-response studies on proliferation found that uterine leiomyoma was more sensitive to inhibition by ciglitizone treatments than normal myometrium. We also found that ciglitizone significantly stimulated gene expression driven by a PPAR-responsive element in cultured leiomyoma cells and reduced the survival of leiomyoma cells relative to the control cells. The reduced survival of ciglitizone treated leiomyoma cells resulted from a mechanism that involved the Fas receptor-mediated apoptosis signaling cascade. These results suggest that uterine leiomyomas growth and differentiation might be modulated through PPARgamma receptors and that PPARgamma ligands may be of potential use for uterine leiomyoma treatment.


Granulosa Cell Apoptosis in the Ovarian Follicle-A Changing View.
Recent studies challenge the previous view that apoptosis within the granulosa cells of the maturing ovarian follicle is a reflection of aging and consequently a marker for poor quality of the contained oocyte. On the contrary, apoptosis within the granulosa cells is an integral part of normal development and has limited predictive capability regarding oocyte quality or the ensuing pregnancy rate in in vitro fertilization programs. This review article covers our revised understanding of the process of apoptosis within the ovarian follicle, its three phenotypes, the major signaling pathways underlying apoptosis as well as the associated mitochondrial pathways.


A low-level X chromosome mosaicism in mares, detected by chromosome painting.
Fluorescence in situ hybridization with the use of the equine X whole chromosome painting probe was carried out on chromosome spreads originating from three mares with poor reproductive performance (infertility, miscarriage or stillbirth). The numbers of analysed spreads were high (105, 300 and 480) and in all three mares a low frequency of mosaicism was identified. The mares had the following karyotypes: 64,XX/63,X/65,XXX (93.6%/5.7%/0.7%), 64,XX/63,X (98.9%/1.1%) and 64,XX/63,X (94.3%/5.7%). The incidence and importance of the low percentage X chromosome mosaicism are discussed.


Worldwide prevalence, risk factors and psychological impact of infertility among women: a systematic review and meta-analysis.
To assess the prevalence, risk factors and psychological impact of infertility among females. This review summarises the available evidence, effect estimates and strength of statistical associations between infertility and its risk factors. Systematic review and meta-analysis. MEDLINE, CINAHL and ScienceDirect were searched through 23 January 2022. The inclusion criteria involved studies that reported the psychological impact of infertility among women. We included cross-sectional, case-control and cohort designs, published in the English language, conducted in the community, and performed at health institution levels on prevalence, risk factors and psychological impact of infertility in women. Two reviewers independently extracted and assess the quality of data using the Joanna Briggs Institute Meta-Analysis. The outcomes were assessed with random-effects model and reported as the OR with 95% CI using the Review Manager software. Thirty-two studies with low risk of bias involving 124 556 women were included. The findings indicated the overall pooled prevalence to be 46.25% and 51.5% for infertility and primary infertility, respectively. Smoking was significantly related to infertility, with the OR of 1.85 (95% CI 1.08 to 3.14) times higher than females who do not smoke. There was a statistical significance between infertility and psychological distress among females, with the OR of 1.63 (95% CI 1.24 to 2.13). A statistical significance was noted between depression and infertility among females, with the OR of 1.40 (95% CI 1.11 to 1.75) compared with those fertile. The study results highlight an essential and increasing mental disorder among females associated with infertility and may be overlooked. Acknowledging the problem and providing positive, supportive measures to females with infertility ensure more positive outcomes during the therapeutic process. This review is limited by the differences in definitions, diagnostic cut points, study designs and source populations. CRD42021226414.


Reconstruction and Use of Microbial Metabolic Networks: the Core Escherichia coli Metabolic Model as an Educational Guide.
Biochemical network reconstructions have become popular tools in systems biology. Metabolicnetwork reconstructions are biochemically, genetically, and genomically (BiGG) structured databases of biochemical reactions and metabolites. They contain information such as exact reaction stoichiometry, reaction reversibility, and the relationships between genes, proteins, and reactions. Network reconstructions have been used extensively to study the phenotypic behavior of wild-type and mutant stains under a variety of conditions, linking genotypes with phenotypes. Such phenotypic simulations have allowed for the prediction of growth after genetic manipulations, prediction of growth phenotypes after adaptive evolution, and prediction of essential genes. Additionally, because network reconstructions are organism specific, they can be used to understand differences between organisms of species in a functional context.There are different types of reconstructions representing various types of biological networks (metabolic, regulatory, transcription/translation). This chapter serves as an introduction to metabolic and regulatory network reconstructions and models and gives a complete description of the core Escherichia coli metabolic model. This model can be analyzed in any computational format (such as MATLAB or Mathematica) based on the information given in this chapter. The core E. coli model is a small-scale model that can be used for educational purposes. It is meant to be used by senior undergraduate and first-year graduate students learning about constraint-based modeling and systems biology. This model has enough reactions and pathways to enable interesting and insightful calculations, but it is also simple enough that the results of such calculations can be understoodeasily.


Efficient field-theoretic simulation of polymer solutions.
We present several developments that facilitate the efficient field-theoretic simulation of polymers by complex Langevin sampling. A regularization scheme using finite Gaussian excluded volume interactions is used to derive a polymer solution model that appears free of ultraviolet divergences and hence is well-suited for lattice-discretized field theoretic simulation. We show that such models can exhibit ultraviolet sensitivity, a numerical pathology that dramatically increases sampling error in the continuum lattice limit, and further show that this pathology can be eliminated by appropriate model reformulation by variable transformation. We present an exponential time differencing algorithm for integrating complex Langevin equations for field theoretic simulation, and show that the algorithm exhibits excellent accuracy and stability properties for our regularized polymer model. These developments collectively enable substantially more efficient field-theoretic simulation of polymers, and illustrate the importance of simultaneously addressing analytical and numerical pathologies when implementing such computations.


Development of In Vitro Endothelialised Stents - Review.
Endovascular treatment is prevalent as a primary treatment for coronary and peripheral arterial diseases. Although the introduction of drug-eluting stents (DES) dramatically reduced the risk of in-stent restenosis, stent thrombosis persists as an issue. Notwithstanding improvements in newer generation DES, they are yet to address the urgent clinical need to abolish the late stent complications that result from in-stent restenosis and are associated with late thrombus formation. These often lead to acute coronary syndromes with high mortality in coronary artery disease and acute limb ischemia with a high risk of limb amputation in peripheral arterial disease. Recently, a significant amount of research has focused on alternative solutions to improve stent biocompatibility by using tissue engineering. There are two types of tissue engineering endothelialisation methods: in vitro and in vivo. To date, commercially available in vivo endothelialised stents have failed to demonstrate antithrombotic or anti-stenosis efficacy in clinical trials. In contrast, the in vitro endothelialisation methods exhibit the advantage of monitoring cell type and growth prior to implantation, enabling better quality control. The present review discusses tissue-engineered candidate stents constructed by distinct in vitro endothelialisation approaches, with a particular focus on fabrication processes, including cell source selection, stent material composition, stent surface modifications, efficacy and safety evidence from in vitro and in vivo studies, and future directions.


Fish oil supplementation of rats during pregnancy reduces adult disease risks in their offspring.
Metabolic programming in utero due to maternal undernutrition is considered to increase the risk of adult diseases in offspring. It is therefore of relevance to investigate how dietary supplementation of specific nutrients can ameliorate the negative effects of maternal malnutrition. We examined the effects of supplementing fish oil or folic acid, both of which are conventional supplements in maternal intervention, on risk factors in the offspring as adults. Pregnant female rats from 4 groups (n = 6/group) were fed casein diets with 18 g/100 g protein (control diet), 12 g/100 g protein supplemented with 8 mg folic acid/kg diet (0.08 mg/kg diet) (FAS), 12 g/100 g protein without folic acid (FAD) or 12 g/100 g protein supplemented with 7 g/100 g fish oil (FOIL). Pups were weaned to a standard laboratory diet with 18 g/100 g protein. Serum glucose, insulin and cholesterol and plasma homocysteine levels were measured in the offspring at 6 and 11 mo of age. Serum glucose in 11-mo-old male and female pups was greater (P < 0.05) in both the FAS (males 2.46 +/- 0.51, females 2.49 +/- 0.29 mmol/L) and FAD groups (2.48 +/- 0.28 and 2.67 +/- 0.41 mmol/L) than in controls (2.03 +/- 0.15 and 2.02 +/- 0.18 mmol/L). Serum insulin concentrations were higher (P < 0.05) in the FAD group (males 1476 +/- 317, females 1441 +/- 220 pmol/L) but were lower in males from the FAS group (483 +/- 165 pmol/L) compared with controls (males 917 +/- 373, females 981 +/- 264 pmol/L). Glucose and insulin concentrations did not differ between the control and FOIL groups. Plasma homocysteine levels were lower (P < 0.05) only in 11-mo-old folate-deficient males; none of the other groups differed from the controls. Maternal supplementation of fish oil to a diet containing marginal protein was beneficial in maintaining circulating glucose, insulin, cholesterol and homocysteine levels in the offspring as adults.


[Difficulties in the diagnosis of prolonged pulmonary eosinophilic infiltration in a child].
The paper deals with a 6-year-old child admitted to hospital for prolonged febrile syndrome, hemoptic sputum with radiological persistence of some pulmonary opacities which raised many hypotheses concerning the etiological diagnosis. A prolonged eosinophilic pulmonary infiltrate due to an infestation with Ascaris lumbricoides and Giardia was the matter in the study case. The specific anti-parasitic treatment has a decisive role in the clinical radiological improvement in case of a parasitic eosinophilic lung.


Acute-phase reactants and coronary heart disease.
Inflammation is considered to play an essential role in the initiation, progression, and the final pathophysiological steps of atherosclerosis, plaque erosion or fissure, and eventually plaque rupture. Prospective studies have identified several markers of systemic inflammation that are predictors of future cardiovascular events, not only in apparently healthy subjects, but also in patients with unstable angina and previous myocardial infarction. Measurement of inflammatory markers may add to the predictive value of total and high-density lipoprotein cholesterol in assessing coronary risk long-term. Various biological mechanisms exist that could explain the pathological effects of these inflammatory molecules. Finally, the results from recent clinical trials indicate that the net benefit of various compounds in primary and secondary prevention of coronary heart disease, like aspirin, statins, and ACE inhibitors, may be mediated, at least in part, by modifying the consequences of the inflammatory response on vascular risk. However, further studies are required to address these associations because the mechanisms that cause an inflammatory response are only incompletely understood and deserve further investigation.


A multilevel examination of the relationships among training outcomes, mediating regulatory processes, and adaptive performance.
This study examined whether cognitive, affective-motivational, and behavioral training outcomes relate to posttraining regulatory processes and adaptive performance similarly at the individual and team levels of analysis. Longitudinal data were collected from 156 individuals composing 78 teams who were trained on and then performed a simulated flight task. Results showed that posttraining regulation processes related similarly to adaptive performance across levels. Also, regulation processes fully mediated the influences of self- and collective efficacy beliefs on individual and team adaptive performance. Finally, knowledge and skill more strongly and directly related to adaptive performance at the individual than the team level of analysis. Implications to theory and practice, limitations, and future directions are discussed.


Consolidation of Fir Wood by Poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) Treatment: Study of Surface and Mechanical Characteristics.
The ability of poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) (PVBVA) to consolidate Fir wood was studied in terms of the surface and mechanical properties' changes. Two variables were considered to treat the wood: (i) the concentration (5 and 10 wt.%) of PVBVA solutions and (ii) the method of application (brushing and immersion). The presence of PVBVA on the wood surfaces was confirmed by infrared spectroscopy. Surface roughness measured by optical profilometry did not reveal changes in the topography of the samples, and appropriate visual appearance was confirmed. Contact angle measurements showed that a droplet of the 10%-PVBVA solution needed 50 s to reach the same contact angle decreasing rate as that measured for the 5%-PVBVA solution, suggesting there was some kind of induction time till the spreading process was no longer controlled by the viscosity, but by the solution-wood interactions. Water contact angle (WCA) measurements proved a more hydrophobic surface of the PVBVA-treated samples, compared to untreated wood. Mechanical characterization of the samples was done macroscopically by a three-point bending test and locally by the Shore D and Martens hardness (MH). Only results from MH experiments provided comparative results, indicating that treatment with PVBVA solutions increased wood hardness locally, being enhanced with solution concentration. The best surface mechanical properties were obtained for the samples immersed in the 10%-PVBVA solution.


Therapeutic gold, silver, and platinum nanoparticles.
There are an abundance of nanoparticle technologies being developed for use as part of therapeutic strategies. This review focuses on a narrow class of metal nanoparticles that have therapeutic potential that is a consequence of elemental composition and size. The most widely known of these are gold nanoshells that have been developed over the last two decades for photothermal ablation in superficial cancers. The therapeutic effect is the outcome of the thickness and diameter of the gold shell that enables fine tuning of the plasmon resonance. When these metal nanoparticles are exposed to the relevant wavelength of light, their temperature rapidly increases. This in turn induces a localized photothermal ablation that kills the surrounding tumor tissue. Similarly, gold nanoparticles have been developed to enhance radiotherapy. The high-Z nature of gold dramatically increases the photoelectric cross-section. Thus, the photoelectric effects are significantly increased. The outcome of these interactions is enhanced tumor killing with lower doses of radiation, all while sparing tissue without gold nanoparticles. Silver nanoparticles have been used for their wound healing properties in addition to enhancing the tumor-killing effects of anticancer drugs. Finally, platinum nanoparticles are thought to serve as a reservoir for platinum ions that can induce DNA damage in cancer cells. The future is bright with the path to clinical trials is largely cleared for some of the less complex therapeutic metal nanoparticle systems.


Voltage-Dependent Membrane Properties Shape the Size But Not the Frequency Content of Spontaneous Voltage Fluctuations in Layer 2/3 Somatosensory Cortex.
Under awake and idling conditions, spontaneous intracellular membrane voltage is characterized by large, synchronous, low-frequency fluctuations. Although these properties reflect correlations in synaptic inputs, intrinsic membrane properties often indicate voltage-dependent changes in membrane resistance and time constant values that can amplify and help to generate low-frequency voltage fluctuations. The specific contribution of intrinsic and synaptic factors to the generation of spontaneous fluctuations, however, remains poorly understood. Using visually guided intracellular recordings of somatosensory layer 2/3 pyramidal cells and interneurons in awake male and female mice, we measured the spectrum and size of voltage fluctuation and intrinsic cellular properties at different voltages. In both cell types, depolarizing neurons increased the size of voltage fluctuations. Amplitude changes scaled with voltage-dependent changes in membrane input resistance. Because of the small membrane time constants observed in both pyramidal cells and interneuron cell bodies, the low-frequency content of membrane fluctuations reflects correlations in the synaptic current inputs rather than significant filtering associated with membrane capacitance. Further, blocking synaptic inputs minimally altered somatic membrane resistance and time constant values. Overall, these results indicate that spontaneous synaptic inputs generate a low-conductance state in which the amplitude, but not frequency structure, is influenced by intrinsic membrane properties.SIGNIFICANCE STATEMENT In the absence of sensory drive, cortical activity in awake animals is associated with self-generated and seemingly random membrane voltage fluctuations characterized by large amplitude and low frequency. Partially, these properties reflect correlations in synaptic input. Nonetheless, neurons express voltage-dependent intrinsic properties that can potentially influence the amplitude and frequency of spontaneous activity. Using visually guided intracellular recordings of cortical neurons in awake mice, we measured the voltage dependence of spontaneous voltage fluctuations and intrinsic membrane properties. We show that voltage-dependent changes in membrane resistance amplify synaptic activity, whereas the frequency of voltage fluctuations reflects correlations in synaptic inputs. Last, synaptic activity has a small impact on intrinsic membrane properties in both pyramidal cells and interneurons.


Tailoring of the Tell-us Card communication tool for nurses to increase patient participation using Intervention Mapping.
To describe the tailoring of the Tell-us Card intervention for enhanced patient participation to the Dutch hospital setting using Intervention Mapping as a systematic approach. Even though patient participation is essential in any patient-to-nurse encounter, care plans often fail to take patients' preferences into account. The Tell-us Card intervention seems promising, but needs to be tailored and tested before implementation in a different setting or on large scale. Description of the Intervention Mapping framework to systematically tailor the Tell-us Card intervention to the Dutch hospital setting. Intervention Mapping consists of: (i) identification of the problem through needs assessment and determination of fit, based on patients and nurses interviews and focus group interviews; (ii) developing a logic model of change and matrices, based on literature and interviews; (iii) selection of theory-based methods and practical applications; (iv) producing programme components and piloting; (v) planning for adoption, implementation and sustainability; and (vi) preparing for programme evaluation. Knowledge, attitude, outcome expectations, self-efficacy and skills were identified as the main determinants influencing the use of the Tell-us Card. Linking identified determinants and performance objectives with behaviour change techniques from the literature resulted in a well-defined and tailored intervention and evaluation plan. The Tell-us Card intervention was adapted to fit the Dutch hospital setting and prepared for evaluation. The Medical Research Council framework was followed, and the Intervention Mapping approach was used to prepare a pilot study to confirm feasibility and relevant outcomes. This article shows how Intervention Mapping is applied within the Medical Research Council framework to adapt the Tell-us Card intervention, which could serve as a guide for the tailoring of similar interventions.


[Relationship between the intensity of protein synthesis in fibroblasts and the width of the channels of the cytoplasmic network].
The relationship between the rate of protein and RNA synthesis in fibroblasts and different width of the rough endoplasmic reticulum canals was studied in electron autoradiography experiments by the double labeling method. It was found that protein synthesis in fibroblasts with narrow canals of the rough endoplasmic reticulum proceeds faster than in the cells with wide canals. A possibility of periodic changes in protein synthesis and secretion by fibroblasts is discussed.


New Biochemical Insights into the Mechanisms of Pulmonary Arterial Hypertension in Humans.
Diagnosis of pulmonary arterial hypertension (PAH) is difficult due to the lack of specific clinical symptoms and biomarkers, especially at early stages. We compared plasma metabolic fingerprints of PAH patients (n = 20) with matched healthy volunteers (n = 20) using, for the first time, untargeted multiplatform metabolomics approach consisting of high-performance liquid and gas chromatography coupled with mass spectrometry. Multivariate statistical analyses were performed to select metabolites that contribute most to groups' classification (21 from liquid in both ionization modes and 9 from gas chromatography-mass spectrometry). We found metabolites related to energy imbalance, such as glycolysis-derived metabolites, as well as metabolites involved in fatty acid, lipid and amino acid metabolism. We observed statistically significant changes in threitol and aminomalonic acid in PAH patients, which could provide new biochemical insights into the pathogenesis of the disease. The results were externally validated on independent case and control cohorts, confirming up to 16 metabolites as statistically significant in the validation study. Multiplatform metabolomics, followed by multivariate chemometric data analysis has a huge potential for explaining pathogenesis of PAH and for searching potential and new more specific and less invasive markers of the disease.


The positive regulatory function of the 5'-proximal open reading frames in GCN4 mRNA can be mimicked by heterologous, short coding sequences.
Translational control of GCN4 expression in the yeast Saccharomyces cerevisiae is mediated by multiple AUG codons present in the leader of GCN4 mRNA, each of which initiates a short open reading frame of only two or three codons. Upstream AUG codons 3 and 4 are required to repress GCN4 expression in normal growth conditions; AUG codons 1 and 2 are needed to overcome this repression in amino acid starvation conditions. We show that the regulatory function of AUG codons 1 and 2 can be qualitatively mimicked by the AUG codons of two heterologous upstream open reading frames (URFs) containing the initiation regions of the yeast genes PGK and TRP1. These AUG codons inhibit GCN4 expression when present singly in the mRNA leader; however, they stimulate GCN4 expression in derepressing conditions when inserted upstream from AUG codons 3 and 4. This finding supports the idea that AUG codons 1 and 2 function in the control mechanism as translation initiation sites and further suggests that suppression of the inhibitory effects of AUG codons 3 and 4 is a general consequence of the translation of URF 1 and 2 sequences upstream. Several observations suggest that AUG codons 3 and 4 are efficient initiation sites; however, these sequences do not act as positive regulatory elements when placed upstream from URF 1. This result suggests that efficient translation is only one of the important properties of the 5' proximal URFs in GCN4 mRNA. We propose that a second property is the ability to permit reinitiation following termination of translation and that URF 1 is optimized for this regulatory function.


Rectification of oxygen transfer through the rat colonic epithelium.
To assess whether higher sensitivity of colonic epithelium to hypoxia at the serosal side is associated with oxygen transfer asymmetry. Rats were fed either with normal chow or a low-sodium diet. Tissues were mounted as flat sheets in a modified, airtight Ussing chamber with oxygen meters in each hemichamber. Mucosal samples from normal diet animals were studied under control conditions, in low-chloride solution and after adding chloride secretion inhibitors and chloride secretagogues. Samples from sodium-deprived rats were studied before and after ouabain addition. In separate experiments, the correlation between short-circuit current and oxygen consumption was analyzed. Finally, hypoxia was induced in one hemichamber to assess the relationship between its oxygen content and the oxygen pressure difference between both hemichambers. In all studied conditions, oxygen consumption was larger in the serosal hemichamber than in the mucosal one (P = 0.0025 to P < 0.0001). Short-circuit current showed significant correlation with both total oxygen consumption (r = 0.765; P = 0.009) in normoxia and oxygen consumption in the serosal hemichamber (r = 0.754; P = 0.011) during mucosal hypoxia, but not with oxygen consumption in the mucosal hemichamber. When hypoxia was induced in the mucosal hemichamber, an oxygen pressure difference of 13 kPa with the serosal hemichamber was enough to keep its oxygen content constant. However, when hypoxia was induced in the serosal hemichamber, the oxygen pressure difference with the mucosal hemichamber necessary to keep its oxygen content constant was 40 kPa (P < 0.0001). Serosal oxygen supply is more readily available to support short-circuit current. This may be partly due to a rectifying behavior of transepithelial oxygen transfer.


Keratin transgenic and knockout mice: functional analysis and validation of disease-causing mutations.
The intermediate filament (IF) cytoskeleton of mammalian epithelia is generated from pairs of type I and type II keratins that are encoded by two large gene families, made up of 54 genes in humans and the mouse. These genes are expressed in a spatiotemporal and tissue-specific manner from the blastocyst stage onward. Since the discovery of keratin mutations leading to epidermolysis bullosa simplex, mutations in at least 18 keratin genes have been identified that result in keratinopathies of the epidermis and its appendages. Recently, noncanonical mutations in simple epithelial keratins were associated with pancreatic, liver, and intestinal disorders, demonstrating that keratins protect epithelia against mechanical and other forms of stress. In recent years, animal models provided novel insight and significantly improved understanding of IF function in tissue homeostasis and its role in disease. Pathological phenotypes detected in mutant mice generated so far range from embryonic lethality to tissue fragility to subtlety, which often depends on their genetic background. This range implies at least a partial influence of yet unidentified modifier genes on the phenotype after the ablation of the respective keratin. To date, nearly all available keratin mouse models were generated by taking advantage of conventional gene-targeting strategies. To reveal their cell type-specific functions and the mechanisms by which mutations lead to disease, it will be necessary to use conditional gene-targeting strategies and the introduction of point-mutated gene copies. Furthermore, conditional strategies offer the possibility to overcome embryonic or neonatal lethality in some of the keratin-deficient mice.


Factors that modulate clearance and ultimate fate of a specific schistosome antigen (GASP) in schistosome infections.
To understand factors that modulate the amount and removal of antigen found in the circulation of schistosome-infected mice, a specific schistosome antigen, GASP, found in the circulation of infected animals, was radiolabeled with Bolton-Hunter reagent and injected into infected and control mice. The rates of clearance, levels of antigen binding, and the fate of the injected antigen were determined. Within 1 to 3 wk after injection, infected animals developed enhanced antigen clearance that paralleled the increase in antibody to GASP. Lightly infected animals showed faster clearance rates and increased antibody levels compared with heavily infected mice. The level of antibody in the sera, irrespective of the duration or intensity of infection, correlated with enhanced clearance. Heavily infected animals removed preformed immune complexes as rapidly as lightly infected mice. This indicates that the relative inability to clear antigen was not due to blockade of Kupffer cells. Circulating GASP antigen, determined by countercurrent electrophoresis, was detected in heavily infected animals in the presence of increased antibody, suggesting that circulating GASP was in immune complexes. Both free and complexed antigen were primarily cleared by the liver and then excreted in the urine as low m.w. nonantigenic products. With sensitive radioimmunoassays, GASP could not be detected in infected human or mouse urine.


Micro-CT analysis of the Lisfranc complex reveals higher bone mineral density in dorsal compared to plantar regions.
Injuries to the Lisfranc complex may require surgical fixation, the stability of which may be correlated with bone mineral density (BMD). However, there is limited research on regional BMD variations in the Lisfranc complex. This study used quantitative micro-CT to characterize regional BMD in the four bones (medial cuneiform, intermediate cuneiform, first metatarsal, and second metatarsal) of this complex. Twenty-four cadaveric specimens were imaged with a calibration phantom using micro-CT. Each bone was segmented and divided into eight regions based on an anatomical coordinate system. BMD for each octant was calculated using scan-specific calibration equations and average image intensity. Differences between regions were analyzed using ANOVA with post hoc analysis and differences between groups of four octants in each plane were analyzed with t-tests with significance level α = 0.05. The highest density region in the medial cuneiform was the distal-dorsal-lateral and dorsal regions showed significantly higher BMD than plantar regions. The intermediate cuneiform had the highest density in the distal-dorsal-medial region and the dorsal and medial regions had higher BMD than the plantar and lateral regions, respectively. The densest region of the first metatarsal was the distal-dorsal-lateral and distal regions had significantly higher BMD than proximal regions. In the second metatarsal, the distal-dorsal-medial region had the highest density, and the distal, dorsal, and medial regions had significantly higher BMD than the proximal, plantar, and lateral regions, respectively. The predominant finding was a pattern of increased density in the dorsal bone regions, which may be relevant in the surgical management of Lisfranc injuries.


Life cycle assessment of high-rate anaerobic treatment, microbial fuel cells, and microbial electrolysis cells.
Existing wastewater treatment options are generally perceived as energy intensive and environmentally unfriendly. Much attention has been focused on two new approaches in the past years, (i) microbial fuel cells and (ii) microbial electrolysis cells, which directly generate electrical current or chemical products, respectively, during wastewater treatment. These systems are commonly denominated as bioelectrochemical systems, and a multitude of claims have been made in the past regarding the environmental impact of these treatment options. However, an in-depth study backing these claims has not been performed. Here, we have conducted a life cycle assessment (LCA) to compare the environmental impact of three industrial wastewater treatment options, (i) anaerobic treatment with biogas generation, (ii) a microbial fuel cell treatment, with direct electricity generation, and (iii) a microbial electrolysis cell, with hydrogen peroxide production. Our analysis showed that a microbial fuel cell does not provide a significant environmental benefit relative to the "conventional" anaerobic treatment option. However, a microbial electrolysis cell provides significant environmental benefits through the displacement of chemical production by conventional means. Provided that the target conversion level of 1000 A.m(-3) can be met, the decrease in greenhouse gas emissions and other environmentally harmful emissions (e.g., aromatic hydrocarbons) of the microbial electrolysis cell will be a key driver for the development of an industrial standard for this technology. Evidently, this assessment is highly dependent on the underlying assumptions, such as the used reactor materials and target performance. This provides a challenge and an opportunity for researchers in the field to select and develop appropriate and environmentally benign materials of construction, as well as demonstrate the required 1000 A.m(-3) performance at pilot and full scale.


The role of TRIM family in metabolic associated fatty liver disease.
Metabolic associated fatty liver disease (MAFLD) ranks among the most prevalent chronic liver conditions globally. At present, the mechanism of MAFLD has not been fully elucidated. Tripartite motif (TRIM) protein is a kind of protein with E3 ubiquitin ligase activity, which participates in highly diversified cell activities and processes. It not only plays an important role in innate immunity, but also participates in liver steatosis, insulin resistance and other processes. In this review, we focused on the role of TRIM family in metabolic associated fatty liver disease. We also introduced the structure and functions of TRIM proteins. We summarized the TRIM family's regulation involved in the occurrence and development of metabolic associated fatty liver disease, as well as insulin resistance. We deeply discussed the potential of TRIM proteins as targets for the treatment of metabolic associated fatty liver disease.


Prostaglandins in muscle regeneration.
Muscle regeneration is a tightly orchestrated process where activated satellite cells (myoblasts) respond to external stimuli in order to proliferate, differentiate and fuse to damaged myofibers. Simultaneously, the injured tissue undergoes an inflammatory response and communication between leukocytes and the spectrum of differentiated and undifferentiated muscle cells is essential for proper healing. This communication is mediated by cytokines, growth factors and prostaglandins and dissecting the role of these signaling molecules might be the key to positively manipulate muscle regeneration in the future. This review will focus on the roles of prostaglandins and will consider the potential cost of using non-steroidal inflammatory drugs as popular treatment of muscle injury.


Gadolinium chelates in angiography and interventional radiology: a useful alternative to iodinated contrast media for angiography.
Gadolinium has physical properties that are well suited for radiographic imaging. Digital subtraction angiography with a gadolinium chelate as contrast medium can provide images of suitable quality for diagnosis and intervention. The overall safety profile of gadolinium-based contrast media is excellent. In particular, these contrast media are well tolerated in patients with renal insufficiency when administered intraarterially in doses of less than 0.3-0.4 mmol per kilogram body weight, with a decreased incidence of contrast medium-induced nephropathy, as compared with similar volumes of iodinated contrast material. The currently available formulations of gadolinium chelates can be injected safely into every arterial and venous structure. However, substantial data are lacking on the intraarterial use of gadolinium in patients with renal insufficiency, particularly at doses that exceed those routinely used in magnetic resonance angiography. Gadolinium chelates in appropriate volumes are useful alternative contrast media in selected high-risk patients undergoing angiographic studies.


Serum tumor markers.
Monoclonal antibodies are used to detect serum antigens associated with specific malignancies. These tumor markers are most useful for monitoring response to therapy and detecting early relapse. With the exception of prostate-specific antigen (PSA), tumor markers do not have sufficient sensitivity or specificity for use in screening. Cancer antigen (CA) 27.29 most frequently is used to follow response to therapy in patients with metastatic breast cancer. Carcinoembryonic antigen is used to detect relapse of colorectal cancer, and CA 19-9 may be helpful in establishing the nature of pancreatic masses. CA 125 is useful for evaluating pelvic masses in postmenopausal women, monitoring response to therapy in women with ovarian cancer, and detecting recurrence of this malignancy. Alpha-fetoprotein (AFP), a marker for hepatocellular carcinoma, sometimes is used to screen highly selected populations and to assess hepatic masses in patients at particular risk for developing hepatic malignancy. Testing for the beta subunit of human chorionic gonadotropin (beta-hCG) is an integral part of the diagnosis and management of gestational trophoblastic disease. Combined AFP and beta-hCG testing is an essential adjunct in the evaluation and treatment of nonseminomatous germ cell tumors, and in monitoring the response to therapy. AFP and beta-hCG also may be useful in evaluating potential origins of poorly differentiated metastatic cancer. PSA is used to screen for prostate cancer, detect recurrence of the malignancy, and evaluate specific syndromes of adenocarcinoma of unknown primary.


Comparisons of therapeutic outcomes in patients with nonampullary duodenal neuroendocrine tumors (NADNETs): A multicenter retrospective study.
Duodenal neuroendocrine tumors (DNETs) are rare tumors that are occasionally found during upper endoscopies. The incidence of DNETs is increasing, although the data regarding treatment outcomes are insufficient. The aim of this study was to evaluate the treatment outcomes in patients with nonampullary DNETs who underwent endoscopic resection or surgery. We evaluated the medical records of patients who were diagnosed with nonampullary DNETs from 2004 to 2017 in 7 university hospitals. We retrospectively analyzed clinical characteristics and compared therapeutic outcomes based on the endoscopic lesion size and treatment method. We ultimately enrolled 60 patients with nonampullary DNETs who underwent endoscopic and surgical treatments. In the endoscopic treatment group, the en bloc resection, endoscopic complete resection (CR) and pathologic CR rates were 88%, 92%, and 50%, respectively. The endoscopic treatment group was divided into 3 subgroups based on the lesion size (1-5 mm, 6-10 mm, and ≥11 mm). The pathologic CR rate was significantly lower in the subgroup with a lesion size ≥11 mm (0%, P = .003) than those in the other 2 subgroups. Lymphovascular invasion occurred significantly more frequently (33.3%, P = .043) among those with a lesion size ≥11 mm. The pathologic CR rate in the surgical treatment group was higher (90.9%) than that in the endoscopic treatment group (50%, P = .017). Surgical treatment appears to be a more appropriate choice because of the risks of incomplete resection and lymphovascular invasion after endoscopic treatment for lesions larger than 11 mm.


Specific localization in the equatorial region of gp20, a 20 kDa sialylglycoprotein of the capacitated human spermatozoon acquired during epididymal transit which is necessary to penetrate zona-free hamster eggs.
In this study we set out to characterize gp20, a 20 kDa glycoprotein of the human sperm surface, first identified by us by radiolabelling the sialic acid residues of the sperm surface [R. Focarelli et al. (1995), Mol. Hum. Reprod., 2, 2755-2759]. The protein was partially purified from pooled sperm samples of several healthy donors and used to raise a specific antiserum to study its localization in the reproductive system. When tested with freshly ejaculated spermatozoa, the anti-gp20 antibody intensely stained the head and midpiece. However, on capacitated spermatozoa the antigen was restricted to a sharp zone in the equatorial region. The antibody did not bind to differentiating germ cells but the antigen was present in epididymal epithelial cells and also in seminal plasma. Anti-gp20 exerted a blocking effect in a test for sperm penetration of zona-free hamster eggs, thus suggesting that gp20 is involved in the early stages of fertilization.


Total Number Is Important: Using the Disector Method in Design-Based Stereology to Understand the Structure of the Rodent Brain.
The advantages of using design-based stereology in the collection of quantitative data, have been highlighted, in numerous publications, since the description of the disector method by Sterio (1984). This review article discusses the importance of total number derived with the disector method, as a key variable that must continue to be used to understand the rodent brain and that such data can be used to develop quantitative networks of the brain. The review article will highlight the huge impact total number has had on our understanding of the rodent brain and it will suggest that neuroscientists need to be aware of the increasing number of studies where density, not total number, is the quantitative measure used. It will emphasize that density can result in data that is misleading, most often in an unknown direction, and that we run the risk of this type of data being accepted into the collective neuroscience knowledge database. It will also suggest that design-based stereology using the disector method, can be used alongside recent developments in electron microscopy, such as serial block-face scanning electron microscopy (SEM), to obtain total number data very efficiently at the ultrastructural level. Throughout the article total number is discussed as a key parameter in understanding the micro-networks of the rodent brain as they can be represented as both anatomical and quantitative networks.


Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.
White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.


Trends and exceptions of physical properties on antibacterial activity for Gram-positive and Gram-negative pathogens.
To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ∼3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput (HTS) screens conducted on both biochemical and phenotypic bacterial targets. The output from 23 antibacterial HTS screens illustrated that when compared to the properties of the antibacterial project compounds, the HTS actives were significantly more hydrophobic than antibacterial project compounds (typically 2-4 log units higher), and furthermore, for 14/23 HTS screens, the average clogD was higher than the screening collection average (screening collection clogD = 2.45). It was found that the consequences of this were the following: (a) lead identification programs often further gained hydrophobic character with increased biochemical potency, making the separation even larger between the physicochemical properties of known antibacterial agents and the HTS active starting point, (b) the probability of plasma protein binding and cytotoxicity are often increased, and (c) cell-based activity in Gram-negative bacteria was severely limited or, if present, demonstrated significant efflux. Our analysis illustrated that compounds least susceptible to efflux were those which were highly polar and small in MW or very large and typically zwitterionic. Hydrophobicity was often the dominant driver for HTS actives but, more often than not, precluded whole cell antibacterial activity. However, simply designing polar compounds was not sufficient for antibacterial activity and pointed to a lack of understanding of complex and specific bacterial penetration mechanisms.


Exercise-induced muscle injury: a calpain hypothesis.
It is well established that periods of increased contractile activity result in significant changes in muscle structure and function. Such morphological changes as sarcomeric Z-line disruption and sarcoplasmic reticulum vacuolization are characteristic of exercise-induced muscle injury. While the precise mechanism(s) underlying the perturbations to muscle following exercise remains to be elucidated, it is clear that disturbances in Ca2+ homeostasis and changes in the rate of protein degradation occur. The resulting elevation in intracellular [Ca2+] activates the non-lysosomal cysteine protease, calpain. Because calpain cleaves a variety of protein substrates including cytoskeletal and myofibrillar proteins, calpain-mediated degradation is thought to contribute to the changes in muscle structure and function that occur immediately following exercise. In addition, calpain activation may trigger the adaptation response to muscle injury. The purpose of this paper is to: (i) review the chemistry of the calpain-calpastatin system; (ii) provide evidence for the involvement of the non-lysosomal, calcium-activated neutral protease (calpain) in the response of skeletal muscle protein breakdown to exercise (calpain hypothesis); and (iii) describe the possible involvement of calpain in the inflammatory and regeneration response to exercise.


Personal characteristics, cooking at home and shopping frequency influence consumption.
This study examines how the consumption of fruits and vegetables is affected by home cooking habits and shopping patterns, including distance to patronized stores and frequency of shopping, in two low-income predominantly African American urban neighborhoods in New Orleans, Louisiana. In-person interviews were conducted in 2013 with 901 adult residents who identified themselves as the primary household shopper. Respondents were asked where and how often they shopped and answered a food frequency questionnaire. Addresses were geocoded and distances to the stores where respondents shopped were calculated. Multivariable logistic regression was used to examine the relationship between food consumption and personal factors, neighborhood factors and shopping habits. Consumption of daily servings of fresh produce increased by 3% for each additional trip to a grocery store, by 76% for shopping at a farmer's market, and by 38% for preparing food at home. Each additional trip to a convenience store increased the frequency of consumption of chips, candy and pastries by 3%. The distance from residence to the type of store patronized was not associated with consumption of produce or chips, candy or pastries. Shopping at full-service grocery stores, farmer's markets and cooking at home were positively associated with the consumption of fresh produce while shopping at convenience stores was associated with increased consumption of chips, candy and pastries. These findings are useful for designing programmatic interventions to increase fresh fruit and vegetable consumption among residents in low-income urban communities.


A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS.
Micro-inflammation is considered an element in the pathogenesis of irritable bowel syndrome (IBS). High-sensitivity C reactive protein (hs-CRP) was previously shown to be higher in IBS compared to healthy controls, albeit within the normal range. Since probiotics may suppress micro-inflammation in the gut, we tested if they reduce symptoms and inflammatory markers (hs-CRP and fecal calprotectin (FC) in diarrhea-predominant IBS (IBS-D). The aim of this study was to assess the clinical and laboratory effects of BIO-25, a multispecies probiotic, in women with IBS-D. A double-blind, placebo-controlled study. Following a 2-week run-in, eligible women were assigned at random to a probiotic capsule or an indistinguishable placebo, twice daily for 8 weeks. IBS symptoms and stool consistency were rated daily by Visual Analogue Scales (VAS) and the Bristol Stool Scale (BSS). High-sensitivity C reactive protein was tested at baseline, 4 and 8 weeks. FC was tested at baseline and 8 weeks. One hundred and seventy-two IBS-D patients were recruited and 107 eligible patients were allocated to the intervention (n=54) or placebo (n=53) group. All symptoms improved in both groups with no significant difference between them in symptom improvement, hs-CRP or FC levels. An 8-week treatment with BIO-25 improved symptoms in women with IBS-D, but was not superior to placebo. This rigorously designed and executed study supports the findings of other studies that did not demonstrate superiority of probiotics over placebo in IBS. High quality clinical studies are necessary to examine the efficacy of other specific probiotics in IBS-D patients since data are still conflicting.


Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB.
Menin is a scaffold protein that interacts with several epigenetic mediators to regulate gene transcription, and suppresses pancreatic β-cell proliferation. Tamoxifen-inducible deletion of multiple endocrine neoplasia type 1 (MEN1) gene, which encodes the protein menin, increases β-cell mass in multiple murine models of diabetes and ameliorates diabetes. Glucagon-like-peptide-1 (GLP1) is another key physiological modulator of β-cell mass and glucose homeostasis. However, it is not clearly understood whether menin crosstalks with GLP1 signaling. Here, we show that menin and protein arginine methyltransferase 5 (PRMT5) suppress GLP1 receptor (GLP1R) transcript levels. Notably, a GLP1R agonist induces phosphorylation of forkhead box protein O1 (FOXO1) at S253, and the phosphorylation is mediated by PKA. Interestingly, menin suppresses GLP1-induced and PKA-mediated phosphorylation of both FOXO1 and cAMP response element binding protein (CREB), likely through a protein arginine methyltransferase. Menin-mediated suppression of FOXO1 and CREB phosphorylation increases FOXO1 levels and suppresses CREB target genes, respectively. A small-molecule menin inhibitor reverses menin-mediated suppression of both FOXO1 and CREB phosphorylation. In addition, ex vivo treatment of both mouse and human pancreatic islets with a menin inhibitor increases levels of proliferation marker Ki67. In conclusion, our results suggest that menin and PRMT5 suppress GLP1R transcript levels and PKA-mediated phosphorylation of FOXO1 and CREB, and a menin inhibitor may reverse this suppression to induce β-cell proliferation.


Socio-Psychological and Design Features Related to Transport Choices: A Focus Group Research in the Metropolitan Area of Cagliari (Sardinia, Italy).
Due to the environmental and health impact of the private transport sector, social scientists have largely focused on psychosocial and contextual factors associated with people's choice over transport means. This study aims to contribute to this line of research by applying a user-centered approach, with the objective of taking into account the specific environmental and social context of the metropolitan area of Cagliari city (Sardinia, Italy). To accomplish this aim, four groups of people were matched according to their shared starting point: car users vs. public transport users (Study 1), and light-rail users vs. non-light-rail users (Study 2). Groups were interviewed using a focus group method. Participants were invited to discuss their everyday travel experiences and to exchange their ideas on different sustainable (e.g., bicycles and public transport) and less sustainable (i.e., private cars) means of transport. Both consolidated drivers/barriers in the field of environmental psychology (e.g., perceived behavioral control, social norms) and public transportation design features (e.g., lighting) have been investigated. Other than highlighting the importance of socio-psychological factors to promote more sustainable transport choices like in previous studies, the present research offers an insight into how these aspects and factors are shaped and experienced in the narratives of residents.


A vertebrate-conserved cis-regulatory module for targeted expression in the main hypothalamic regulatory region for the stress response.
The homeodomain transcription factor orthopedia (Otp) is an evolutionarily conserved regulator of neuronal fates. In vertebrates, Otp is necessary for the proper development of different regions of the brain and is required in the diencephalon to specify several hypothalamic cell types, including the cells that control the stress response. To understand how this widely expressed transcription factor accomplishes hypothalamus-specific functions, we performed a comprehensive screening of otp cis-regulatory regions in zebrafish. Here, we report the identification of an evolutionarily conserved vertebrate enhancer module with activity in a restricted area of the forebrain, which includes the region of the hypothalamus that controls the stress response. This region includes neurosecretory cells producing Corticotropin-releasing hormone (Crh), Oxytocin (Oxt) and Arginine vasopressin (Avp), which are key components of the stress axis. Lastly, expression of the bacterial nitroreductase gene under this specific enhancer allowed pharmacological attenuation of the stress response in zebrafish larvae. Vertebrates share many cellular and molecular components of the stress response and our work identified a striking conservation at the cis-regulatory level of a key hypothalamic developmental gene. In addition, this enhancer provides a useful tool to manipulate and visualize stress-regulatory hypothalamic cells in vivo with the long-term goal of understanding the ontogeny of the stress axis in vertebrates.


Different Flavonoids Can Shape Unique Gut Microbiota Profile In Vitro.
The impact of flavonoids has been discussed on the relative viability of bacterial groups in human microbiota. This study was aimed to compare the modulation of various flavonoids, including quercetin, catechin and puerarin, on gut microbiota culture in vitro, and analyze the interactions between bacterial species using fructo-oligosaccharide (FOS) as carbon source under the stress of flavonoids. Three plant flavonoids, quercetin, catechin, and puerarin, were added into multispecies culture to ferment for 24 h, respectively. The bacterial 16S rDNA amplicons were sequenced, and the composition of microbiota community was analyzed. The results revealed that the tested flavonoids, quercetin, catechin, and puerarin, presented different activities of regulating gut microbiota; flavonoid aglycones, but not glycosides, may inhibit growth of certain species. Quercetin and catechin shaped unique biological webs. Bifidobacterium spp. was the center of the biological web constructed in this study.