Motivation and synthesis of the FIAC experiment: Reproducibility of fMRI results across expert analyses.
The Functional Imaging Analysis Contest (FIAC) culminated in the FIAC Workshop held at the 11th Annual Meeting of the Organization for Human Brain Mapping in Toronto in 2005. This special issue summarizes various analyses used by contestants with a single functional magnetic resonance imaging (fMRI) study, a cortical-language study using sentence repetition. The results from the cognitive neuroscientists who developed the test-base language study, and report their data analysis, are complemented by expert analyses of the same test-base data by most of the major groups actively developing fMRI software packages. Analyses include many variants of the general linear model (GLM), cutting-edge spatial- and temporal-wavelets, permutation-based, and ICA approaches. A number of authors also include surface-based approaches. Several articles describe the important emerging areas of diagnostics for GLM analysis, multivariate predictive modeling, and functional connectivity analysis. While the FIAC did not achieve all of its goals, it helped identify new activation regions in the test-base data, and more important, through this special issue it illustrates the significant methods-driven variability that potentially exists in the literature. Variable results from different methods reported here should provide a cautionary note and motivate the Human Brain Mapping community to explore more thoroughly the methodologies they use for analyzing fMRI data.


p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene.
Hypoxia-induced neovascularization mediated by vascular endothelial growth factor (VEGF) contributes to tumor progression. Based on its effects when overexpressed in transient transfection assays, p53 has been proposed to repress VEGF transcription. To investigate this hypothesis, we have analyzed endogenous VEGF mRNA levels in Hep3B cells stably expressing an inducible p53-estrogen receptor fusion protein and in irradiated RKO cells expressing endogenous wild-type p53. In both cell lines, VEGF mRNA levels increased in response to hypoxia, either in the presence or absence of functional p53. Our data provide no evidence for a causal relationship between the loss of p53 activity and increased VEGF expression that is observed during tumor progression. Studies that attribute repressor functions to p53 based on analysis of cells transiently overexpressing this protein should be interpreted cautiously.


Influence of Single-Stranded DNA Coatings on the Interaction between Graphene Nanoflakes and Lipid Bilayers.
Using molecular dynamics simulations, it is demonstrated that a partial coating of single-stranded DNA (ssDNA) reduces the penetration depth of a graphene nanoflake (GNF) into a phospholipid bilayer by attenuating the hydrophobic force that drives the penetration. As the GNF penetrates the bilayer, the ssDNA remains adsorbed to the GNF outside of the bilayer where it shields the graphene from the surrounding water. The penetration depth is found to be controlled by the amount of ssDNA coating the GNF, with a sparser coating resulting in a deeper penetration since the ssDNA shields less of the GNF surface. As the coating density is increased, the likelihood of the GNF entering the bilayer is reduced where it instead tends to lie flat on the bilayer surface with the sugar phosphate backbone of ssDNA interacting with the hydrophilic lipid head groups. While no bilayer disruption is observed for a partially inserted ssDNA-coated GNF, a larger, bare, partially inserted GNF is found to preferentially extract phospholipids from the bilayer, offering further evidence of lipid extraction as a main cytotoxicity mechanism of GNFs. Therefore, a coating of ssDNA may reduce the cytotoxicity of GNFs by shielding the unfavorable graphene-water interaction, thus preventing graphene penetration and lipid extraction.


Tyrosine phosphorylation of caveolin 1 by oxidative stress is reversible and dependent on the c-src tyrosine kinase but not mitogen-activated protein kinase pathways in placental artery endothelial cells.
Acute H(2)O(2) exposure to placental artery endothelial cells induced an array of tyrosine-phosphorylated proteins, including caveolin 1 (CAV1) rapid and transient tyr(14) phosphorylated in a time- and concentration-dependent manner. Basal tyr(14) phosphorylated CAV1 was primarily located at the edges of cells and associated with actin filaments. Phosphorylated CAV1 was markedly increased and diffused with the disorganization of actin filaments at 20 min, disappeared at 120 min treatment with 0.2 mM H(2)O(2). Treatment with H(2)O(2) also disorganized actin filaments and changed cell shape in a time-dependent manner. Pretreatment with antioxidants catalase completely, whereas the other tested superoxide dismutase, N-acetyl-l-cysteine and sodium formate partially attenuated H(2)O(2)-induced CAV1 phosphorylation in a concentration-dependent manner. Acute treatment with H(2)O(2) activated multiple signaling pathways, including the mitogen-activated protein kinases (MAPK) members (MAPK3/1-ERK2/1, MAPK8/9-JNK1/2, and MAPK11-p38(mapk)) and the c-src tyrosine kinase (CSK). Pharmacological studies demonstrated that, among these pathways, only the blockade of CSK activation abolished H(2)O(2)-induced CAV1 phosphorylation. Additionally, H(2)O(2)-induced CAV1 phosphorylation was reversible rapidly (<10 min) upon H(2)O(2) withdrawal. Because maternal and fetal endothelia must make dynamic adaptations to oxidative stress resulting from enhanced pregnancy-specific oxygen metabolism favoring prooxidant production, which is emerging as one of the leading causes of the dysfunctional activated endothelium during pregnancy, these unique features of CAV1 phosphorylation on oxidative stress observed implicate an important role of CAV1 in placental endothelial cell biology during pregnancy.


The SMARTscreen Trial: a randomised controlled trial investigating the efficacy of a GP-endorsed narrative SMS to increase participation in the Australian National Bowel Cancer Screening Program.
Increasing participation in the Australian National Bowel Cancer Screening Program (NBCSP) is the most efficient and cost-effective way of reducing mortality associated with colorectal cancer by detecting and treating early-stage disease. Currently, only 44% of Australians aged 50-74 years complete the NBCSP. This efficacy trial aims to test whether this SMS intervention is an effective method for increasing participation in the NBCSP. Furthermore, a process evaluation will explore the barriers and facilitators to sending the SMS from general practice. We will recruit 20 general practices in the western region of Victoria, Australia to participate in a cluster randomised controlled trial. General practices will be randomly allocated with a 1:1 ratio to either a control or intervention group. Established general practice software will be used to identify patients aged 50 to 60 years old who are due to receive a NBCSP kit in the next month. The SMS intervention includes GP endorsement and links to narrative messages about the benefits of and instructions on how to complete the NBCSP kit. It will be sent from intervention general practices to eligible patients prior to receiving the NBCSP kit. We require 1400 eligible patients to provide 80% power with a two-sided 5% significance level to detect a 10% increase in CRC screening participation in the intervention group compared to the control group. Our primary outcome is the difference in the proportion of eligible patients who completed a faecal occult blood test (FOBT) between the intervention and control group for up to 12 months after the SMS was sent, as recorded in their electronic medical record (EMR). A process evaluation using interview data collected from general practice staff (GP, practice managers, nurses) and patients will explore the feasibility and acceptability of sending and receiving a SMS to prompt completing a NBCSP kit. This efficacy trial will provide initial trial evidence of the utility of an SMS narrative intervention to increase participation in the NBCSP. The results will inform decisions about the need for and design of a larger, multi-state trial of this SMS intervention to determine its cost-effectiveness and future implementation. Australian New Zealand Clinical Trials Registry ACTRN12620001020976 . Registered on 17 October 2020.


Telomeres as hotspots for innate immunity and inflammation.
Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a subject of ongoing research, there are several cellular and molecular hallmarks that contribute to this biological process. This review focuses on two factors, namely telomere dysfunction and inflammation, which have emerged as crucial contributors to the aging process. We aim to discuss the mechanistic connections between these two distinct hallmarks and provide compelling evidence highlighting the loss of telomere protection as a driver of pro-inflammatory states associated with aging. By reevaluating the interplay between telomeres, innate immunity, and inflammation, we present novel perspectives on the etiology of aging and its associated diseases.


Effect of Level of Urology Training on Gleason Score and Prostate Volume Estimation Agreement between Transrectal Ultrasound Guided Biopsy and Radical Prostatectomy Specimen.
Transrectal ultrasound guided prostate biopsy may be performed by operators with various levels of training. Little is known about the impact of training level on biopsy results. We evaluated the effect of training level on the accuracy of transrectal ultrasound guided prostate biopsy findings. We retrospectively reviewed 500 consecutive patients who underwent transrectal ultrasound guided prostate biopsy and subsequent radical prostatectomy. Transrectal ultrasound operators were stratified based on level of training as junior, senior, chief, fellow or staff. Linear regression was performed to analyze the effect of training level on volume estimates. A weighted Kappa statistic evaluated agreement between biopsy and pathological Gleason scores while an adjusted cumulative logistic regression model analyzed the effects of training level. A total of 482 patients were included in the final analysis. Transrectal ultrasound guided biopsy was performed by staff in 78 (16%) patients, by fellows in 18 (4%), chief residents in 48 (10%), senior residents in 126 (26%) and junior residents in 212 (44%). There was no significant difference between transrectal ultrasound and radical prostatectomy specimen volume estimates among the training levels. Level of training was not significantly associated with pathological features, including Gleason score, primary Gleason grade, highest single Gleason grade and estimated tumor volume. Study limitations include the retrospective design and the variability among members of the same group. Agreement between biopsy and pathological Gleason scores is high for all levels of training. Training level has no impact on prostate volume estimations or the prediction of pathological features.


Spontaneous rupture of the spleen as a result of primary splenic lymphoma.
Spontaneous rupture of the spleen is a true surgical emergency that requires immediate management to prevent rapid exsanguination. It occurs mostly as a result of splenic infiltration by infectious or haematological diseases. We present a case of a 79-year-old male who was admitted to our emergency department with 3 days history of feeling unwell, abdominal pain, and dizziness, with no history of trauma. He was hypotensive, but all other observations were within normal limits. Examination revealed abdominal tenderness, mainly on the left side, with no palpable organs or masses. Computed tomography scan showed an abnormal spleen with signs of intraabdominal bleeding; emergency splenectomy was performed successfully. Histological examination showed infiltration of the spleen by diffuse large B cell lymphoma, which was later confirmed to be primary. The patient went through an uneventful post-operative recovery, and remains disease free so far.


The effects of temperature and season of collection on the onset and duration of diapause in embryos of the annual fish Nothobranchius guentheri.
Annual fish are found in temporary bodies of water in habitats of alternating rainy and dry seasons. The populations survive the dry seasons in the form of embryos encased in the bottom mud. Several genera of annual fish have been reported to exhibit diapause (developmental arrest) at three specific stages of development and it has been proposed that through this adaptation the populations are able to survive the variable durations of the dry seasons. The effects of incubation ans spawning temperatures, and season of collection on the onset and duration of diapause in laboratory populations of the annual fish, Nothobranchius guentheri, were studied. At low incubation and spawning temperatures there was a prolongation of Diapause I and Diapause II. In addition, fish spawned at 25 degrees C during the short days of winter produced embryos that entered a prolonged duration of Diapause II, whereas embryos produced during the long days of summer bypassed Diapause II.


Drug approval highlights for 2003.
In the past 12 months, the FDA has approved important new pharmaceutical drugs and devices of particular interest to primary health care providers. The drugs include: Oxytrol (for urinary incontinence), Valtrex (for reducing the risk of heterosexual transmission of genital herpes), Femring (for vaginal delivery of hormone therapy), Uroxatral (for benign prostatic hypertrophy), Levitra (for erectile dysfunction), Flumist (for preventing influenza), Xolair (for asthma), Raptiva (for psoriasis), Cubicin (for skin infections), Crestor (for hypercholesterolemia), and Coreg (for severe heart failure).


Effort Foraging Task reveals positive correlation between individual differences in the cost of cognitive and physical effort in humans.
Effort-based decisions, in which people weigh potential future rewards against effort costs required to achieve those rewards involve both cognitive and physical effort, though the mechanistic relationship between them is not yet understood. Here, we use an individual differences approach to isolate and measure the computational processes underlying effort-based decisions and test the association between cognitive and physical domains. Patch foraging is an ecologically valid reward rate maximization problem with well-developed theoretical tools. We developed the Effort Foraging Task, which embedded cognitive or physical effort into patch foraging, to quantify the cost of both cognitive and physical effort indirectly, by their effects on foraging choices. Participants chose between harvesting a depleting patch, or traveling to a new patch that was costly in time and effort. Participants' exit thresholds (reflecting the reward they expected to receive by harvesting when they chose to travel to a new patch) were sensitive to cognitive and physical effort demands, allowing us to quantify the perceived effort cost in monetary terms. The indirect sequential choice style revealed effort-seeking behavior in a minority of participants (preferring high over low effort) that has apparently been missed by many previous approaches. Individual differences in cognitive and physical effort costs were positively correlated, suggesting that these are perceived and processed in common. We used canonical correlation analysis to probe the relationship of task measures to self-reported affect and motivation, and found correlations of cognitive effort with anxiety, cognitive function, behavioral activation, and self-efficacy, but no similar correlations with physical effort.


Discordance between the anti-Xa activity and the antithrombotic activity in an ultra-low molecular weight heparin fraction.
The relationship between the in vivo antithrombotic effect of heparin and ex vivo anti-Xa activity has been investigated using an animal thrombosis model. Three low molecular weight heparins were compared with the standard heparin from which they were fractionated. All four heparins showed a dose-dependent antithrombotic effect enabling the relative antithrombotic and anti-Xa activities to be compared over a dosage range. A correlation between ex vivo anti-Xa heparin levels and antithrombotic effect was demonstrated for the standard (MW 16,000), intermediate (MW 7,600) and low (MW 4,600) molecular weight heparins but not for the ultra-low molecular weight (MW 3,000) fraction. The lack of relationship between anti-Xa activity and inhibition of thrombosis for the very low molecular weight fraction indicates that a very high anti-Xa activity (measured in vitro or ex vivo) is not always predictive of in vivo antithrombotic efficacy. These findings suggest that other properties of low molecular weight heparins contribute to their antithrombotic effectiveness.


Working with my brain and not against it.
When attempts to capitalize on her undiagnosed ADHD traits led to repeated cycles of overwork and burnout, a postdoc re-evaluated how she faces the daily challenges of being a neurodivergent scientist.


24-hour blood pressure control by once-daily administration of irbesartan assessed by ambulatory blood pressure monitoring. Irbesartan Multicenter Investigators' Group.
To compare 24 h ambulatory blood pressure and trough office blood pressure lowerings after 8 weeks of therapy with 75 mg irbesartan once a day, 150 mg irbesartan once a day , and 75 mg irbesartan twice a day versus placebo; and to assess safety and tolerability of irbesartan therapy. Multicenter, double-blind, randomized, placebo-controlled trial. Sixteen centers in Italy. Caucasian patients (n = 215) aged > or = 18 years with seated diastolic blood pressure 95-110 mmHg and ambulatory diastolic blood pressure (ADBP) > or = 85 mmHg. Mean 24 h ADBP after 8 weeks of irbesartan therapy. Mean changes (value before treatment minus value after treatment) in ADBP for placebo, 75 mg irbesartan once a day, 150 mg irbesartan once a day, and 75 mg irbesartan twice a day were -0.2, -5.4, -7.2, and -7.2 mmHg, respectively; respective changes in ambulatory systolic blood pressure were +1.6, -8.3, -10.5, and -9.7 mmHg. All irbesartan regimens reduced trough office seated diastolic blood pressure and seated systolic blood pressure after 2 and 8 weeks of treatment (all P < 0.01, versus placebo except for seated systolic blood pressure in patients in the 75 mg irbesartan once a day group). Trough: peak ratios were > or = 55% with 150 mg irbesartan once a day. Percentages of patients whose blood pressures were normalized with 150 mg irbesartan once a day (45%) and 75 mg irbesartan twice a day (47%) were greater than those with placebo (14%, P < 0.01) and with 75 mg irbesartan once a day (19%, NS, versus placebo). Adverse events with irbesartan were similar to those with placebo. All irbesartan regimens significantly reduced mean 24 h ADBP and ambulatory systolic blood pressure, and were well tolerated. Administration of 150 mg irbesartan once a day provided significant reduction of blood pressure for 24 h, equivalent to that obtained with the same daily dose divided into two separate administrations.


[Intrauterine growth in a selected group of Peruvian twins].
Newborn twins have high risk of morbidity and mortality. They are classified with intrauterine growth curves of unique fetuses; they do not exist Peruvian curves for this group. To know the intrauterine growth of a selected group of Peruvian twins and compare it with patterns of unique newborns. In a descriptive, transversal and prospective study made during 13 years (1992-2004) at the Hospital Hipólito Unanue of Tacna-Peru we selected 282 twins (54%) without factors that alter the intrauterine growth. We obtained averages, standard deviation and percentiles 10, 50 and 90 of weight, height, and cephalic perimeter for gestational age of 32 to 41 weeks, which were corrected with a second-order polynomial. We compared the values of the percentiles and the averages with the unique newborns curves. The value of p < 0.05 was considered significant. From 36,909 newborns alive, 518 were twins, and of those we selected 282. The most representative group was formed by those who were in the week 38, in which percentiles 10 and 90 of weight were 2,275 and 3,180 g, of size 45.8 and 48.4 cm, and of cephalic perimeter 323 and 354 mm, respectively. Comparing the twins with the unique newborns at week 38, the difference of weight in percentile 50 was 452 g. Regarding the somatometric parameters, weight was the most affected, 44.3% of the twins were under percentile 10 of the curve of weight for unique newborns; followed by height with 22.3% and cephalic perimeter with 5%. When comparing the intrauterine growth for weight of twins with unique newborns the performance was similar until week 34, from which growth had a significant deterioration. When classifying the newborn twins we found a frequency of 12.3%, which increases to 37% with the curves of unique newborns. The twin intrauterine growth curves differ significantly from the unique newborns growth. It is recommended to use specific charts for twins in order to evaluate their intrauterine growth appropriately.


A Case of Breast Carcinoma en Cuirasse in Male.
A 63-year-old male presented with a painful skin lesion on the left side of the neck and upper chest approximately two months prior to presentation. Diffuse erythematous to purplish-colored sclerotic patches were observed. He had been treated with intravenous antibiotics for two weeks for cellulitis, but the lesion did not improve. Punch biopsy, and neck computed tomography (CT) with contrast enhancement were performed to differentiate between cellulitis and scleroderma. Histopathological examination revealed infiltration of pleomorphic and poorly differentiated tumor cells extending into thickened collagen bundles, and mitotic activity. Based on histologic and radiologic findings, the patient was suspected to have poorly differentiated carcinoma, and further evaluation of the origin of the carcinoma was performed. A subareolar mass on the left breast was observed on chest CT, and a needle biopsy was performed; results were consistent with findings from the skin biopsy. Finally, the patient was diagnosed with carcinoma en cuirasse, a subtype of cutaneous metastasis of breast cancer, was transferred to oncology, and underwent palliative chemotherapy.


Relationships between volatile production, fruit quality, and sensory evaluation in Granny Smith apples stored in different controlled-atmosphere treatments by means of multivariate analysis.
Aroma compounds, quality parameters, and sensory evaluation of Granny Smith apples were analyzed after 3, 5, and 7 months of cold storage in three controlled-atmosphere (CA) treatments, in which oxygen and carbon dioxide were held at 1, 2, and 3%. During poststorage ripening, the apples were kept at 20 degrees C for 1, 5, and 10 days before analytical measurements were made. The highest volatile emission was obtained after 5 months of storage in all CA treatments, reaching its highest value when a low-oxygen CA (LO) was used. Ultralow-oxygen CA (ULO) showed the highest ability to maintain apple firmness. The correlation among analytical and sensory parameters suggests that ethyl 2-methylbutyrate, 1-butanol, pentyl acetate, and tert-butyl propionate are the aroma compounds with the highest influence in the sensorial score. Concerning CA treatments, LO and ULO appear to be very valuable technologies for maintaining the sensorial quality even after 7 months of storage.


Repeated High-Intensity-Effort Activity in Elite and Semielite Rugby League Match Play.
No study has investigated the frequency and nature of repeated high-intensity-effort (RHIE) bouts across elite and semielite rugby league competitions. This study examined RHIE activity in rugby league match play across playing standards. 36 elite and 64 semielite rugby league players. Global positioning system analysis was completed during 17 elite and 14 semielite matches. The most commonly occurring RHIE bouts involved 2 efforts (2-RHIE) for both elite and semielite players. Only small differences were found in 2-RHIE activity between elite and semielite match play (effect size [ES] ≥ 0.31 ± 0.15, ≥ 88%, likely). RHIE bouts were more likely to involve contact as the number of efforts in a bout increased (ES ≥0.40 ± 0.15, 100%, almost certainly). Semielite players performed a greater proportion of 2-contact-effort RHIE bouts than their elite counterparts (68.2% vs 60.6%, ES 0.33 ± 0.15, 92%, likely), while elite players performed a greater proportion of 3-effort bouts (26.9% vs 21.1%, ES 0.31 ± 0.15, 88%, likely). Elite players also had a shorter recovery (1.00-3.99 vs ≥4.00 min) between RHIE bouts (ES ≥ 1.60 ± 0.71, ≥ 94%, likely). These findings highlight the RHIE demands of elite and semielite rugby league match play. Elite players are more likely to perform RHIE bouts consisting of 3 efforts and to have a shorter recovery time between bouts. Exposing players to these RHIE demands in training is likely to improve their ability to tolerate the most demanding passages of match play.


Outcomes of cataract surgery in diabetic patients: results of the Pan American Collaborative Retina Study Group.
This study was designed to evaluate the visual and anatomical outcomes after cataract surgery in diabetic patients with different intraoperative therapeutic strategies. The research design comprised of a multicentric, retrospective, interventional study conducted at 6 centers in Argentina, Brazil, Costa Rica, Puerto Rico, Spain, and Venezuela. We included 138 diabetic patients with at least 6-month follow-up following phacoemulsification and intraocular lens implantation. Best-corrected visual acuity (BCVA) and central subfield thickness were collected at baseline and at 1-, 2-, 3-, and 6-month follow-up. Of these, 42 cases were not treated with any intraoperative coadjuvant medication (Group 1), 59 patients received intraoperative bevacizumab (Group 2) and 37 patients received intraoperative triamcinolone (4 mg/0.1 ml) (Group 3). The mean logMAR [± standard deviation (SD)] BCVA improved from 0.82 (± 0.43) at baseline, to 0.14 (± 0.23) at 6-month follow-up (p<0.001) in Group 1; from 0.80 (± 0.48) to 0.54 (± 0.45) (p<0.001) in Group 2; and from 1.0 (± 0.40) to 0.46 (± 0.34) (p<0.001) in Group 3. The mean central subfield thickness increased from 263.57 µm (± 35.7) at baseline to 274.57 µm (± 48.7) at 6-month follow-up (p=0.088) in Group 1; from 316.02 µm (± 100.4) to 339.56 µm (± 145.3) (p=0.184) in Group 2; and from 259.18 µm (± 97.9) to 282.21 µm (± 87.24) (p=0.044) in Group 3. Diabetic patients may significantly benefit from cataract surgery. This study provides evidence to support the use of intravitreal triamcinolone or bevacizumab at the time of cataract surgery in cases with pre-existent diabetic macular edema or moderate-severe non-proliferative diabetic retinopathy.


Remember walking in their shoes? The relation of self-referential source memory and emotion recognition.
ABSTRACTDeficits in the ability to read the emotions of others have been demonstrated in mental disorders, such as dissociation and schizophrenia, which involve a distorted sense of self. This study examined whether weakened self-referential source memory, being unable to remember whether a piece of information has been processed with reference to oneself, is linked to ineffective emotion recognition. In two samples from a college and community, we quantified the participants' ability to remember the self-generated versus non-self-generated origins of sentences they had previously read or partially generated. We also measured their ability to read others' emotions accurately when viewing photos of people in affect-charged situations. Multinomial processing tree modelling was applied to obtain a measure of self-referential source memory that was not biased by non-mnemonic factors. Our first experiment with college participants revealed a positive correlation between correctly remembering the origins of sentences and accurately recognising the emotions of others. This correlation was successfully replicated in the second experiment with community participants. The current study offers evidence of a link between self-referential source memory and emotion recognition.


Roles of the Dal82p domains in allophanate/oxalurate-dependent gene expression in Saccharomyces cerevisiae.
Allophanate/oxalurate-induced gene expression in Saccharomyces cerevisiae requires at least five transcription factors, four of which act positively (Gln3p, Gat1p, Dal81p, and Dal82p) and one negatively (Dal80p). Gln3p binds to and Gat1p is proposed to bind to single GATA sequences; Dal80p binds to pairs of specifically oriented and spaced GATA sequences, and Dal82p binds to a pathway-specific element, UIS(ALL). Dal82p consists of at least three domains as follows: (i) UIS(ALL) DNA-binding, (ii) transcriptional activation, and (iii) coiled-coil(DAL82). Here we show that the coiled-coil(DAL82) domain possesses two demonstrable functions. (i) It prevents Dal82p-mediated transcription when inducer is absent. (ii) It is a major, although not exclusive, domain through which the inducer signal is received. Supporting the latter conclusion, a 38-amino acid fragment, containing little more than the coiled-coil(DAL82) domain, supports oxalurate-inducible, Dal81p-dependent, reporter gene transcription. Dal81p is required for inducer responsiveness of LexAp-Dal82p and LexAp coiled-coil(DAL82)-mediated transcription but isn't needed for inducer-dependent activation mediated by a Dal82p containing deletions in both the coiled-coil(DAL82), UIS(ALL)-binding domains. There may be an interaction between Dal81p and the coiled-coil(DAL82) domain since (i) Dal81p is required for transcription mediated by LexA-coiled-coil(DAL82)p and (ii) a Dal81p-Dal82p complex is detected by two-hybrid assay.


Group-theoretical analysis of structural instability, vacancy ordering and magnetic transitions in the system troilite (FeS)-pyrrhotite (Fe1-xS).
A group-theoretical framework to describe vacancy ordering and magnetism in the Fe1-xS system is developed. This framework is used to determine the sequence of crystal structures consistent with the observed magnetic structures of troilite (FeS), and to determine the crystallographic nature of the low-temperature Besnus transition in Fe0.875S. It is concluded that the Besnus transition is a magnetically driven transition characterized by the rotation of the moments out of the crystallographic plane to which they are confined above the transition, accompanied by small atomic displacements that lower the symmetry from monoclinic to triclinic at low temperatures. Based on the phase diagram, magnetically driven phase transitions at low temperatures are predicted in all the commensurate superstructures of pyrrhotite. Based on the phase diagram, magnetically driven spin reorientations at low temperatures are predicted in all the commensurate superstructures of pyrrhotite. The exact nature of the spin rotation is determined by the symmetry of the vacancy-ordered state and based on this spin-flop transitions in 3C and 5C pyrrhotite and a continuous rotation akin to that seen in 4C pyrrhotite are predicted. A Besnus-type transition is also possible in 6C pyrrhotite. Furthermore, it is clarified that 3C and 4C pyrrhotite carry a ferrimagnetic moment whereas 5C and 6C are antiferromagnetic.


Fulminant hepatic failure in a patient with advanced extragonadal germ cell tumour.
Fulminant hepatic failure (FHF) in association with metastatic cancer, without evidence of liver metastases, has not been previously reported in the literature. This report concerns a case of FHF in a 36-year-old man with advanced germ cell tumour arising from an extragonadal (retroperitoneal) primary. Liver function and encephalopathy improved following chemotherapy, suggesting prompt diagnosis and treatment may have cured the patient. Following completion of chemotherapy, he developed spontaneous bacterial endocarditis, requiring aortic valve replacement, a rare complication of curative chemotherapy. At 44 months post completion of chemotherapy, he has regained his premorbid performance status and has returned to work.


Investigation of the effects of patulin on thyroid and testis, and hormone levels in growing male rats.
Patulin is a mycotoxin produced by several species of Penicillium, Aspergillus and Byssachlamys. Patulin can be produced on different food products including fruits, grains, cheese, cured meats, but in natural situations patulin is usually found in apple and apple products. In the present study, the time-dependent effects of patulin on the T3, T4, thyroid stimulating hormone, testosterone, luteinizing hormone and growth hormone levels of growing male rats were investigated. Patulin, at a dose of 0.1 mg/kg bw/day, was administered by gavage to growing male rats aged 5-6 weeks for a period of 60 or 90 days. The dose of patulin used in the present study was based on estimated human exposure levels. At the end of the experiment, serum T3, T4, TSH, testosterone, LH and GH levels of rats in control and treatment groups were analysed. In addition, the thyroid and testes were histopathologically examined by light microscopy. Results revealed that while patulin caused an increase (66.6%) in testosterone levels and a decrease (17.3%) in T4 levels of rats treated for 60 days, there was no change in the other hormone levels compared to those of the control group. When patulin treatment was extended to 90 days, increased serum testosterone (75%) and LH levels (146%) were observed. In histological examinations of the testes of rats treated with patulin, oedema, fibrosis and local Leydig cell hyperplasia in the interstitial tissue, and disorganization of seminiferous tubule epithelium were also observed. In addition, the thyroid of rats treated with patulin revealed lymphoid cell inflitration and enlargement of interstitial tissue between follicles, and degenerated colloid.


On computing the Discrete Fourier Transform.
New algorithms for computing the Discrete Fourier Transform of n points are described. For n in the range of a few tens to a few thousands these algorithms use substantially fewer multiplications than the best algorithm previously known, and about the same number of additions.


Body Fluid Degradomics and Characterization of Basic N-Terminome.
Rapid improvements in instrumentation and data analysis make mass spectrometry-based proteomics the method of choice for global characterization of proteomes and discovery of protein-based biomarkers. On the contrary to tissue biopsies, body fluids-e.g., blood, wound fluid, urine, and saliva-are noninvasive and easy to collect and process. However, they are very complex and present high dynamic ranges of protein concentrations, rendering direct shotgun proteomics analysis as inefficient for identification of low-abundance proteins in these specimens. Sample prefractionation, immunoaffinity depletion of highly abundant proteins, and enrichment of posttranslational modifications (PTM) are common strategies for proteome simplification of body fluids. Combinatorial peptide ligand libraries (CPLL) relatively deplete high-abundance proteins by binding equimolar amounts of protein species in the sample and provide an elegant species-independent alternative to immunoaffinity-based approaches. By cleaving target proteins, proteases catalyze an irreversible PTM, whereby uncontrolled proteolysis is associated with many diseases. Thus, proteolytic events represent powerful indicators for disease progression and their specific identification in body fluids holds great promises for establishment of novel biomarkers. Quantitative N-terminal enrichment strategies, such as terminal amine isotopic labeling of substrates (TAILS) detect protease-generated neo-N-termini with high specificity and increase coverage of low-abundance proteins by inherent proteome simplification. In this chapter, we describe a protocol that combines the CPLL technology with iTRAQ-based TAILS to systematically characterize the basic N-terminome of body fluid proteomes and its alterations in disease conditions that we have successfully applied to explore the wound fluid degradome at multiple time points after skin injury.


Global sulfur emissions from 1850 to 2000.
The ASL database provides continuous time-series of sulfur emissions for most countries in the World from 1850 to 1990, but academic and official estimates for the 1990s either do not cover all years or countries. This paper develops continuous time series of sulfur emissions by country for the period 1850-2000 with a particular focus on developments in the 1990s. Global estimates for 1996-2000 are the first that are based on actual observed data. Raw estimates are obtained in two ways. For countries and years with existing published data I compile and integrate that data. Previously published data covers the majority of emissions and almost all countries have published emissions for at least 1995. For the remaining countries and for missing years for countries with some published data, I interpolate or extrapolate estimates using either an econometric emissions frontier model, an environmental Kuznets curve model, or a simple extrapolation, depending on the availability of data. Finally, I discuss the main movements in global and regional emissions in the 1990s and earlier decades and compare the results to other studies. Global emissions peaked in 1989 and declined rapidly thereafter. The locus of emissions shifted towards East and South Asia, but even this region peaked in 1996. My estimates for the 1990s show a much more rapid decline than other global studies, reflecting the view that technological progress in reducing sulfur based pollution has been rapid and is beginning to diffuse worldwide.


Identification of phenolic compounds that suppress the virulence of Xanthomonas oryzae on rice via the type III secretion system.
The targeting of bacterial type III secretion systems (T3SSs), which are critical virulence factors in most Gram-negative pathogens, is regarded as an alternative strategy for the development of novel anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc) are two of the most important bacterial pathogens on rice, which cause leaf blight and leaf streak diseases, respectively. To identify potential anti-virulence drugs against these two pathogens, we screened a library of plant phenolic compounds and derivatives for their effects on the Xoo T3SS. Ten of 56 compounds significantly inhibited the promoter activity of a harpin gene, hpa1. These inhibitors were further tested for their impact on the hypersensitive response (HR) caused by Xoo on non-host tobacco plants. The results showed that pretreatment of Xoo with TS006 (o-coumaric acid, OCA), TS010, TS015 and TS018 resulted in significantly attenuated HR without affecting bacterial growth or survival. In addition, Cya translocation assays demonstrated that the translocation of two T3 effectors was suppressed by the four inhibitors. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that mRNA levels of representative genes in the hrp (hypersensitive response and pathogenicity) cluster, as well as the regulatory genes hrpG and hrpX, were reduced by treatment with the four inhibitors, suggesting that expression of the Xoo T3SS was suppressed. The expression of other virulence factors was not suppressed, which indicated possible T3SS-specific inhibition. Finally, we demonstrated that these inhibitors reduced the disease symptoms of Xoo and Xoc on the rice cultivar (Oryza sativa) IR24 to varying extents.


Independent predictors of cognitive decline in healthy elderly persons.
Several studies have shown that individually memory, hippocampal volume, and motor measures presage the onset of dementia. It is unclear if these independently contribute to the prediction of mild cognitive impairment. To determine the ability of memory, hippocampal volume, and a gait speed to independently predict cognitive decline in healthy elderly persons. A prospective, longitudinal, observational cohort study with a mean follow-up of 6 years. One hundred eight optimally healthy elderly cognitively intact subjects. Any cognitive impairment noted on the Clinical Dementia Rating Scale (score = 0.5) or persistent or progressive cognitive impairment. Cox modeling determined if time to onset of cognitive impairment was associated with baseline logical memory II test score (a measure of delayed recall), hippocampal volume (magnetic resonance imaging), or gait speed (time to walk 30 ft [9 m]) independent of age, sex, depression, or the allele producing the epsilon4 type of apolipoprotein E (APOE epsilon4). Questionable dementia occurred in 48 participants in a mean (SD) of 3.7 (2.4) years. This progressed to persistent cognitive impairment in 38 of these participants in a mean (SD) of 4.4 (2.4) years. Logical memory II test performance and hippocampal volume each predicted onset of questionable dementia, independent of age and sex. Time to walk 30 ft additionally contributed independently to the prediction of time to onset of persistent cognitive impairment. Possessing the APOE epsilon4 allele and depression did not enter either model significantly. Models combining multiple risk factors should refine the prediction of questionable dementia and persistent cognitive impairment, harbingers of dementia. Individuals at risk for cognitive impairment may represent a high-risk group for intervention.


Immune modulation and stereotactic radiation: improving local and abscopal responses.
New and innovative treatment strategies for cancer patients in the fields of immunotherapy and radiotherapy are rapidly developing in parallel. Among the most promising preclinical treatment approaches is combining immunotherapy with radiotherapy where early data suggest synergistic effects in several tumor model systems. These studies demonstrate that radiation combined with immunotherapy can result in superior efficacy for local tumor control. More alluring is the emergence of data suggesting an equally profound systemic response also known as "abscopal" effects with the combination of radiation and certain immunotherapies. Studies addressing optimal radiation dose, fractionation, and modality to be used in combination with immunotherapy still require further exploration. However, recent anecdotal clinical reports combining stereotactic or hypofractionated radiation regimens with immunotherapy have resulted in dramatic sustained clinical responses, both local and abscopal. Technologic advances in clinical radiation therapy has made it possible to deliver hypofractionated regimens anywhere in the body using stereotactic radiation techniques, facilitating further clinical investigations. Thus, stereotactic radiation in combination with immunotherapy agents represents an exciting and potentially fruitful new space for improving cancer therapeutic responses.


GM-CSF improves endometrial receptivity in a thin endometrium rat model by upregulating HOXA10.
Endometrial receptivity is a prerequisite for the success of assisted reproduction., Patients with a consistently thin endometrium frequently fail to conceive, owing to low endometrial receptivity, and there are currently very few therapeutic options available. Our previous study demonstrated that intrauterine granulocyte-macrophage colony-stimulating factor (GM-CSF) administration resulted in a significant improvement in clinical pregnancy and implantation rates and was an effective means of increasing endometrial thickness on the day of embryo transfer in patients with thin endometrium. In order to explore the underlying process, an animal model with a thin endometrium was constructed, the homeobox A10 gene (HOXA10) was downregulated, and inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway (MAPK/ERK) were employed. Our findings strongly suggest a marked decrease in GM-CSF levels in the thin endometrial rat model, and a suppression of HOXA10 impeded the therapeutic efficacy of GM-CSF in this model. Moreover, we showed that GM-CSF significantly increases endometrial receptivity in the rat model and upregulates HOXA10 via the MAPK/ERK pathway. Our data provide new molecular insights into the mechanisms underlying formation of a thin endometrium and highlight a novel, potential clinical treatment strategy as well as directions for further research.


Decreasing Compensatory Ability of Concentric Ventricular Hypertrophy in Aortic-Banded Rat Hearts.
The cardiac system compensates for variations in physiological and pathophysiological conditions through a dynamic remodeling at the organ, tissue, and intracellular levels in order to maintain function. However, on longer time scales following the onset of ventricular pressure overload, such remodeling may begin to inhibit physiological function and ultimately lead to heart failure. This progression from compensatory to decompensatory behavior is poorly understood, in particular owing to the absence of a unified perspective of the concomitantly remodeling subsystems. To address this issue, the present study investigates the evolution of compensatory mechanisms, in response to overload, by integrating diffusion-tensor MRI, echocardiography, and intracellular and hemodynamic measurements within consistent computational simulations of aortic-banded rat hearts. This approach allows a comparison of the relative leverage of different cardiac properties (geometry, passive mechanical stiffness, fiber configuration, diastolic and peak calcium concentrations, calcium-binding affinity, and aortic impedance) to affect cardiac contraction. Measurements indicate that, following aortic banding, an ejection fraction (EF) of 75% was maintained, relative to control rats, despite significant remodeling of the left-ventricular wall thickness (increasing by ~90% over 4 weeks). Applying our framework, we identified the left-ventricular wall thickness (concentric hypertrophy) and the intracellular calcium dynamics as playing the dominant roles in preserving EF acutely, whereas the significance of hypertrophy decreased subsequently. This trend suggests an increasing reliance on intracellular mechanisms (average increase ~50%), rather than on anatomical features (average decrease ~60%), to achieve compensation of pump function in the early phase of heart failure.


Turning carbon dioxide into fuel.
Our present dependence on fossil fuels means that, as our demand for energy inevitably increases, so do emissions of greenhouse gases, most notably carbon dioxide (CO2). To avoid the obvious consequences on climate change, the concentration of such greenhouse gases in the atmosphere must be stabilized. But, as populations grow and economies develop, future demands now ensure that energy will be one of the defining issues of this century. This unique set of (coupled) challenges also means that science and engineering have a unique opportunity-and a burgeoning challenge-to apply their understanding to provide sustainable energy solutions. Integrated carbon capture and subsequent sequestration is generally advanced as the most promising option to tackle greenhouse gases in the short to medium term. Here, we provide a brief overview of an alternative mid- to long-term option, namely, the capture and conversion of CO2, to produce sustainable, synthetic hydrocarbon or carbonaceous fuels, most notably for transportation purposes. Basically, the approach centres on the concept of the large-scale re-use of CO2 released by human activity to produce synthetic fuels, and how this challenging approach could assume an important role in tackling the issue of global CO2 emissions. We highlight three possible strategies involving CO2 conversion by physico-chemical approaches: sustainable (or renewable) synthetic methanol, syngas production derived from flue gases from coal-, gas- or oil-fired electric power stations, and photochemical production of synthetic fuels. The use of CO2 to synthesize commodity chemicals is covered elsewhere (Arakawa et al. 2001 Chem. Rev. 101, 953-996); this review is focused on the possibilities for the conversion of CO2 to fuels. Although these three prototypical areas differ in their ultimate applications, the underpinning thermodynamic considerations centre on the conversion-and hence the utilization-of CO2. Here, we hope to illustrate that advances in the science and engineering of materials are critical for these new energy technologies, and specific examples are given for all three examples. With sufficient advances, and institutional and political support, such scientific and technological innovations could help to regulate/stabilize the CO2 levels in the atmosphere and thereby extend the use of fossil-fuel-derived feedstocks.


A Switch from Latent to Typical Infection during Pectobacterium atrosepticum-Tobacco Interactions: Predicted and True Molecular Players.
Phytopathogenic microorganisms, being able to cause plant diseases, usually interact with hosts asymptomatically, resulting in the development of latent infections. Knowledge of the mechanisms that trigger a switch from latent to typical, symptomatic infection is of great importance from the perspectives of both fundamental science and disease management. No studies to date have compared, at the systemic molecular level, the physiological portraits of plants when different infection types (typical and latent) are developed. The only phytopathogenic bacterium for which latent infections were not only widely described but also at least fluently characterized at the molecular level is Pectobacterium atrosepticum (Pba). The present study aimed at the comparison of plant transcriptome responses during typical and latent infections caused by Pba in order to identify and then experimentally verify the key molecular players that act as switchers, turning peaceful plant-Pba coexistence into a typical infection. Based on RNA-Seq, we predicted plant cell wall-, secondary metabolism-, and phytohormone-related genes whose products contributed to the development of the disease or provided asymptomatic plant-Pba interactions. By treatment tests, we confirmed that a switch from latent to typical Pba-caused infection is determined by the plant susceptible responses mediated by the joint action of ethylene and jasmonates.


The Perceptions of Professionals Toward Siblings of Individuals With Intellectual and Developmental Disabilities.
Adult siblings of individuals with intellectual and developmental disabilities (IDD) report struggling to navigate the adult disability service delivery system and collaborate with professionals. To date, though, it is unclear how professionals encourage sibling involvement and, accordingly, the facilitators and challenges in working with siblings. For this study, 290 professionals participated in a national web-based survey; participants answered three open-ended questions about ways to involve siblings, positive experiences with siblings, and challenges in working with siblings. Professionals reported person-level and systems-level supports to encourage sibling involvement. Also, professionals reported enjoying working with cohesive families of individuals with IDD and witnessing the benefits that siblings bring to their brothers and sisters with IDD. Challenges in working with siblings included: lack of sibling involvement, systemic barriers, and caregiving burden. Implications for future research and practice are discussed.


Investigating heterogeneity in the characterization of risks using best worst scaling.
This research proposes and implements a new approach to the elicitation and analysis of perceptions of risk. We use best worst scaling (BWS) to elicit the levels of control respondents believe they have over risks and the level of concern those risks prompt. The approach seeks perceptions of control and concern over a large risk set and the elicitation method is structured so as to reduce the cognitive burden typically associated with ranking over large sets. The BWS approach is designed to yield strong discrimination over items. Further, the approach permits derivation of individual-level values, in this case of perceptions of control and worry, and analysis of how these vary over observable characteristics, through estimation of random parameter logit models. The approach is implemented for a set of 20 food and nonfood risks. The results show considerable heterogeneity in perceptions of control and worry, that the degree of heterogeneity varies across the risks, and that women systematically consider themselves to have less control over the risks than men.


Psoas muscle metastasis from cervical carcinoma: Correlation and comparison of diagnostic features on FDG-PET/CT and diffusion-weighted MRI.
Psoas muscle metastasis, though rare, is the commonest site of skeletal muscle involvement in cervical carcinoma. The appropriate clinical management of this condition, particularly of the pain related to malignant psoas syndrome, is still evolving and the diagnostic features on conventional morphological imaging modalities are often non specific, with the differential diagnosis lying between sarcoma, hematoma, and abscess. In this report, a comparison of various morphofunctional imaging modalities was made. Fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) was the first to suspect disease involvement of the psoas muscle, demonstrating intense FDG uptake (compared with the contralateral muscle), while ultrasound showed heterogeneous echotexture, and magnetic resonance imaging (MRI) showed subtle altered signal intensity in the right psoas muscle. Both anatomical imaging modalities and non contrast CT of the PET-CT examination demonstrated a bulky psoas muscle, without any focal abnormality. On diffusion-weighted imaging of MRI (DWI-MRI), restricted diffusion of the involved muscle was an important observation. The psoas muscle metastatic involvement was proven histopathologically. Thus, enhanced glucose metabolism and restricted diffusion in the newer non-invasive molecular imaging modalities (e.g., PET/CT and DWI-MRI) could serve as valuable adjunctive parameters in diagnosing this entity in the absence of a focal abnormality in the anatomical modalities. In the treatment response monitoring scenario, FDG-PET/CT demonstrated near complete resolution following administration of 3 cycles of systemic chemotherapy and local external radiotherapy.


AStrap: identification of alternative splicing from transcript sequences without a reference genome.
Alternative splicing (AS) is a well-established mechanism for increasing transcriptome and proteome diversity, however, detecting AS events and distinguishing among AS types in organisms without available reference genomes remains challenging. We developed a de novo approach called AStrap for AS analysis without using a reference genome. AStrap identifies AS events by extensive pair-wise alignments of transcript sequences and predicts AS types by a machine-learning model integrating more than 500 assembled features. We evaluated AStrap using collected AS events from reference genomes of rice and human as well as single-molecule real-time sequencing data from Amborella trichopoda. Results show that AStrap can identify much more AS events with comparable or higher accuracy than the competing method. AStrap also possesses a unique feature of predicting AS types, which achieves an overall accuracy of ∼0.87 for different species. Extensive evaluation of AStrap using different parameters, sample sizes and machine-learning models on different species also demonstrates the robustness and flexibility of AStrap. AStrap could be a valuable addition to the community for the study of AS in non-model organisms with limited genetic resources. AStrap is available for download at https://github.com/BMILAB/AStrap. Supplementary data are available at Bioinformatics online.


Micronutrients in Support to The Carbon Cycle Activate Antioxidant Defences and Reduce Sperm DNA Damage in Infertile Men Attending Assisted Reproductive Technology Programs: Clinical Trial Study.
Micronutrients in support to the carbon cycle were shown to reduce sperm DNA damage both in animal models and infertile men. Besides supporting DNA methylation, their positive effect may be mediated by an improved performance of the endogenous antioxidant system but this has not yet been proven in clinical settings. The present study aimed at evaluating the effects of micronutrient supplementation in infertile male partners of assisted reproductive technology (ART) resistant couples. In this experimental clinical trial study, infertile male partners of couples resistant to at least one ART cycle, with a sperm fragmentation rate >20% (TUNEL), underwent a 4-month oral supplementation with micronutrients in support to the carbon cycle including folates, B vitamins, zinc and cysteines. Semen, sperm DNA fragmentation (TUNEL), nuclear maturation (CMA3 and blue aniline staining) and lipid peroxidation (BODIPY) were assessed before and after treatment. The couples were followed-up to record clinical outcomes. Forty-three patients completed the program but full data of pre- and post-treatment were available only for 25 patients. The treatment did not modify sperm concentration or motility but improved morphology. Nuclear maturation, DNA fragmentation and lipid peroxidation significantly improved after the treatment. Overall, 10 clinical pregnancies (23.3%) and 4 live births (9.3%) were recorded during the follow-up following expectant management (25 couples) or a new intracytoplasmic sperm injection (ICSI) cycle (18 couples). The micronutrients appeared to induce both DNA methylation, resulting in improved sperm nuclear maturation, and antioxidant defences, resulting in less DNA fragmentation and lipid peroxidation. The clinical outcomes were aligned with a possible positive effect on reproductive function. Micronutrients could be regarded as an alternative to antioxidants in correcting oxidative damage in infertile men; however, to confirm such findings, further clinical investigations are warranted (Registration number: IRCT201510207223N6).


Anti-hepatitis C antibody carriage and risk of liver impairment in rural-Cameroon: adapting the control of hepatocellular carcinoma for resource-limited settings.
The Viral hepatitis elimination by 2030 is uncertain in resource-limited settings (RLS), due to high burdens and poor diagnostic coverage. This sounds more challenging for hepatitis C virus (HCV) given that antibody (HCVAb) sero-positivity still lacks wide access to HCV RNA molecular testing. This warrants context-specific strategies for appropriate management of liver impairment in RLS. We herein determine the association between anti-HCV positivity and liver impairment in an African RLS. A facility-based observational study was conducted from July-August 2021 among individuals attending the "St Monique" Health Center at Ottou, a rural community of Yaounde,Cameroon. Following a consecutive sampling, consenting individuals were tested for anti-HCV antibodies, hepatitis B surface antigen (HBsAg) and HIV antibodies (HIVAb) as per the national guidelines. After excluding positive cases for HBsAg and/or HIVAb, liver function tests (ALT/AST) were performed on eligible participants (HBsAg and HIVAb negative) and outcomes were compared according to HCVAb status; with p < 0.05 considered statistically significant. Out of 306 eligible participants (negative for HBsAg and HIVAb) enrolled, the mean age was 34.35 ± 3.67 years. 252(82.35%) were female and 129 (42.17%) were single. The overall HCVAb sero-positivity was 15.68%(48/306), with 17.86% (45/252) among women vs. 5.55%(3/54) among men [OR (95%CI) = 3.69(2.11-9.29),p = 0.04]. HCVAb Carriage was greater among participants aged > 50 years compared to younger ones [38.46%(15/39) versus 12.36% (33/267) respectively, OR(95%CI) = 4.43(2.11-9.29), p < 0.000] and in multipartnership [26.67%(12/45)vs.13.79%(36/261) monopartnership, OR (95%CI) = 2.27(1.07-4.80),p = 0.03]. The liver impairment rate (abnormal ALT+AST levels) was 30.39%(93/306), with 40.19%(123/306) of abnormal ALT alone. Moreover, the burden of Liver impairment was significantly with aged> 50 versus younger ones [69.23% (27/39) versus 24.72%(66/267) respectively, p < 0.000). Interestingly, the burden of liver impairment (abnormal AST + ALAT) was significantly higher in HCVAb positive (62.5%, 30/48) versus HCVAb negative (24.42%, 63/258) participants, OR: 3.90 [1.96; 7.79], p = 0.0001. In this rural health facility, HCVAb is highly endemic and the burden of liver impairment is concerning. Interestingly, HCVAb carriage is associated with abnormal liver levels of enzyme (ALT/AST), especially among the elderly populations. Hence, in the absence of nuclei acid testing, ALT/AST are relevant sentinel markers to screen HCVAb carriers who require monitoring/care for HCV-associated hepatocellular carcinoma in RLS.


Cardiometabolic Risk and Cognitive Decline: The Role of Socioeconomic Status in Childhood and Adulthood.
Socioeconomic conditions in childhood predict cognitive functioning in later life. It is unclear whether poor childhood socioeconomic status (SES) also predicts the acceleration of cognitive decline. One proposed pathway is via cardiometabolic risk, which has been linked to both childhood SES and earlier onset of cognitive impairment. Using data from the Health and Retirement Study, we examine the impact of childhood SES on cognitive trajectories over six years and test whether it operates through increased cardiometabolic risk and adult SES. We find that higher childhood SES leads to slower cognitive decline, partially due to lower levels of cardiometabolic risk. However, these pathways operate entirely through adult socioeconomic attainment. The results have important implications for future trends in cognitive population health within the context of growing social inequality and reduced social mobility.


LCLUC as an entry point for transdisciplinary research--reflections from an agriculture land use change study in South Asia.
This article highlights applied understanding of classifying earth imaging data for land cover land use change (LCLUC) information. Compared to the many previous studies of LCLUC, the present study is innovative in that it applied geospatial data, tools and techniques for transdisciplinary research. It contributes to a wider discourse on practical decision making for multi-level governance. Undertaken as part of the BioDIVA project, the research adopted a multi-tiered methodical approach across three key dimensions: socioecology as the sphere of interest, a transdisciplinary approach as the disciplinary framework, and geospatial analysis as the applied methodology. The area of interest was the agroecosystem of Wayanad district in Kerala, India (South Asia). The methodology was structured to enable analysis of multi-scalar and multi-temporal data, using Wayanad as a case study. Three levels of analysis included: District (Landsat TM-30m), Taluk or sub-district (ASTER-15m) and Village or Gram Panchayat (GeoEye-0.5m). Our hypothesis, that analyzing patterns of land use change is pertinent for up-to-date assessment of agroecosystem resources and their wise management is supported by the outcome of the multi-tiered geospatial analysis. In addition, two examples from the project that highlight the adoption of LCLUC by different disciplinary experts are presented. A sociologist assessed the land ownership boundary for a selected tribal community. A faunal ecologist used it to assess the effect of landscape structure on arthropods and plant groups in rice fields. Furthermore, the Google Earth interface was used to support the overall validation process. Our key conclusion was that a multi-level understanding of the causes, effects, processes and mechanisms that govern agroecosystem transformation requires close attention to spatial, temporal and seasonal dynamics, for which the incorporation of local knowledge and participation of local communities is crucial.


Health care resource utilization and costs among patients with spasticity or cervical dystonia.
Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect health care cost implications. Although several studies have discussed their clinical impact, few have calculated the economic burden of these disorders. To assess the all-cause health care resource utilization (HCRU) and costs in adults and children with spasticity or CD. This retrospective, observational cohort-based study was conducted using administrative insurance claims from the IQVIA PharMetrics Plus database from October 1, 2015, to December 31, 2019. Patients were selected based on International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for first evidence of spasticity (associated with a spasticity etiology) or CD (index date) during the selection window, from April 1, 2016, through December 31, 2018. Cases were stratified into 3 mutually exclusive cohorts: adult patients with spasticity, pediatric patients with spasticity, and patients with CD; those with spasticity who had a history of stroke or cerebral palsy were also evaluated in subcohorts. Patients without evidence of spasticity or CD during the study period were identified as a matched comparator group and were randomly assigned an index date. Patients with spasticity were matched 1:1 to the comparator group based on age, sex, index year, and payer type using descriptive analyses. 215,739 adult patients with spasticity, 29,644 pediatric patients with spasticity, and 9,035 adult patients with CD were identified after matching. Adult patients with spasticity and CD had mean (SD) ages of 48.4 (15.6) years and 48.0 (13.1) years, respectively. Stroke was identified in 31.9% (n = 68,928) of adult patients with spasticity, and cerebral palsy was identified in 11.3% (n = 3,364) of pediatric patients with spasticity. Adult and pediatric patients with spasticity and patients with CD had significantly higher HCRU (including mean number of outpatient, emergency department, and inpatient visits and proportions of patients with prescription fills) and higher mean total health care costs per patient (adult patients with spasticity $29,912 vs $7,464; pediatric patients with spasticity $16,089 vs $2,963; and patients with CD $20,168 vs $7,141) than matched comparators (all P<0.0001). The management of patients with spasticity or CD results in considerably higher health care expenses. Within managed health care systems, more effective management of spasticity and CD in adult and pediatric patients represents a significant opportunity for cost savings.


Between universalism and relativism: a conceptual exploration of problems in formulating and applying international biomedical ethical guidelines.
In this paper, the author attempts to explore some of the problems connected with the formulation and application of international biomedical ethical guidelines, with particular reference to Africa. Recent attempts at revising and updating some international medical ethical guidelines have been bedevilled by intractable controversies and wrangling regarding both the content and formulation. From the vantage position of relative familiarity with both African and Western contexts, and the privilege of having been involved in the revision and updating of one of the international ethical guidelines, the author reflects broadly on these issues and attempts prescribing an approach from both the theoretical and practical angles liable to mitigate, if not completely eliminate, some of the problems and difficulties.


Laparoscopic treatment of mesenteric cysts. Report of two cases.
Mesenteric cysts are rare intraabdominal tumors. Since the first report by Benevial in 1507, approximately 800 cases of mesenteric cysts have been described in the literature. Clinical presentation is variable and depends on the size and location of the cyst. This lesion are often asymptomatic or can present as an abdominal palpable mass or with abdominal pain, nausea, vomiting, diarrhea or constipation. Laboratory tests are usually helpless. Ultrasonography and CT scan are the best diagnostic tools. In the past the treatment of choice was totally resection performed by open surgery. With the advent of laparoscopic surgery same authors report mesenteric cysts excised laparoscopically. The Authors report two cases of mesenteric cysts that were excised by laparoscopic surgery using. The cysts of both patients were located in the mesenterium of colon. There were no intraoperative of postoperative complications and the postoperative course was uneventful and both patients returned to full activity within a short time. The follow-up period ranged from 6 to 36 months and there were no recurrences. The laparoscopic surgery is a minimally invasive techniques and represent an alternative safe and less invasive operation for these abdominal cysts.


Nonphosphorylated human La antigen interacts with nucleolin at nucleolar sites involved in rRNA biogenesis.
La is a RNA-binding protein implicated in multiple pathways related to the production of tRNAs, ribosomal proteins, and other components of the translational machinery (D. J. Kenan and J. D. Keene, Nat. Struct. Mol. Biol. 11:303-305, 2004). While most La is phosphorylated and resides in the nucleoplasm, a fraction is in the nucleolus, the site of ribosome production, although the determinants of this localization are incompletely known. In addition to its conserved N-terminal domain, human La harbors a C-terminal domain that contains an atypical RNA recognition motif and a short basic motif (SBM) adjacent to phosphoserine-366. We report that nonphosphorylated La (npLa) is concentrated in nucleolar sites that correspond to the dense fibrillar component that harbors nascent pol I transcripts as well as fibrillarin and nucleolin, which function in early phases of rRNA maturation. Affinity purification and native immunoprecipitation of La and fluorescence resonance energy transfer in the nucleolus reveal close association with nucleolin. Moreover, La lacking the SBM does not localize to nucleoli. Lastly, La exhibits SBM-dependent, phosphorylation-sensitive interaction with nucleolin in a yeast two-hybrid assay. The data suggest that interaction with nucleolin is, at least in part, responsible for nucleolar accumulation of La and that npLa may be involved in ribosome biogenesis.


Anopheles immune genes and amino acid sites evolving under the effect of positive selection.
It has long been the goal of vector biology to generate genetic knowledge that can be used to "manipulate" natural populations of vectors to eliminate or lessen disease burden. While long in coming, progress towards reaching this goal has been made. Aiming to increase our understanding regarding the interactions between Plasmodium and the Anopheles immune genes, we investigated the patterns of genetic diversity of four anti-Plasmodium genes in the Anopheles gambiae complex of species. Within a comparative phylogenetic and population genetics framework, the evolutionary history of four innate immunity genes within the An. gambiae complex (including the two most important human malaria vectors, An. gambiae and An. arabiensis) is reconstructed. The effect of natural selection in shaping the genes' diversity is examined. Introgression and retention of ancestral polymorphisms are relatively rare at all loci. Despite the potential confounding effects of these processes, we could identify sites that exhibited dN/dS ratios greater than 1. In two of the studied genes, CLIPB14 and FBN8, several sites indicated evolution under positive selection, with CLIPB14 exhibiting the most consistent evidence. Considering only the sites that were consistently identified by all methods, two sites in CLIPB14 are adaptively driven. However, the analysis inferring the lineage -specific evolution of each gene was not in favor of any of the Anopheles lineages evolving under the constraints imposed by positive selection. Nevertheless, the loci and the specific amino acids that were identified as evolving under strong evolutionary pressure merit further investigation for their involvement in the Anopheles defense against microbes in general.


Manifestations of intense noise stimulation on spontaneous otoacoustic emission and threshold microstructure: experiment and model.
Comparison between changes that occur simultaneously on spontaneous otoacoustic emissions (SOAEs) and on other cochlear origin phenomena can contribute to the understanding of cochlear micromechanical activity. The temporary changes that arise after short noise exposure are investigated in the following paper. The effects of noise exposure on the threshold microstructure near an SOAE and on the amplitude and frequency of the SOAE were measured. These experimental results indicate the following: (1) exposure to wideband noise for a short time causes a temporary reduction in the SOAE frequency and amplitude, and alters reversibly the threshold microstructure in the vicinity of the SOAE. The difference between the minimum and maximum in the threshold microstructure is reduced, and the frequency that yields the minimum threshold decreases; (2) the threshold at the SOAE frequency is most sensitive to noise exposure; (3) intense stimulation causes a relatively small increase, or even a decrease, in threshold at frequencies near the SOAE. The experimental results are interpreted in terms of a nonlinear transmission line model which includes nonlinear amplifiers. The effect of the noise exposure is modeled by reduction in the cochlear partition amplification term. Most of the experimental results are predicted by this model.


Degradation of porstaglandin F2alpha in the human pulmonary circulation.
Degradation of prostaglandins (PGs) during passage through the human pulmonary circulation was investigated by measuring the transpulmonary plasma PGF2 alpha difference during continuous intravenous infusion of PGF2 alpha (5-10 mug/min). Seven patients with cardiological disorders and two patients with extensive pulmonary abnormalities were investigated during diagnostic cardiac catheterization. PGF2 alpha levels were measured by radioimmunoassay. The seven cardiac patients were found to have transpulmonary PGF2 alpha differences of 47-88%, indicating metabolism of the PG in the lungs. A patient with extensive bronchiectasis had an apparently normal transpulmonary PGF2alpha difference despite gross abnormalities in routine lung function tests. A patient with primary pulmonary arterial hypertension showed no metabolism of PGF2alpha in the pulmonary circulation. The results show that PG degradation is an aspect of normal lung function and suggest that it becomes imparied when extensive pulmonary vascular damage exists.


Successful treatment of withdrawal symptoms with delta sleep-inducing peptide, a neuropeptide with potential agonistic activity on opiate receptors.
It has been postulated that delta sleep-inducing peptide (DSIP) possesses an agonistic activity on opiate receptors and might be of value in the treatment of withdrawal syndromes. To test this hypothesis, DSIP (25 nmol/kg) was injected intravenously as sole treatment to 67 patients presenting withdrawal symptoms (28 from ethyl alcohol, 39 from opiates). 27% of the patients were lost or unsuitable for evaluation. From the 49 evaluable patients, DSIP produced a beneficial effect in 48 (22 alcoholics and 26 from 27 opiate addicts), with an immediate onset of action, a good and lasting suspension of the somatic symptoms and signs. Anxiety resolved more slowly, within hours. No major side-effect occurred. DSIP offers a new physiologically-based approach for the treatment of established withdrawal syndrome.


Destabilization mechanism of R3-R4 tau protofilament by purpurin: a molecular dynamics study.
The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established that the structure of the tau protofilament in Chronic traumatic encephalopathy (CTE) is similar to that of Alzheimer's disease (AD). In addition, a previous study found that purpurin, an anthraquinone, could inhibit and disassemble the pre-formed 306VQIVYK311 isoform of AD-tau protofilament. Herein, we used all-atom molecular dynamic (MD) simulation to investigate the distinctive features between CTE-tau and AD-tau protofilament and the influence of purpurin on CTE-tau protofilament. Our findings revealed notable differences at the atomic level between CTE-tau and AD-tau protofilaments, particularly in the β6-β7 angle and the solvent-accessible surface area (SASA) of the β4-β6 region. These structural disparities contributed to the distinct characteristics observed in the two types of tau protofilaments. Our simulations substantiated that purpurin could destabilize the CTE-tau protofilament and decrease β-sheet content. Purpurin molecules could insert the β4-β6 region and weaken the hydrophobic packing between β1 and β8 through π-π stacking. Interestingly, each of the three rings in purpurin exhibited unique binding preferences with the CTE-tau protofilament. Overall, our study sheds light on the structural distinctions between CTE-tau and AD-tau protofilaments, as well as the destabilizing mechanism of purpurin on CTE-tau protofilament, which may be helpful to the development of drugs to prevent CTE.


9-[(2-Hy-droxy-benzyl-idene)amino]-11-(2-hy-droxy-phen-yl)-10,13-diphenyl-8-oxa-12-azoniatricyclo-[184.108.40.206]trideca-2(7),3,5-triene acetate ethanol disolvate.
The title compound, C(36)H(31)N(2)O(3) (+),C(2)H(3)O(2) (-)·2C(2)H(5)OH, the product of a domino condensation of dibenzyl ketone with salicylic aldehyde and ammonium acetate, crystallized as the ethanol disolvate. The cation of the salt comprises a fused tricyclic system containing three six-membered rings (piperidine, dihydro-2H-pyran and benzene). The piperidine ring has the usual chair conformation, while the dihydro-pyran ring adopts a slightly distorted sofa conformation. In the crystal, there are six (one intra- and five inter-molecular) independent hydrogen-bonding inter-actions: the inter-molecular hydrogen bonds link the cations and anions and ethanol solvent mol-ecules into ribbons along [001]. The ribbons are stacked along the a axis.


[Establishment of experimental ventricular septal defect in pigs].
This is a study on the method for establishing experimental animal model of ventricular septal defect(VSD) in pigs. Thoracotomy was performed on 15 young pigs under general anaesthesia. A spool-like ring amounted on a specially designed centesis tool was put into right ventricle via an incision on right auricle which was pushed to puncture through the septum. The ring was then left on the septum to create the artificial VSD. 3 days after the operation, echocardiography was conducted to verify the existence of VSDs. The animals were catheterized one month later to obtain hemodynamic data. Ten pigs survived the operation with successful acquisition of VSDs. Doppler echocardiography demonstrated the transseptal shunts with peak velocities ranging from 1.7-4.4 m/sec. Cardiac catheterization showed the Qp/Qs of 1.68-2.12 although the pulmonary pressures remained in normal limits. The authors report their experience in the establishment of experimental VSD model in pigs using revised Synhorst method. The preliminary result shows that the VSD model using pigs is feasible and worth improving further in order to provide a useful animal model for the pathophysiological study of intracardiac left to right shunt in the future.


Scalp psoriasis: topical calcipotriol 50 micrograms/g/ml solution vs. betamethasone valerate 1% lotion.
Forty-two patients aged between 6 and 61 years (mean: 33.5 years) with psoriasis of the scalp were enrolled in this study. Twenty-seven patients (69%) were males and 15 (31%) were females. The aim of our study was to evaluate the efficacy, safety and tolerability of topical calcipotriol 50 micrograms/g/ml solution vs. betamethasone valerate 1% lotion in the treatment of psoriasis of the scalp. The study was randomized with the twice-daily application of either calcipotriol solution or betamethasone valerate lotion for 6 weeks. Treatment evaluation was clinically based on signs of psoriasis (thickness, redness, scaliness) which were scored from 0 = absent to 4 = severest possible involvement and was performed at the start of treatment and at weeks 2 and 6 of treatment. The results showed a marked improvement and clearance at the end of treatment in 15 (72.8%) of the 24 patients in the calcipotriol group and in 13 of the 18 patients (72%) in the betamethasone group. The mean total sign score at baseline was 5.1 in the calcipotriol group and 5.4 in the betamethasone valerate group. At the end of treatment, this score was decreased to 2.1 and 1.49, respectively. No significant adverse effects were reported in either group except in two patients (8.3%) in the calcipotriol group who developed signs of irritation including itching and erythema. In conclusion, both drugs were effective and well tolerated in the treatment of scalp psoriasis but in some patients calcipotriol had to be given for more prolonged courses.


Infection by choleraphage phi 138: bacteriophage DNA and replicative intermediates.
Choleraphage phi 138 contains a linear, double-stranded, circularly permuted DNA molecule of 30 X 10(6) daltons or 45 kilobase pairs. Upon infection, the host DNA is degraded, and synthesis of phage-specific DNA is detectable 20 min after infection. The phage utilizes primarily the host DNA degradation products for its own DNA synthesis. A physical map of phi 138 DNA was constructed with the restriction endonucleases Bg/II, HindIII, and PstI. A concatemeric replicative DNA intermediate equivalent to eight mature genome lengths was identified. The concatemer was shown to be the precursor for the synthesis of mature bacteriophage DNA which is subsequently packaged by a headful mechanism.


[The legal framework to prevent teenage pregnancies].
There are legal regulations about sexual and reproductive rights of adolescents. However, this legal framework (LF) may have contradictory elements: there are laws assuring confidentiality and access to contraception at any age but there are other laws that consider any sexual contact with an adolescent younger than 14 a sexual assault, whose report to the legal authorities in mandatory. To explore the knowledge and clinical practice of primary health care (PHC) providers regarding prevention of teenage pregnancy. Qualitative study collecting data using semi-structured interviews made to midwives and directors of PHC centers. Analysis of the data was based on Grounded Theory. There is a differentiated clinical care for pregnancy prevention among adolescents if they are over 14 years old. This is due to the LF, specifically to the sexual crime's law (19,927) and the law about regulation of the fertility (20,418). The differences affect health care, access and counseling about contraception and confidentiality. Healthcare of teenagers under the age of 14 is perceived as problematic for providers, due to the possible legal implications. The LF causes insecurity on health care providers and derives in a differentiated clinical approach according to the patient´s age. This is a barrier to provide timely and confidential access to counseling and contraception.


Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous well-defined pathological samples.
High-resolution array comparative genomic hybridization (aCGH) is a powerful molecular cytogenetic tool that is being adopted for diagnostic evaluation of genomic imbalances and study disease mechanisms and pathogenesis. We report on the design and use, of a custom whole-genome oligonucleotide-based array (called KaryoArray®v3.0; Agilent-based 8 × 60 K) for diagnostic setting, which was able to detect new and unexpected rearrangements in 11/63 (~17.5%) of previous known pathological cases associated with known genetic disorders, and in the second step it identified at least one causal genomic imbalance responsible of the phenotype in ~20% of patients with psychomotor development delay and/or intellectual disability. To validate the array, first; we blindly tested 120 samples; 63 genomic imbalances that had previously been detected by karyotyping, FISH and/or MLPA, and 57 sex-matched control samples from healthy individuals; secondly a prospective study of 540 patients with intellectual disabilities, autism spectrum disorder and multiple congenital anomalies were evaluated to confirm the utility of the tool. These data indicate that implementation of array technologies as the first-tier test may reveal that additional genomic imbalances could co-exist in patients with trisomies and classical del/dup syndromes, suggesting that aCGH may also be indicated in these individuals, at least when phenotype does not match completely with genotype.


Protective Effect of Hydroxysafflor Yellow A on Nephropathy by Attenuating Oxidative Stress and Inhibiting Apoptosis in Induced Type 2 Diabetes in Rat.
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and its prevalence has been increasing all over the world, which is also the leading cause of end-stage renal failure. Hydroxysafflor yellow A (HSYA) is the main active chemical component of Carthamus tinctorius L., and it is commonly used in patients with cardiovascular and cerebrovascular diseases in China. The aim of this study was to investigate the renal protective effects and molecular mechanisms of HSYA on high-fat diet (HFD) and streptozotocin- (STZ-) induced DN in rats. The DN rats were treated with HSYA for eight weeks. We assessed creatinine (CR), urea nitrogen (UN), glomerular volume, podocyte number, renal inflammation, oxidative stress, and cells apoptosis markers after HSYA treatment. The number of apoptotic cells was measured by the TUNEL assay, and apoptosis-related proteins BAX, caspase-3, and BCL-2 in the renal tissue were analyzed by western blot. The treatment with HSYA significantly decreased fasting blood glucose, CR, UN, and blood lipid profile, including triglyceride and total and low-density lipoprotein cholesterol, even though it did not change the rats' body weights. The western blot results indicated that HSYA reversed the upregulation of BAX and caspase-3 and significantly increased BCL-2 in renal tissue. Moreover, the levels of TNF-α and the inflammatory products, including free fatty acids (FFA) and lactic dehydrogenase (LDH) in the HSYA group, were significantly decreased. For the oxidative stress marker, the superoxide dismutase (SOD) markedly increased in the HSYA treatment group, while the malondialdehyde (MDA) in the serum and kidney tissue evidently decreased. In conclusion, HSYA treatment preserved kidney function in diabetic nephropathy in the HFD- and STZ-induced rats. The potential mechanism of renal protective effect of HSYA might be through inhibiting oxidative stress, reducing inflammatory reaction, and attenuating renal cell apoptosis. Our studies present a promising use for Hydroxysafflor yellow A in the treatment of type 2 diabetes mellitus.


Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice.
Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis with increased risk of mortality. Pulmonary microvascular alterations are key features of HPS; but underlying mechanisms are incompletely understood, and studies on HPS are limited to rats. Placental growth factor (PlGF), a proangiogenic molecule that is selectively involved in pathological angiogenesis, may play an important role in HPS development; however, its role has never been investigated. In this study, we validated an HPS model by common bile duct ligation (CBDL) in mice, investigated the kinetic changes in pulmonary angiogenesis and inflammation during HPS development, and provide evidence for a novel therapeutic strategy by targeting pathological angiogenesis. Mice with CBDL developed hypoxemia and intrapulmonary shunting on a background of liver fibrosis. Pulmonary alterations included increased levels of proangiogenic and inflammatory markers, which was confirmed in serum of human HPS patients. Increased PlGF production in HPS mice originated from alveolar type II cells and lung macrophages, as demonstrated by immunofluorescent staining. Dysfunctional vessel formation in CBDL mice was visualized by microscopy on vascular corrosion casts. Both prophylactic and therapeutic anti-PlGF (αPlGF) antibody treatment impeded HPS development, as demonstrated by significantly less intrapulmonary shunting and improved gas exchange. αPlGF treatment decreased endothelial cell dysfunction in vivo and in vitro and was accompanied by reduced pulmonary inflammation. Importantly, αPlGF therapy did not affect liver alterations, supporting αPlGF's ability to directly target the pulmonary compartment. CBDL in mice induces HPS, which is mediated by PlGF production; αPlGF treatment improves experimental HPS by counteracting pulmonary angiogenesis and might be an attractive therapeutic strategy for human HPS. (Hepatology 2017).


Natural history of Helicobacter pylori VacA toxin in human gastric epithelium in vivo: vacuoles and beyond.
Uptake, intracellular trafficking and pathologic effects of VacA toxin from Helicobacter pylori have been widely investigated in vitro. However, no systematic analysis investigated VacA intracellular distribution and fate in H. pylori-infected human gastric epithelium in vivo, using ultrastructural immunocytochemistry that combines precise toxin localization with analysis of the overall cell ultrastructure and intercompartimental/interorganellar relationships. By immunogold procedure, in this study we investigated gastric biopsies taken from dyspeptic patients to characterize the overall toxin's journey inside human gastric epithelial cells in vivo. Endocytic pits were found to take up VacA at sites of bacterial adhesion, leading to a population of peripheral endosomes, which in deeper (juxtanuclear) cytoplasm enlarged and fused each other to form large VacA-containing vacuoles (VCVs). These directly opened into endoplasmic reticulum (ER) cisternae, which in turn enveloped mitochondria and contacted the Golgi apparatus. In all such organelles we found toxin molecules, often coupled with structural damage. These findings suggest direct toxin transfer from VCVs to other target organelles such as ER/Golgi and mitochondria. VacA-induced cytotoxic changes were associated with the appearance of auto(phago)lysosomes containing VacA, polyubiquitinated proteins, p62/SQSTM1 protein, cathepsin D, damaged mitochondria and bacterial remnants, thus leading to persistent cell accumulation of degradative products.


Trinucleotide repeat containing 6a (Tnrc6a)-mediated microRNA function is required for development of yolk sac endoderm.
Tnrc6 family members (Tnrc6a/b/c) are key components of the RNA-induced silencing complex in microRNA (miRNA)-mediated gene suppression. Here, we show that Tnrc6a, also known as GW182, is selectively expressed in the yolk sac endoderm and that gene trap disruption of GW182 leads to growth arrest and apoptosis. We found that targets of miRNAs highly expressed in the yolk sac are significantly derepressed in GW182(gt/gt) mutant mice, although levels of miRNAs are not altered. Specifically, growth arrest and apoptosis phenotype are associated with significant derepression of Cdkn1a (p21), Cdkn1c (P27), Lats1, Lats2, Rb1, Rbl, Bim, and Pten, known targets of miRNAs from miR-17/20/93/106 clusters highly expressed in yolk sac endoderm. Together, these data strongly suggest that GW182 is an essential functional component in the RNA-induced silencing complex for miRNA-mediated gene silencing in vivo, and selectively regulation of miRNA activity plays an important role in the proper development of yolk sac.


Tolerance of the spinal cord of rats to irradiation with cyclotron-accelerated heliumions.
Spinal cords of rats were exposed to either single doses of helium ions ranging from 500 to 3500 rads, or to fractionated doses of helium ions ranging from 1300 to 6530 rads using 10 equal fractions given over 22 days. Both plateau and spread-out Bragg peak regions of ionization were used. For single doses there was no difference betweenplateau or spread-out Bragg peak ionization regions for production of paralysis; thetolerance dose for production of paralysis was about 1900 rads. For the fractionation experiment, there was also no difference between plateau or spread-out Bragg peak ionization regions for production of paralysis; the tolerance dose was between 5220 and 6530rads. Comparison of dose levels producing about 10% partial paralysis indicates that about 500 rads of dose is recovered between fractions. In both single dose and fractionated experiments, latency between onset of paralysis was between 20 to 24 weeks.


Sowing Seeds to Harvest Healthier Adults: The Working Principles and Impact of Participatory Health Research with Children in a Primary School Context.
Participatory research on health-related topics with children is promising but current literature offers limited guidance on how to involve children and falls short on the reporting impact. The purpose of this article is to heighten our understanding of the working principles and impact of participatory health research (PHR) with children. We completed a PHR project in two primary schools, which included children from a multiethnic, deprived neighborhood in the second largest city in The Netherlands over a period of three school years (2016-2019). The impact on the children's subjective health has been measured via process evaluation using qualitative and quantitative methods from the perspectives of all involved (children, their teachers, parents, and community partners). The main working principles included: Experiential learning; addressing uncomfortable issues; stepping outside your environment; and keeping it simple. Participatory actions valued most by the children included: Walking tours, photovoice, foodlabs, sportlabs, and to a lesser extent: Making a newspaper, mindfulness, and Capoeira. The project reached and engaged many children, parents, teachers, and community partners into healthy lifestyles and broadened and deepened the children's awareness and understanding of health behavior. 'Sowing seeds' is the metaphor that captures the broader impact of this project: Planting seeds to harvest healthier adults.


Apoptosis and development.
Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.


Evidence-based use of colony-stimulating factors in elderly cancer patients.
Neutropenia and its complications represent the major dose-limiting toxicity of cancer chemotherapy, especially in the elderly. Hematopoietic growth factors have been shown to reduce the severity and duration of febrile neutropenia (FN) and to sustain chemotherapy dose intensity. A systematic review was undertaken of studies of the relationship between age and the risk of neutropenia and its complications. Recent studies of the "Awareness of Neutropenia in Chemotherapy Study Group" related to the impact of age on neutropenic complications are also summarized. The risk of FN associated with standard regimens increases with age and appears to be greatest during the first cycle of chemotherapy. FN continues to have a considerable clinical, economic, and quality-of-life impact on affected individuals. The risk of mortality associated with hospitalization with FN also increases with age but is largely associated with the higher rate of comorbidities observed in the elderly population. Despite increasing evidence that elderly patients experience similar benefit from cancer chemotherapy, reductions in dose intensity often compromise response rates and long-term survival. The hematopoietic growth factors reduce the risk of neutropenic events and the need for reduced dose intensity in elderly cancer patients. Primary prophylaxis with colony-stimulating factors (CSFs) reduces the risk of FN and its complications in elderly patients receiving moderately intensive systemic chemotherapy for responsive malignancies. CSFs also appear to reduce cost and improve quality of life in selected elderly patients receiving chemotherapy. Primary prophylaxis with CSFs should be considered in elderly patients with responsive and potentially curable malignancies who receive moderately intensive chemotherapy.